Atlas of Diabetes Mellitus

This completely revised and updated fourth edition of the Atlas of Diabetes Mellitus provides broad
coverage of all aspects of diabetes mellitus and an extensive collection of common and rare clinical
images. It aims to provide an invaluable resource for anyone interested in the management of this ubiq-
uitous clinical condition, including primary care/family physicians, endocrinologists, physicians in
training, diabetic specialist nurses and other key professionals who are likely to be involved in the care
of patients with diabetes mellitus.
Atlas of Diabetes Mellitus
Fourth Edition

Ian N. Scobie and David Hopkins

Cover images courtesy of Ian N Scobie and David Hopkins

Fourth edition published 2024

by CRC Press
2385 NW Executive Center Drive, Suite 320, Boca Raton FL 33431

and by CRC Press

4 Park Square, Milton Park, Abingdon, Oxon, OX14 4RN

CRC Press is an imprint of Taylor & Francis Group, LLC

© 2024 Ian N Scobie and David Hopkins

Third edition published by Informa Healthcare 2006

This book contains information obtained from authentic and highly regarded sources. While all reasonable efforts have
been made to publish reliable data and information, neither the author[s] nor the publisher can accept any legal respon-
sibility or liability for any errors or omissions that may be made. The publishers wish to make clear that any views or
opinions expressed in this book by individual editors, authors or contributors are personal to them and do not neces-
sarily reflect the views/opinions of the publishers. The information or guidance contained in this book is intended for
use by medical, scientific or health-care professionals and is provided strictly as a supplement to the medical or other
professional’s own judgement, their knowledge of the patient’s medical history, relevant manufacturer’s instructions and
the appropriate best practice guidelines. Because of the rapid advances in medical science, any information or advice on
dosages, procedures or diagnoses should be independently verified. The reader is strongly urged to consult the relevant
national drug formulary and the drug companies’ and device or material manufacturers’ printed instructions, and their
websites, before administering or utilizing any of the drugs, devices or materials mentioned in this book. This book does
not indicate whether a particular treatment is appropriate or suitable for a particular individual. Ultimately it is the
sole responsibility of the medical professional to make his or her own professional judgements, so as to advise and treat
patients appropriately. The authors and publishers have also attempted to trace the copyright holders of all material repro-
duced in this publication and apologize to copyright holders if permission to publish in this form has not been obtained.
If any copyright material has not been acknowledged please write and let us know so we may rectify in any future reprint.

Except as permitted under U.S. Copyright Law, no part of this book may be reprinted, reproduced, transmitted, or utilized
in any form by any electronic, mechanical, or other means, now known or hereafter invented, including photocopying,
microfilming, and recording, or in any information storage or retrieval system, without written permission from the
publishers.

For permission to photocopy or use material electronically from this work, access www.copyright.com or contact the
Copyright Clearance Center, Inc. (CCC), 222 Rosewood Drive, Danvers, MA 01923, 978-750-8400. For works that are not
available on CCC please contact [email protected]

Trademark notice: Product or corporate names may be trademarks or registered trademarks and are used only for iden-
tification and explanation without intent to infringe.

ISBN: 9781032379456 (hbk)

ISBN: 9781032379463 (pbk)
ISBN: 9781003342700 (ebk)

DOI: 10.1201/9781003342700

Typeset in Minion
by KnowledgeWorks Global Ltd.
Contents

Author biographies vii

Foreword ix
Acknowledgments xi
Abbreviations xiii

1 Introduction 1
2 Pathogenesis 7
3 Treatment of type 1 diabetes mellitus 29
4 Treatment of type 2 diabetes mellitus 41
5 Treatment of children and adolescents with diabetes 51
6 Diabetes and surgery: Inpatient and perioperative diabetes care 53
7 Acute complications of diabetes 56
8 Chronic complications of diabetes 63
9 Diabetic dyslipidaemia 98
10 Diabetes and pregnancy 100
11 Living with diabetes 103
12 Future developments in diabetes care 105

Index 111

v
Author Biographies

Dr Ian N. Scobie qualified MBChB and MD from the Dr David Hopkins is a consultant physician with
University of Glasgow, subsequently being elected a more than 30 years of experience in clinical and
Fellow of the Royal College of Physicians of London. academic diabetes. He qualified in medicine in
He trained in Internal Medicine and Endocrinology Liverpool and completed specialty training in
and Diabetes at the Glasgow Royal Infirmary and Liverpool and London. For most of his career, he
at St Thomas’ Hospital, London. Dr Scobie was has been associated with King’s College London and
appointed as Consultant Physician in Medicine and its associated academic health science partnership,
Endocrinology and Diabetes at Medway Maritime King’s Health Partners, where he was a Director
Hospital, Kent, England, and later Honorary of the Institute of Diabetes, Endocrinology and
Senior Lecturer at King’s College London School Obesity from 2014 to 2022 and an Honorary Reader
of Medicine related to his appointment as Clinical in Diabetic Medicine. He recently moved to Jersey,
Sub-Dean responsible for undergraduate students where he is leading the development of diabetes
at his institution. He also served as site director for services for the island. He has held regional and
The American University of the Caribbean School national leadership positions in diabetes, notably
of Medicine between 2003 and 2009. Dr Scobie’s as the medical chair of the Council of Healthcare
research interest is in his specialty of endocrinology Professionals at Diabetes UK from 2016 to 2023.
and diabetes, and he has published extensively in his He has broad clinical and academic interests
field. He has authored and co-authored chapters in across the whole spectrum of diabetes, with particu-
diabetes and metabolism and textbooks of diabetes. lar focus on diabetes technology and psychosocial
He has had a longstanding commitment to medi- factors in diabetes care. He maintains close academic
cal education at both the undergraduate and post- links with King’s Health Partners and is diabetes lead
graduate level. Dr Scobie’s current appointment is for the Health Outcomes Observatory (H2O), an EU
Assistant Clinical Dean, United Kingdom, American programme to develop a network of data observato-
University of the Caribbean School of Medicine. ries for long-term conditions across Europe.

vii
Foreword

As a third-year medical student, I could not construe lessons imparted by the Atlas of Diabetes Mellitus
of a more boring disease than type 2 diabetes melli- remain very relevant.
tus. After all, if this were merely a side-effect of sloth What is diabetes? It is a unique disease defined
and gluttony, why expend effort in learning about it by the presence of hyperglycaemia. Although,
(and making it a part of one’s career)? Further expo- broadly speaking, there are two categories of
sure to the disease and its complications disabused diabetes—immune-mediated or type 1 diabetes
me of these impressions and also brought home the and type 2 diabetes—it should be apparent that one
realization that a knowledge of diabetes would serve is defined by the (imperfect) exclusion of the other.
as a summary of most of internal medicine. With The complications of hyperglycaemia and hypogly-
this in mind, it is certainly my pleasure to write the caemia are nevertheless common to both. Beyond
Foreword to the fourth edition of Dr Ian N. Scobie’s overlap between type 1 and type 2 diabetes, there
Atlas of Diabetes Mellitus, co-authored by Dr David is significant heterogeneity in the causation of type
Hopkins. In doing so, I am following in the foot- 2 diabetes. While this may be obvious to the spe-
steps of my teacher, mentor and friend Dr Robert A. cialist, the generalist may not appreciate the subtle
Rizza, to whom I owe the realization that diabetes is clues underlying a diagnosis of haemochromato-
a complex, heterogenous disease with diverse con- sis- or acromegaly-associated diabetes. Similarly,
tributions to its pathogenesis. specialists usually require years of experience to see
What is diabetes and why is it important? Let and understand rare conditions, such as lipodys-
us answer the latter question first. Diabetes is well trophy, that are associated with diabetes. For these
on its way to becoming, directly and indirectly, cases alone, Atlas of Diabetes Mellitus remains an
the most economically important chronic disease invaluable contribution to the literature.
of the 21st century. Its contribution to the costs of Although, or perhaps because, a picture is ‘only’
care and the burdens of limb loss, blindness, renal worth a thousand words, this book provides a
failure and vascular disease are readily appreci- depth and breadth to an overview of diabetes that
ated. Although the diagnosis is fairly straightfor- will serve its readers well by facilitating the acqui-
ward, chronic therapy, coupled with the necessity sition of new and useful information. Therefore, in
to change behaviour, means that management can conclusion, I would like to echo the Foreword of
be anything but. In the past decade, progress has the previous edition where Dr. Rizza stated that ‘…
been made on multiple fronts in the treatment of those of you who choose to add this excellent Atlas
this disease. However, the implementation of these to your library will find that you will also share my
advances is costly and complex, which means that enthusiasm for this delightful book.’
they are far from becoming universal. Moreover,
newer therapies may make subsets of the disease Adrian Vella MD
easier to treat but are far from curative—the Rochester, MN, US

ix
Acknowledgments

Great thanks go to Professor Peter Sönksen and Smith-Laing (Chapter 2, Figures 2.36, 2.37 and
Dr Clara Lowy, formerly of St Thomas’ Hospital, 2.39) and Dr Richard Day, formerly of Medway
London, UK, who kindly supplied many of the Maritime Hospital, Gillingham, Kent, UK
images in this Atlas. Thanks also to Dr Tom (Chapter 2, Figure 2.38); MiniMed, Ashtead, UK
Barrie, of The Glasgow Eye Infirmary, Glasgow, (Chapter 3, Figure 3.13); MediSense, Maidenhead,
UK, who provided a splendid set of eye pho- UK (Chapter 3, Figure 3.12); Dr David Kerr, Royal
tographs (Chapter 8, Figures 8.2, 8.7, 8.18 and Bournemouth Hospital, Dorset, UK (Chapter 3,
8.20–8.22), Dr Alan Foulis, formerly of The Figure 3.11); Professor Pratik Choudhary, University
Royal Infirmary in Glasgow, UK, who supplied of Leicester (Chapter 3, Figure 3.20).
some magnificent pathology images (Chapter 2, Dr William Campbell, Royal Victorian Eye
Figures 2.17–2.20, 2.23–2.27, 2.29–2.33, 2.35) and & Ear Hospital, Melbourne, Australia (Chapter
Eli Lilly and Company for providing a series of 8, Figures 8.10–8.12 and 8.16, 8.17); Professor
images (Chapter 1, Figures 1.1–1.3; Chapter 3, Stephanie Amiel, King’s College Hospital, London,
Figures 3.1–3.4 and 3.6–3.8). UK (Chapter 6, Figure 6.4, Chapter 7, Figure 7.2,
We are grateful to the following who also con- Chapter 10, Figure 10.1 and Chapter 12, Figures 12.1
tributed their images: and 12.2); Xeris Pharmaceuticals UK (Chapter 6,
Professor Andrew Hattersley, University of Figure 6.3a); Professor Peter Thomas, formerly of
Exeter Medical School, UK (Chapter 2, Figure 2.1), the Royal Free School of Medicine, Hampstead,
Dr Nick Finer, Luton and Dunstable Hospital, London, UK (Chapter 8, Figure 8.25); Mr Grant
Bedfordshire, UK (Chapter 2, Figure 2.2); Professor Fullarton, Gartnavel General Hospital, Glasgow,
Ian Campbell, Victoria Hospital, Kirkaldy, Fife, UK UK (Chapter 8, Figure 8.32); Pfizer Limited,
(Chapter 2, Figure 2.8 and Chapter 8, Figure 8.28); Sandwich, UK (Chapter 8, Figures 8.33–8.36); Dr
Dr Sam Chong, Medway Maritime Hospital, Roger Lindley (Chapter 8, Figure 8.37); Dr Brian
Gillingham, Kent, UK (Chapter 2, Figure 2.11); Ayres, formerly of St Thomas’ Hospital, London,
Drs Angus MacCuish and John Quin, formerly UK (Chapter 8, Figures 8.42 and 8.43); Dr Kumar
of The Royal Infirmary, Glasgow, UK (Chapter 2, Segaran, formerly of Medway Maritime Hospital,
Figure 2.12); Dr Julian Shield, University of Bristol, Gillingham, Kent, UK (Chapter 8, Figures 8.44
UK (Chapter 2, Figure 2.13); Professor Julia Polak, and 8.45); Mrs Ali Foster, formerly of King’s
Royal Postgraduate Medical School, Hammersmith, College Hospital, London, UK (Chapter 8, Figure
London, UK (Chapter 2, Figures 2.21 and 8.46); Mr Mike Green (Chapter 8, Figures 8.47
2.22); Professor GianFranco Bottazzo, previ- and 8.48), Dr Kishore Reddy (Chapter 8, Figure
ously of The London Hospital Medical College, 8.53), Dr Paul Ryan (Chapter 8, Figures 8.55 and
London, UK (Chapter 2, Figure 2.28); Dr Gray 8.56), Dr Larry Shall (Chapter 8, Figures 8.58,

xi
xii Acknowledgments

8.63–8.64, 8.66), all formerly of Medway Maritime & West Birmingham NHS Trust & GI Dynamics
Hospital, Gillingham, Kent, UK; Dr Peter Watkins, (Chapter 12, Figure 12.5).
formerly of King’s College Hospital, London, Finally, thanks go to Mrs Daniella James, Mrs
UK (Chapter 8, Figure 8.70); Mr Harry Belcher, Carol Esson and Mrs Elizabeth Cannell for help
Queen Victoria Hospital, East Grinstead, Sussex, with previous editions.
UK (Chapter 8, Figure 8.72); Dr Annieke Van
Barr Amsterdam University Medical Centre & Dr Ian N. Scobie MD FRCP
Editorial team of Gut (Chapter 12, Figure 12.3); Dr Bearsted, Kent
Kelly White, Fractyl Health Inc, Lexington MA;
Dr David Hopkins FRCP
(Chapter 12, Figure 12.4); Dr Bob Ryder, Sandwell
Grouville, Jersey
Abbreviations

4S Trial Scandinavian Simvastatin Survival EDIC Epidemiology of Diabetes Interventions

Study and Complications study
ABBOS Bovine serum albumin EDKA Euglycaemic diabetic ketoacidosis
AGP Ambulatory glucose profile ESRD End-stage renal disease
ACC American College of Cardiology FDA Food and Drug Administration
ACE Angiotensin-converting enzyme FFA Free fatty acids
ACR Albumin-to-creatinine ratio FIELD Fenofibrate Intervention and Event
ADA American Diabetes Association Lowering in Diabetes
AGEs Advanced glycation end products FINDIA Finnish Dietary Intervention Trial for
ARB Angiotensin receptor blocker the Prevention of Type 2 Diabetes
BABY DIET Primary Prevention of Type 1 FGF-19 Fibroblast growth factor 19
Diabetes in Relatives at Increased FPG Fasting plasma glucose
Genetic Risk GAD Glutamic acid decarboxylase
BMI Body mass index GCK Glucokinase
CAPD Continuous ambulatory peritoneal GDM Gestational diabetes mellitus
dialysis GIP Gastrointestinal inhibitory
CARDS Collaborative Atorvastatin Diabetes polypeptide
Study GLP-1 Glucagon-like peptide-1
CARE Cholesterol and Recurrent Events Trial GLUT4 Insulin-regulated glucose transporter
CHD Coronary heart disease GWAS Genome-wide association studies
CKD Chronic kidney disease HHS Hyperosmolar hyperglycaemic state
CTG Cardiotocography HLA Human leucocyte antigen
CVD Cardiovascular disease HMG-CoA Hydroxymethylglutaryl-coenzyme A
DAFNE Dose adjustment for normal eating HNF Hepatocyte nuclear factor
DAISY Diabetes Autoimmunity Study in the HNS Hyperglycaemic hyperosmolar
Young nonketotic syndrome
DCCT Diabetes Control and Complications HONK Hyperglycaemic hyperosmolar
Trial nonketotic coma
DESMOND Diabetes Education and Self- HPS Heart Protection Study
Management for Ongoing & Newly IA-2 Antibodies to tyrosyl phosphatase
Diagnosed diabetes IAA Insulin autoantibodies
DKA Diabetic ketoacidosis IAAP Islet amyloid polypeptides
DM Diabetes mellitus IAK Islet after kidney transplantation
DMR Duodenal mucosal resurfacing ICA Islet cell antibodies
DVLA Driver and Vehicle Licencing Agency IDDM Insulin-dependent diabetes mellitus
EASD European Association for the Study of IDL Intermediate-density lipoprotein
Diabetes IFG Impaired fasting glucose
ED Erectile dysfunction IFN Interferon

xiii
xiv Abbreviations

IGT Impaired glucose tolerance PCSK9 Proprotein convertase subtilisin/

IL Interleukin kexin type 9
INS Proinsulin gene PDE Phosphodiesterase
KATP ATP-sensitive potassium channel PNDM Permanent prenatal diabetes mellitus
LADA Latent autoimmune diabetes of RAAS Renin-angiotensin-aldosterone
adulthood system
LMWH Low molecular weight heparin RNA Ribonucleic acid
Lp(a) Lipoprotein A SBP Systolic blood pressure
MHC Major histocompatibility complex SPK Simultaneous pancreas and kidney
MI Myocardial infarction transplantation
MODY Maturity-onset diabetes of the young SGLT Sodium-glucose co-transporter
MRI Magnetic resonance imaging T1DM Type 1 diabetes mellitus
MRSA Methicillin-resistant Staphylococcus T2DM Type 2 diabetes mellitus
aureus TCC Total contact cast
NADiA National diabetes inpatient audit TNDM Transient neonatal diabetes mellitus
NAFLD Non-alcoholic fatty liver disease TNF Tumour necrosis factor
NASH Non-alcoholic steatohepatosis TRIGR Trial to Reduce IDDM in the
NDM Neonatal diabetes mellitus Genetically at Risk
NIDDM Non-insulin-dependent diabetes UKPDS United Kingdom Prospective Diabetes
mellitus Study
NIP Nutritional intervention to prevent VEGF Vascular endothelial growth factor
NSAID Non-steroidal anti-inflammatory drug VLDL Very-low-density lipoprotein
OGTT Oral glucose tolerance test WHO World Health Organisation
PAID scale Problem Areas in Diabetes scale ZnT8 Antibodies to zinc transporter
 1
Introduction

Diabetes mellitus (DM) is recognised as one of the The word diabetes means ‘to run through’ or ‘a
world’s biggest health issues with immense social siphon’ in Greek, and the condition has been rec-
and economic consequences owing to the ever- ognised since the time of the ancient Egyptians.
increasing burden of new cases. The year 2022 saw Mellitus (from the Latin and Greek roots for
the 100th anniversary of the discovery of insulin ‘honey’) was later added to the name of this disor-
in Toronto, Canada. In the ensuing century, great der when it became appreciated that diabetic urine
progress has been made in the understanding of tasted sweet.
this ubiquitous condition, but still there remains An epidemic of T2DM has occurred throughout
no cure for type 1 diabetes mellitus (T1DM) and the world, particularly affecting developing coun-
scant hope for most people with type 2 diabetes tries and migrants from these countries to industri-
mellitus (T2DM) being able to reverse their condi- alised societies. T2DM is more prevalent in people
tion (Figures 1.1–1.3). of lower socioeconomic status, and its prevalence

Figure 1.1 The discovery of insulin in 1922 is accredited to Frederick Banting (above right) and Charles
Best (a medical student, above, left), supervised by JJR MacLeod and assisted by James Collip. The work
was carried out at the University of Toronto.

DOI: 10.1201/9781003342700-1 1
2 Introduction

Figure 1.2 A 3-year-old child with type 1 diabetes mellitus, photographed in 1922 before insulin
treatment was available. The only treatment then was a ‘starvation’ diet; patients rarely survived
for more than 2 years.

Figure 1.3 The same child as seen in the figure in 1923 after insulin treatment became available
following its discovery by the Toronto group. The effect of this new therapy was ‘miraculous’.
 Classification of diabetes 3

is rising more rapidly in low- and middle-income diabetes is seldom a problem. When symptoms
countries. Among the US population, crude esti- of hyperglycaemia exist (thirst, polyuria, weight
mates for the prevalence of diabetes for 2019 esti- loss, etc.), a random plasma glucose concentration
mate that 8.7% of the population has diabetes. The of ≥11.1 mmol/l (200 mg/dl) or a fasting plasma
prevalence is highest among American Indians and glucose (FPG) of ≥7.0 mmol/l (126 mg/dl) con-
Alaska Natives (14.5%), followed by non-Hispanic firms the diagnosis. Where diagnostic difficulty
Blacks (12.1%), people of Hispanic origin (11.8%), exists, the precise diagnosis can be established
non-Hispanic Asians (9.5%) and non-Hispanic with an oral glucose tolerance test (OGTT) using
Whites (7.4%). According to a population-based a 75 g anhydrous glucose load dissolved in water:
study, 0.5% of US adults had diagnosed T1DM a 2-hour value ≥11.1 mmol/l (200 mg/dl) estab-
while 8.5% had diagnosed T2DM. As of 2019, the lishes the diagnosis of diabetes. An alternative
prevalence of diabetes in the UK was 7% of the pop- criterion for the diagnosis of diabetes is a HbA1C of
ulation, but it will have risen since. 48 mmol/l (≥6.5%) using a measurement method
The incidence of T1DM differs enormously that is certified by the NGSP (https://ngsp.org/)
between populations. The world incidence rate and standardised to the Diabetes Control and
is estimated at 15 per 100,000 people with par- Complications Trial (DCCT) assay. Ideally, a con-
ticularly high incidence rates in Finland, Sweden firmatory test using one of the other methods should
and Saudi Arabia. There is a male preponderance be employed. The OGTT is not recommended for
(male to female ratio 1.8:1). There are peaks of routine clinical use but may be an important test
incidence before school age and around puberty, for epidemiological purposes where using only the
with the diagnosis being made more frequently in FPG may lead to lower prevalence rates than with
spring and winter months. Modelling data in US the combined use of the FPG and OGTT.
children aged less than 20 years showed that the Prediabetes is a term used to denote individu-
overall incidence of T1DM for the period 2002– als whose glucose levels do not meet the criteria for
2015 significantly increased as did, perhaps more diabetes but are too high to be considered normal.
alarmingly, T2DM. Patients with prediabetes may fall into three cat-
The personal costs and costs to society of dia- egories. They may exhibit impaired fasting glucose
betes are very high. Out of every $4 in US health (IFG) defined as a fasting plasma glucose between
costs, $1 is spent caring for people with diabetes. 5.6 mmol (100 mg/dl) and 6.9 mmol/l (125 mg/dl)
Each year, $237 billion is spent on direct medical or they may have a plasma glucose of 7.8 mmol/l
costs and $90 billion on reduced productivity. The (140 mg/dl) to 11.0 mmol/l (199 mg/dl) at 2 hours
UK, with its smaller population, spends £10 bil- during a 75 g OGTT (impaired glucose tolerance
lion on diabetes care, around 10% of the annual or IGT). A further category includes those individ-
National Health Service budget. uals who have a random HbA1C of 39–47 mmol/l
(5.7–6.4%). It is important to state that prediabetes
DEFINITION OF DIABETES is not to be considered a clinical entity or diagnosis,
but rather a set of criteria conferring an increased
DM is a group of metabolic disorders charac- risk of future diabetes and cardiovascular disease
terised by hyperglycaemia. The hyperglycaemia (Figure 1.4).
results from defects in insulin secretion, insulin
action or both. The chronic hyperglycaemia of CLASSIFICATION OF DIABETES
diabetes is associated with specific chronic com-
plications, resulting in damage to or failure of The diagnostic label DM refers not to a unique
various organs, notably the eyes, kidneys, nerves, disease, but rather to multiple disorders of differ-
heart and blood vessels. ent causation. Increasing knowledge has allowed
us to identify discrete conditions caused by specific
DIAGNOSIS OF DIABETES genetic abnormalities, while other types of diabe-
tes remain difficult to classify on an aetiological
The diagnostic criteria for DM were confirmed by basis. The ADA has published an aetiological clas-
the American Diabetes Association (ADA) in 2021. sification of diabetes, an adapted version of which
In clinical practice, establishing the diagnosis of is presented in Figure 1.5.
4 Introduction

Figure 1.4 Although a definitive diagnosis of diabetes may be made using the glucose tolerance
test, it is no longer recommended for routine clinical use. In the presence of diabetic symptoms, the
diagnosis may be established by finding a random plasma glucose level of ≥11.1 mmol/l (200 mg/dl) or
a fasting plasma glucose level of ≥7.0 mmol/l (126 mg/dl). Both impaired fasting glucose and impaired
glucose tolerance are defined in the text.

T1DM (previously insulin-dependent diabetes autoimmune diabetes of adulthood or latent auto-

mellitus [IDDM]) is characterised by autoimmune immune diabetes in adults (LADA).
β-cell destruction, usually leading to absolute insu- Specific monogenetic defects of the β-cell have
lin deficiency and associated with a usually juvenile been identified and usually give rise to maturity-
onset, a tendency to ketosis and diabetic ketoacido- onset diabetes of the young (MODY). MODY is
sis and an absolute need for insulin treatment. Most defined as a genetic defect in β-cell function sub-
patients have type 1A diabetes, which is caused by classified according to the specific gene involved
a cellular-mediated autoimmune destruction of and is described in detail in Chapter 2.
the β-cells of the pancreas and a minority have Diabetes may result from any process that
type 1B diabetes, the precise aetiology of which adversely affects the pancreas and such acquired
is not known. Latent Autoimmune Diabetes of processes include pancreatitis, trauma, pancreatec-
Adulthood (LADA) is a form of T1DM which may tomy and pancreatic cancer. Usually, extensive pan-
initially be confused with T2DM (discussed below). creatic damage or removal must occur for diabetes
T2DM (previously non-insulin-dependent dia- to emerge. Cystic fibrosis, haemochromatosis and
betes mellitus [NIDDM]) is associated with obe- fibrocalculous pancreatopathy may also cause diabe-
sity and an onset later in life (although cases in tes. Diabetes may also be caused by other endocrine
childhood are now being recognised in the US diseases, particularly when there is over-secretion of
and elsewhere). Patients, at least initially and often hormones that antagonise the normal effect of insu-
throughout their lives, do not have a need for insu- lin (including Cushing’s syndrome, acromegaly, pha-
lin therapy to preserve life. The disorder is due to a eochromocytoma). Drugs that have a similar effect
progressive loss of adequate β-cell insulin secretion (glucocorticoids, diazoxide, thiazides) or chemicals
frequently on a background of insulin resistance. A may also cause diabetes. Diabetes may also occur as a
precise cause (or causes) has not been found. This result of certain rare disorders associated with abnor-
type of diabetes frequently remains undiagnosed malities of insulin or the insulin receptor, causing
for many years despite affected individuals being at extreme insulin resistance and are sometimes found
risk of developing serious macrovascular or micro- in association with acanthosis nigricans. These disor-
vascular complications of the disease. Some patients ders are categorised as insulin resistance syndromes.
may masquerade as T2DM patients, but ultimately There is a wide array of other genetic syndromes
are recognised as having a late-onset slowly pro- sometimes associated with diabetes, e.g. Down’s,
gressing immune-mediated T1DM, so called latent Klinefelter’s and Turner’s syndromes.
 Classification of diabetes 5

Figure 1.5 The American Diabetes Association has proposed an aetiological classification of diabetes
based on research findings over the past two decades. The nomenclature has changed from insulin-
dependent diabetes to type 1 diabetes and from non-insulin diabetes mellitus to type 2 diabetes.
All forms of diabetes are characterised according to their known aetiologies, immunologic, genetic
or otherwise. This opens up the concept of ‘the diabetic syndrome’. HNF, hepatic nuclear factor;
MODY, maturity-onset diabetes of the young.

Gestational diabetes mellitus (GDM) is nor- tolerance status needs to be re-classified 6 weeks
mally defined as any degree of glucose intolerance after giving birth. Deterioration of glucose toler-
with onset or first recognition during pregnancy. ance occurs during normal pregnancy, especially
However, recent evidence suggests that many in the third trimester. The criteria for diagnosing
cases of GDM are in individuals with preexisting abnormal glucose tolerance in pregnancy have not
hyperglycaemia detected by routine screening in been universally agreed upon worldwide: in the
pregnancy and perhaps related to the prevalence US, the modified O’Sullivan–Mahan criteria have
of obesity. Care must be taken to exclude T2DM been adopted, but these are at variance with the
that was present before pregnancy and T1DM World Health Organization criteria. Patients with
diagnosed during pregnancy. The patient’s glucose GDM are at future risk of developing T2DM.
6 Introduction

Prediabetes (not a clinical entity but compris- as Native Americans. In North America, T2DM
ing IFG and IGT) refers to a pathophysiologi- is highly prevalent in Native American communi-
cal state between normality and frank diabetes. ties such as the Pima Indians, a feature shared by
Patients with IGT may only manifest as hyper- the Nauru and Papua New Guinea populations
glycaemic when challenged with an oral glucose of the Pacific Islands. US Hispanics, Blacks and
load. Between 5–10% of people with prediabetes Polynesians also exhibit high prevalence rates. In
will progress to frank diabetes annually, although 2019, it was reported that 7% of the UK population
conversion rates vary by population characteris- was living with diabetes. Higher rates have been
tics. Although some may return to normal glucose observed in the South Asian population as reported
tolerance, it is thought that most will be likely to also in the Indian subcontinent.
develop diabetes eventually without significant
lifestyle changes. Patients with IGT do not nor- BIBLIOGRAPHY
mally develop the microvascular complications of
diabetes. However, they commonly display other American Diabetes Association. Type 2 diabetes
features of the insulin resistance syndrome (also in children and adolescents. Diabetes Care.
known as syndrome X, the metabolic syndrome 2000; 23: 381–9
or Reaven’s syndrome), e.g. hypertension and dys- American Diabetes Association. Classification
lipidaemia, and IGT is associated with a major and diagnosis of diabetes: standards of
increase in cardiovascular risk. medical care in diabetes-2021. Diabetes Care.
2021; 44 (Supplement_1): S15–S33 https://doi.
EPIDEMIOLOGY OF DIABETES org/10.2337/dc21-S002
Bao W. Prevalence of diagnosed type 1 and type
The epidemiology of T1DM is complex. The overall 2 diabetes among US adults in 2016 and 2017:
incidence rates are comparable in North America population based study. BMJ. 2018; 362. doi:
and Europe; however, this disguises some marked https://doi.org/10.1136/bmj.k1497
variations in incidence rates between countries Centers for Disease Control and Prevention.
and even within countries. Within Europe, partic- National Diabetes Statistics Report. https://
ularly high incidence rates are found in Finland, www.cdc.gov/diabetes/data/statistics-report/
Sweden and Sardinia. Most Asian populations index.html
have a low incidence rate. In general, the incidence Eisenbarth GS. Type I diabetes mellitus. A chronic
of T1DM seems to be increasing with an average autoimmune disease. N Engl J Med. 1986; 314:
increase in incidence of around 3% per year. About 1360–8
half of all cases of T1DM are diagnosed at an age MacFarlane IA. Diabetes mellitus and endocrine
of <15 years, with an observed peak in incidence disease. In Pickup J, Williams G, eds.
rates in children aged 10–14 years. More recently, Textbook of Diabetes. Oxford: Blackwell
many cases are being diagnosed in children of Scientific Publications, 1991: 263–75
<5 years of age. In many high-risk populations a Mobasseri M, Shirmohammad M, Amiri T et al.
male excess of T1DM is seen, especially after the Prevalence and incidence of type 1 diabetes
age of puberty. in the world: a systematic review and meta-
Cases of T2DM greatly exceed those of T1DM, analysis. 10.34172/hpp.2020.18
accounting for about 85% of cases in Europe and Whicher CA, O’Neill SO, Holt RIG. Diabetes in
significantly more in certain ethnic groups. It is the UK: 2019. Diabet Med. 2020 Feb; 37(2):
estimated that 415 million people are living with 242–247. doi: 10.1111/dme.14225
diabetes worldwide, and this is projected to increase Zimmet PZ, Tuomi T, Mackay IR, et al. Latent
to half a billion by 2040, with a preponderance of autoimmune diabetes mellitus in adults
cases in the developing world. In many populations, (LADA): The role of antibodies to glutamic
there is a declining age of peak incidence with cases acid decarboxylase in diagnosis and
now being identified in children and young adoles- prediction of insulin dependency. Diabet
cents, especially in highly susceptible groups such Med. 1994; 11: 299–303
 2
Pathogenesis

TYPE 1 DIABETES MELLITUS and unknown factors resulting in autoimmune

destruction of the beta (β) cells of the endocrine
Type 1 diabetes mellitus (T1DM) is a disorder of pancreas (Figure 2.1).
multifactorial causation: genetic, environmental
and immunological. Worldwide, there is a marked Genetic factors
geographical variation in prevalence. The overall
prevalence in the general population is 0.4%. T1DM Only 10–15% of patients have a first- or second-
is caused by an interaction between environmen- degree relative with T1DM, so most patients do not
tal factors, an inherited genetic predisposition have a family history of T1DM. In monozygotic

Figure 2.1 Glucose is produced in the liver by the process of gluconeogenesis and glycogenolysis.
The main substrates for gluconeogenesis are the glucogenic amino acids (alanine and glutamine),
glycerol, lactate and pyruvate. Many factors influence the rate of gluconeogenesis; it is suppressed by
insulin and stimulated by the sympathetic nervous system. Glycogenolysis (the breakdown of hepatic
glycogen to release glucose) is stimulated by glucagon and catecholamines, but is inhibited by insulin.

DOI: 10.1201/9781003342700-2 7
8 Pathogenesis

twins, the lifetime risk of developing T1DM is associations include PTPN22, FoxP3, AIRE (auto-
about 50%, the high discordance rate suggesting immune regulator, mainly expressed in the thy-
that other risk factors are at play. The risk to a first- mus marrow), STAT3, HIP14, ERBB3 and IFIH1.
degree relative is approximately 5–6%. Environ­
mental triggers may account for up to two-thirds Environmental factors
of the disease susceptibility.
In genome-wide association studies (GWAS) and Strong evidence for the role of environmental
meta-analyses, more than 50 T1DM genetic risk factors in the causation of T1DM comes from the
loci were identified. The strongest reported linkages fact that the occurrence of T1DM in siblings who
for T1DM are within the major histocompatibility are monozygotic twins is around 50%. It remains
complex (MHC) region also known as human leu- unclear what the precise mode of action is for envi-
cocyte antigen (HLA) located on chromosome 6. ronmental factors. The most likely environmental
HLA complex polymorphic alleles are responsible factor implicated in the causation of T1DM is viral
for 40–50% of the genetic risk of the development of infection. It is noteworthy that children exposed to
T1DM. Other genes are responsible for another 15% rubella in fetal life have an increased incidence of
of the genetic predisposition, including the insulin T1DM. RNA or proteins from viruses have been
gene (Ins-VNTR, IDDM2) polymorphisms on chro- detected in the pancreas of patients with T1DM.
mosome 11 and the cytotoxic T lymphocyte-asso- Numerous viruses attack the pancreatic β-cell
ciated antigen-4 gene (CTLA-4) on chromosome 2. either directly through a cytolytic effect or by trig-
More than 90% of patients who develop T1DM gering an autoimmune attack against the β-cell.
have either HLA-DR3, DQB1*0201 (DR3-DQ2) or Evidence for a viral factor in aetiology has come
HLA-DR4, DQB1*0302 (DR4-DQ8) haplotypes, from animal models and, in humans, from obser-
whereas fewer than 40% of normal controls have vation of seasonal and geographical variations in
these haplotypes. DR3/DR4 heterozygosity is the onset of the disease. In addition, patients newly
highest in children who develop diabetes before the presenting with T1DM may exhibit serological
age of 5 years (50%) and lowest in adults presenting evidence of viral infection. Viruses that have been
with T1DM (20–30%) compared with an overall US linked to human T1DM include mumps, coxsackie
population prevalence of 2.4%. Specific polymor- B, retroviruses, rubella, cytomegalovirus and
phisms of the DQB1 gene encoding the β-chain Epstein–Barr virus (Figures 2.2 and 2.3).
of class II DQ molecules predispose to diabetes in The 17-amino acid peptide ABBOS (bovine serum
Caucasians but not in Japanese. In contrast, other albumin), a major constituent of cow’s milk, has been
DR4 alleles, such as DRB1*0403 and DPB1*0402 implicated as a cause of T1DM in children exposed
reduce the risk of developing T1DM even in the at an early age, but definitive proof is lacking and
presence of the DQB1*0302 high-risk allele. HLA this remains controversial. Nitrosamines (found in
antigens (classes I and II) are cell-surface glyco- smoked and cured meats) and nitrate exposure from
proteins that play a crucial role in presenting auto- water intake may be diabetogenic as may chemicals
antigen peptide fragments to T lymphocytes, thus known to be toxic to pancreatic β-cells, including
initiating an immune response. Polymorphisms in alloxan, streptozotocin and the rat poison Vacor.
the genes encoding specific peptide chains of the Other environmental factors implicated in the devel-
HLA molecules may therefore modulate the abil- opment of T1DM include early ingestion of cereal
ity of β-cell-derived antigens to trigger an autoim- or gluten in the diet, inadequate intake of omega-3
mune response against the β-cell. fatty acids and vitamin D deficiency (although vita-
Polymorphisms located on the short arm of min D supplementation does not confer protec-
chromosome 11 close to the gene encoding for pro- tion). Differences in the gut microbiota may also be
insulin may account for about 10% of the genetic involved in the pathogenesis of T1DM.
predisposition of T1DM. This polymorphic site T1DM is associated with autoimmune destruc-
comprises a variable number of tandem repeats tion of the β-cells of the endocrine pancreas, most
(Insulin-VNTR). Another gene, CTLA-4 (cyto- probably via apoptosis. Examination of islet tissue
toxic T lymphocyte antigen-4), located on the short obtained from pancreatic biopsy or at postmortem
arm of chromosome 2 (2q33), is also associated from patients with recent-onset T1DM confirms a
with the risk of developing T1DM. Other genetic mononuclear cell infiltrate (termed insulitis) with
 Type 1 diabetes mellitus 9

the presence of CD4 and CD8 T lymphocytes, B

lymphocytes and macrophages, suggesting that
these cells have a role in the destruction of β-cells.
This chronic atrophic inflammation within the
islets of Langerhans evolves over months or years
while the patient remains euglycaemic, hypergly-
caemia diagnostic of T1DM only emerging after a
long latency period, reflecting the large number of
β-cells that need to be destroyed before symptom-
atic diabetes ensues. Although the precise mecha-
nism of such an insult has not been elucidated, it
seems likely that an environmental factor, such as
a viral infection, in a subject with an inherited pre-
disposition to the disease, triggers the damaging
immune response whereby β-cell components are
recognised as autoantigens. This results in aberrant
expression of class 1 and 11 major histocompatibil-
ity complexes (MHC) antigen by pancreatic β-cells.
Figure 2.2 Viruses have been suggested to be a
T lymphocytes recognise antigen-presenting cells
cause or factor in the development of type 1 diabe-
tes mellitus (T1DM) and are thought to be the most and are activated, producing proinflammatory
likely agents to trigger the disease, probably on cytokines such as interleukin (IL)-2, interferon
the basis of genetic predisposition, in some cases. (IFN)γ and tumour necrosis factor (TNF)-α.
Evidence comes from epidemiological studies and (Other cytokines may be involved such as IL-6,
the isolation of viruses from the pancreas of a few IL-17 and IL-21, while others may confer protec-
recently diagnosed T1DM patients. Mumps and tion.) A clone of T lymphocytes is generated that
coxsackie viruses can cause acute pancreatitis, and carries receptors specific to the presented antigen.
coxsackievirus can cause β-cell destruction. Such T-helper cells assist B lymphocytes to produce
antibodies directed against the β-cell. Such anti-
bodies include islet cell antibodies (ICA) directed
against cytoplasmic components of the islet cells.
ICA presence may precede the development of
T1DM. Some subjects may develop ICA temporar-
ily and not go on to develop the disease, but persis-
tence of ICA leads to progressive β-cell destruction
associated with insulitis. T1DM ensues. Other
antibodies associated with T1DM are islet cell-sur-
face antibodies, insulin autoantibodies (IAA) and
antibodies to an isoform of glutamic acid decar-
boxylase (GAD), found in approximately 70% of
patients with autoantibody positivity at the time of
diagnosis, antibodies to tyrosyl phosphatase (IA-
Figure 2.3 Autopsy sample of histology of cox- 2), found in approximately 60%, and antibodies to
sackie B viral pancreatitis in a neonate. Coxsackie B zinc transporter (ZnT8), found in 60–80% of newly
viral infection may cause inflammatory destruction presenting patients. In an analysis of data from
of the β-cells and coxsackie B viruses have been three prospective cohort studies, 84% of children
isolated from the pancreas of patients with new- with two or more islet autoantibodies developed
onset type 1 diabetes mellitus (T1DM). Injection of
diabetes over 15 years of follow-up, hence the pres-
such isolates into mice causes insulitis and β-cell
damage. Nevertheless, although coxsackie B virus ence prior to diagnosis of two or three autoantibod-
may be diabetogenic in men, its precise aetio- ies confers a greatly increased risk of progressing to
logical importance in the development of T1DM T1DM. Screening children for T1DM has been sug-
remains unclear. gested as a possible strategy with the added benefit
10 Pathogenesis

Figure 2.4 Insulin deficiency results in increased hepatic glucose production and, hence, hyperglycaemia
by increased gluconeogenesis and glycogenolysis. Insulin deficiency also results in increased proteolysis
releasing both glucogenic and ketogenic amino acids. Lipolysis is increased, elevating both glycerol and
non-esterified fatty acid levels which further contribute to gluconeogenesis and ketogenesis, respec-
tively. The end result is hyperglycaemia, dehydration, breakdown of body fat and protein, and acidaemia.

of preventing children presenting with diabetic

ketoacidosis which has been associated with worse
glycaemic outcomes long term (Figures 2.4–2.17).

TYPE 2 DIABETES MELLITUS

Although genetic predisposition plays a role in the
development of type 2 diabetes mellitus (T2DM),
the main risk factors are obesity, low physical activ-
ity and an unhealthy diet. Several T2DM GWAS
have clearly demonstrated the complex polygenic
nature of T2DM in which most of the loci increase
T2DM risk through reducing insulin secretion while Figure 2.5 Constituents of a normal pancreas,
a minority act through reducing insulin action. No medium-power view: to the left lies an excretory
genome-wide scans have identified any region with duct and, to the right, there is an islet sur-
an effect as large as the HLA region in T1DM, so the rounded by exocrine acinar cells. Haematoxylin
exact mode of inheritance remains to be elucidated. and eosin stain.
 Type 2 diabetes mellitus 11

Figure 2.8 Normal islet immunostained for soma-

tostatin. Somatostatin is contained in the D cells
which are scattered within the islet. Somatostatin
has an extremely wide range of actions. It inhibits
the secretion of insulin, growth hormone and glu-
cagon and also suppresses the release of various
gut peptides. Somatostatinomas (D cell tumours)
cause weight loss, malabsorption, gallstones,
hypochlorhydria and diabetes.

Figure 2.6 Normal islet immunostained for

insulin. The majority (80%) of the endocrine cells
are β-cells.

Figure 2.9 Electron micrograph (EM) of an islet

of Langerhans from a normal pancreas showing
mainly insulin storage granules in a pancreatic
β-cell. A larger α-cell is also seen. The normal adult
pancreas contains around 1 million islets com-
prising mainly β-cells (producing insulin), α-cells
(glucagon), D cells (somatostatin) and pancreatic
polypeptide (PP) cells. Islet cell types can be dis-
tinguished by various histologic stains and by the
Figure 2.7 Normal islet immunostained for gluca- EM appearances of the secretory granules (as seen
gon. Note that the α-cells mark the periphery of here). They can also be identified by immunocyto-
blocks of endocrine cells within the islet. Most of chemical staining of the peptide hormones on light
the cells within these blocks are β-cells. or electron microscopy (see Figures 2.12 and 2.13).
12 Pathogenesis

Figure 2.10 Electron micrograph of insulin

storage granules (higher power view than in
Figure 2.9) in a patient with an insulinoma.

Figure 2.12 The same pancreas as in Figure 2.17

has been immunostained to show β-cells: note
the destruction of the β-cells in this islet owing to
inflammation; compare with Figure 2.6.

Figure 2.13 This histological section of pancreas

was obtained at autopsy from a patient 5 years
after the onset of type 1 diabetes mellitus (T1DM).
Figure 2.11 Insulitis. Histological section of a It shows persistence of an infiltrate of lymphocytes
pancreas from a child who died at clinical pre- (insulitis) some of which are indicated by arrows,
sentation of type 1 diabetes mellitus. There is a affecting this islet, immunostained for insulin. This
heavy, chronic, inflammatory cell infiltrate affect- shows that β-cell destruction takes place over
ing the islet. Haematoxylin and eosin stain. years in patients with T1DM.
 Type 2 diabetes mellitus 13

Figure 2.14 Autopsy section of an islet from a

patient who had diabetes for 16 years. Although
the islet looks fairly normal on haematoxylin and
eosin stain (left), insulin staining (right) shows it is
devoid of β-cells.

Figure 2.16 Circulating cytoplasmic islet-cell anti-

bodies (ICA) can be found in most newly diag-
nosed type 1 diabetes mellitus (T1DM) patients,
thereby providing evidence of an autoimmune
pathogenesis of this disorder. ICA are also seen
in the ‘prediabetic’ period and in siblings of
T1DM patients, and are a marker of susceptibil-
Figure 2.15 This is a section of pancreas from a ity to T1DM. This high-power view of a cryostat
12-year-old boy who died of a cardiomyopathy. section of human pancreas was incubated with
He had a family history of type 1 diabetes melli- serum from a T1DM and stained by an indirect
tus (T1DM) and was considered to be prediabetic immunofluorescence technique using anti-human
because he had high titres of both insulin and IgG fluorescinated antiserum. Although ICA are
islet cell autoantibodies in autopsy blood, but he serological markers of β-cell destruction, the
did not have glycosuria in life. The photograph antibodies also stain the entire islet, including
shows two islets affected by insulitis in his pan- glucagon and somatostatin cells (which, unlike
creas, confirming that immunologically mediated the β-cells, are not destroyed). The positive reac-
β-cell destruction takes place in the preclinical tion is confined to cell cytoplasm and the nuclei
period of T1DM. are unstained (seen as black dots).

The rate of concordance is high in identical twins, reflect low diagnostic rates for monogenic diabetes).
but is much lower in non-identical dizygotic twins. Obesity is the strongest risk factor for T2DM and
Patients with T2DM show an increased frequency there exists an inverse relationship between BMI
of diabetes in other family members compared with and age of diagnosis of T2DM (although, of course,
the non-diabetic population. Only a small propor- not all obese patients develop diabetes). It has been
tion of patients (1–5%) with T2DM have a mono- shown that a sedentary lifestyle is another risk fac-
genic disorder (although this low percentage may tor for T2DM. Physical activity increases blood flow
14 Pathogenesis

increased levels of free fatty acids (FFA) and hyper-

glycaemia. The resultant lipotoxicity and gluco-
toxicity induce metabolic and oxidative stress that
leads to β-cell damage and signalling dysfunction.
Sustained hyperglycaemia leads to the deposition of
islet amyloid polypeptides (IAPP or amylin) which
may further impair β-cell function. Hepatic glu-
cose production will also begin to rise. When FPG
reaches high levels, the plasma insulin response to
a glucose challenge is markedly blunted. Although
fasting insulin levels remain elevated, postprandial
insulin and C-peptide secretory rates are decreased.
Figure 2.17 This section shows that all the endo- This natural history of T2DM starting from nor-
crine cells (A, B, D, etc.) in this insulin-containing mal glucose tolerance, followed by insulin resis-
islet hyperexpress class 1 major histocompat- tance, compensatory hyperinsulinaemia and then
ibility complex (MHC). Note also that the islet by progression to impaired glucose tolerance (IGT)
is not inflamed (no lymphocytes). This suggests
as a consequence of β-cell dysfunction and failure,
that hyperexpression of class 1 MHC precedes
insulitis within any given islet and is not simply
as described previously, leading to overt diabetes,
the result of secretion of cytokines by inflamma- has been documented in a variety of populations
tory cells in the insulitis infiltrate. (Figure 2.18).
T2DM is characterised by loss of the first-phase
insulin response to an intravenous glucose load,
in skeletal muscles, thus increasing glucose uptake. although this abnormality may be acquired sec-
It also reduces intra-abdominal fat, a key factor ondary to glucotoxicity. Loss of the first-phase
which promotes insulin resistance. insulin response is important as this early quick
insulin secretion primes insulin target tissues,
Pathogenesis of T2DM especially the liver.
There are multiple possible causes of the
Subjects with T2DM exhibit abnormalities in impaired insulin secretion in T2DM as alluded
glucose homeostasis owing to impaired insulin to previously, with several abnormalities hav-
secretion, insulin resistance in muscle, liver and ing been shown to disturb the delicate balance
adipocytes and abnormalities of splanchnic glu- between islet neogenesis and apoptosis. Studies in
cose uptake. The two cardinal features in terms first-degree relatives of patients with T2DM and
of causation are defective insulin secretion by the in twins have provided strong evidence for the
pancreatic β-cells and an inability of normally genetic basis of abnormal β-cell function. Patients
insulin-sensitive tissues to respond to insulin. with T2DM also exhibit a reduced response of
the incretin glucagon-like peptide-1 (GLP-1) in
Insulin secretion in T2DM response to oral glucose, while GLP-1 administra-
tion enhances the postprandial insulin secretory
Impaired insulin secretion is a universal finding in response and may restore near-normal glycaemia.
patients with T2DM. In the early stages of T2DM, More recently, changes in the gut microbiota were
insulin resistance can be compensated for by an implicated in the development of insulin resis-
increase in insulin secretion, leading to normal glu- tance and T2DM but this area of research requires
cose tolerance. With increasing insulin resistance, further exploration (Figure 2.19).
the fasting plasma glucose (FPG) will rise, accom-
panied by an increase in fasting plasma insulin lev- Insulin resistance in T2DM
els, until an FPG level is reached when the β-cell
is unable to maintain its elevated rate of insulin Insulin resistance is a characteristic feature of
secretion, at which point the fasting plasma insu- both lean and obese individuals with T2DM and is
lin declines sharply. When a state of excess nutri- described as a decrease in the metabolic response
tion exists, as in obesity, it will be accompanied by of insulin-sensitive cells to insulin.
 Type 2 diabetes mellitus 15

Figure 2.19 Biphasic insulin response to a con-

stant glucose stimulus: when the β-cell is stimu-
lated, there is a rapid first-phase insulin response
1–3 minutes after the glucose level is increased;
this returns towards baseline 6–10 minutes later.
Thereafter, there is a gradual second-phase
insulin response that persists for the duration of
the stimulus. Type 2 diabetes mellitus is charac-
terized by loss of the first-phase insulin response
and a diminished second-phase response.

In recent years adipose tissue has been rec-

ognised as an important metabolically dynamic
Figure 2.18 The characteristic histological
abnormality in type 2 diabetes mellitus (T2DM)
tissue. An impaired response of adipose tissue
is amyloid deposition in the islets, which is sig- to insulin constitutes adipose insulin resistance,
nificant in around two-thirds of cases. Increasing whereby there is impaired suppression of lipoly-
amounts of amyloid deposition are associated sis, impaired glucose uptake and enhanced FFA
with progressive islet cell damage, which release into plasma. This results in hyperglycae-
probably contributes to the insulin deficiency mia and FFA accumulation in muscle, liver and
of T2DM. In this pancreas from a patient who the pancreas. Fat accumulation in the liver results
had T2DM of long standing, two islets contain- in impaired insulin signalling that promotes
ing large deposits of amorphous pink-staining
increased hepatic glucose output via gluconeogen-
amyloid can be seen.
esis and impairs the glucose-stimulated insulin
response. An increased adipose tissue mass leads
Skeletal muscle is the major site of insulin- to an increase in circulating proinflammatory
stimulated glucose disposal in humans. Muscle molecules and the resultant chronic inflamma-
represents the primary site of insulin resistance in tory state is considered to be a key element in the
T2DM subjects, leading to a marked blunting of pathogenesis of insulin resistance. In summary,
glucose uptake into peripheral muscle. Mutations insulin resistance at hepatic level is associated with
which reduce the expression of insulin receptor impaired glycogen synthesis, a failure to suppress
or the glucose transporter GLUT4 as well as any glucose production, increased lipogenesis and a
defects of the signalling pathway could reduce proinflammatory effect leading to glucotoxicity,
muscle glucose uptake leading to hyperglycaemia. lipotoxicity and a chronic inflammatory state. A
Reduced physical activity decreases blood flow into high-calorie Western diet and reduced physical
muscle, thereby reducing muscle glucose uptake. activity also contribute to chronic inflammation.
Obesity has been associated with inflammatory There is increasing evidence that mitochondrial
changes in muscle impairing myocyte function, dysfunction may also be associated with insulin
which could result in insulin resistance. resistance and resultant T2DM. Splanchnic tissues,
16 Pathogenesis

like the brain, are relatively insensitive to insulin 5.4–8.3 mmol/L (97–150 mg/dl) and a HbA1C of
with respect to stimulation of glucose uptake. 5.8–7.6% (40–60 mmol/mol). β-Cell function is
There is a dynamic relationship between insulin otherwise normal. The abnormality is present from
resistance and impaired insulin secretion. Insulin birth and remains stable. GCK-MODY is usu-
resistance is an early and characteristic feature of ally diagnosed incidentally and those affected are
T2DM in high-risk populations. Overt diabetes asymptomatic, require no treatment and exhibit
develops only when the β-cells are unable to increase no diabetic complications.
sufficiently their insulin output to compensate for HNF1A-MODY and the less common HNF4A-
the defect in insulin action (insulin resistance). MODY are caused by mutations in β-cell transcrip-
tion factors with roles in the β-cell, liver and other
MONOGENIC AND OTHER TYPES organs. The importance of diagnosing these forms of
OF DIABETES monogenic diabetes is that the associated hypergly-
caemia responds well to sulphonylurea treatment,
The existence of a monogenic cause of diabetes in thus obviating the need for other glucose-lowering
some cases was suspected by the observation of drugs including insulin. HNFA4A MODY differs
two main clinical phenotypes, namely, the onset from HNF1A-MODY in that fetuses and newborn
of diabetes in neonates or infants (neonatal dia- babies have excess insulin secretion leading to an
betes mellitus [NDM]) and families with several excessive birth weight and possible macrosomia and
generations of diabetes occurring in adolescent or neonatal hypoglycaemia. HNF1B-MODY is charac-
young adults suggesting an autosomal dominant terised by the presence of renal cysts with possible
mode of inheritance (maturity-onset diabetes of developmental abnormalities in multiple systems.
the young [MODY]). Other subtypes of mono- Indeed, it is the commonest genetic causation of
genic diabetes exist and they include certain rare childhood kidney disease. HNF1B-MODY usually
multisystem syndromes, cases of severe insulin presents in adolescence or young adulthood and is
resistance (in the absence of obesity) and patients frequently associated with reduced exocrine pan-
with lipodystrophy (full or partial). The current creatic function, which may require treatment.
approach is to define cases of monogenic diabetes KCNJ11-NDM and ABCC8-NDM are caused
based on molecular genetics. The current classifi- by activating heterozygous mutations in either
cation of monogenic diabetes combines the stan- gene encoding the subunits of the β-cell KATP
dard abbreviation of the gene involved followed channel and are the most common causes of per-
by an accepted abbreviation of the clinical pheno- manent prenatal diabetes mellitus (PNDM) and
type. An example of this would be GCK-MODY. NDM. Treatment with high doses of a sulpho-
The term MODY should not be confused with chil- nylurea can reduce hyperglycaemia stably over
dren or young adults presenting with true T2DM, a many years. Neurodevelopmental abnormalities
sadly increasing occurrence in Western and other may coexist and be responsive to sulphonylurea
societies. The most common causes of monogenic treatment. Transient neonatal diabetes mellitus
diabetes are listed in Figure 2.20. (TNDM) may be associated with overexpression of
maternally methylated genes at chromosome 6q24
Monogenic diabetes subtypes (imprinted locus at 6q24). Diabetes resolves spon-
taneously within the first year of life but usually
GCK-MODY is characterised by a non-progressive recurs in adolescence or young adulthood, fortu-
hyperglycaemia and is the most common cause of nately responding to oral agents.
monogenic diabetes with an estimated prevalence Heterozygous mutations in the proinsulin gene
of 1 in 1000 individuals. GCK-MODY is caused (INS) produce INS-NDM and INS-MODY, the sec-
by heterozygous inactivating mutations in the ond most common cause of PNDM as a result of
enzyme glucokinase, which acts as the β-cell glu- progressive loss of β-cell functional capacity due
cose sensor. Impairment of GCK activity causes an to accumulation of misfolded proinsulin protein.
increase in the threshold level of glucose required Affected individuals require insulin treatment.
to initiate insulin secretion with the result being Multisystem syndromes caused by a single gene
mild fasting hyperglycaemia of the order of abnormality include mitochondrial diabetes and
 Monogenic and other types of diabetes 17

Figure 2.20 Clinical implications of some common and important causes of monogenic diabetes.

Wolfram syndrome. Mitochondrial diabetes is drugs or chemicals. Certain viruses have been
associated with sensorineural deafness and other associated with β-cell destruction (coxsackievirus
possible renal, cardiac and neurological features B, cytomegalovirus, adenovirus, mumps, congeni-
while Wolfram syndrome features sensorineural tal rubella), although, in most cases, the precise
deafness, optic atrophy and diabetes insipidus and nature of the association remains unclear. Many
is usually caused by recessive mutations in WFS1. other genetic syndromes are accompanied by
As previously described, diabetes may result an increased incidence of diabetes (Down’s syn-
from overt diseases of the exocrine pancreas, sec- drome, Klinefelter’s syndrome, Turner’s syndrome,
ondary to specific endocrinopathies and due to Prader-Willi syndrome) (Figures 2.21–2.37).
18 Pathogenesis

Figure 2.21 Prader-Willi syndrome is a syndrome Figure 2.22 The centripetal obesity and promi-
of obesity, muscular hypotonia, hypogonado- nent lipid striae suggest that this is Cushing’s
tropic hypogonadism and mental retardation syndrome and not simple obesity.
associated, in about 50% of cases, with a deletion
or translocation of chromosome 15. A small per-
centage of patients have type 2 diabetes mellitus. compared to Caucasian populations. BMI is not a
direct measurement of body fat but is moderately
correlated with body fat measured directly. BMI
THE OBESITY EPIDEMIC may not accurately reflect fat mass nor its distri-
bution in some individuals, particularly high-level
A dramatic increase in the prevalence of obe- athletes. Fairly accurate estimations of fat distri-
sity has been witnessed in many countries in bution may be gained by measuring the waist–hip
the past quarter of a century. Obesity, at least in ratio or more simply waist circumference, both of
Caucasian populations, is defined as a body mass which correlate well with more sophisticated tech-
index (BMI; weight [kg]/height [m]2) >30. In South niques, such as computed tomography or mag-
Asian populations, a BMI >23 is associated with an netic resonance imaging. Weight-related health
increased health risk while a BMI >25 is defined problems are more common in males with a waist
as obesity. This is because these populations have circumference greater than 102 cm (40 inches) and
an increased body fat content at a given BMI in females with a waist circumference greater than
 The obesity epidemic 19

Figure 2.24 Diabetes occurs in 15–30% of

patients with acromegaly and similarly with
impaired glucose tolerance. The excess growth
hormone secretion, usually from a pituitary
adenoma, is associated with insulin resistance
which, after several years, may result in the dia-
Figure 2.23 This young woman (same patient as
betic state. The diabetes is usually type 2, and is
in Figure 2.22) has the typical facies of Cushing’s
associated with the usual microvascular and other
syndrome—a rounded plethoric face and mild
complications. Glucose tolerance improves after
hirsutism. Glucose tolerance is impaired in most
successful treatment of the acromegaly.
patients with Cushing’s syndrome and about
25% of patients are diabetic. However, many
older patients with type 2 diabetes mellitus have greater trends elsewhere. It is estimated that 12%
features of Cushing’s syndrome, specifically, obe- of the world population is obese, a tripling in prev-
sity, hirsutism, hypertension, striae and diabetes,
alence since 1975. Although there is a suggestion
but do not have the condition.
that the rate of increase in obesity is declining in
high-income countries, it continues to increase in
89 cm (35 inches). The measurement of waist cir- low-income and middle-income countries. People
cumference has become part of the definition of of all ages, races, ethnicities, socioeconomic levels
the metabolic syndrome, a condition associated and geographical areas are experiencing a substan-
with vascular risk factors and which predisposes tial increase in weight. Such data have led to the
to the development of T2DM. The overall preva- coining of the term ‘the obesity epidemic’, some-
lence of obesity in the UK was 28% in 2022, while times stated as ‘the obesity pandemic’, as this prob-
as of 2020 it was 42% in the US (even higher in the lem is not confined to the developed nations of the
Non-Hispanic Black population). One in seven world but is also happening in developing nations,
children in the UK are obese by the age of 5 years particularly in affluent strata of society.
and one in four by the age of 11 years. Childhood
obesity is particularly present in deprived areas. Food intake
At 2018 in the US, one in five children and adoles-
cents between 2 and 19 years of age were obese. In It is clear that obesity results from the interac-
England, the adult prevalence of obesity increased tion of many factors including genetic, metabolic,
by 15% between 1993 and 2019, with similar or behavioural and environmental influences, but the
20 Pathogenesis

Figure 2.25 About 10% of patients with Addison’s

disease have diabetes, usually type 1. Diabetic
patients who develop Addison’s disease exhibit
an increased sensitivity to insulin which is reversed
by glucocorticoid replacement therapy. Addison’s
disease and associated type 1 diabetes mellitus or
other autoimmune endocrinopathy (such as hypo-
thyroidism, Graves’ disease and hypoparathyroid- Figure 2.26 This patient has hereditary haemo-
ism) is referred to as Schmidt’s syndrome. chromatosis transmitted by an autosomal reces-
sive gene. It occurs most commonly as a result of
a mutation in the gene HFE—on the short arm of
rapidity with which obesity is increasing, in the chromosome 6. Patients present with the classic
context of a relatively stable gene pool, suggests triad of bronze skin pigmentation, hepatomegaly
that environmental and behavioural factors largely and diabetes mellitus (hence the term ‘bronze
diabetes’). Cardiac manifestations and pituitary
explain the epidemic. National trends in food con-
dysfunction also occur.
sumption have revealed conflicting data; however,
ecological data seem to support the notion that
energy intake has increased perhaps related to an activity in schools and more jobs being of a seden-
increased percentage of food consumed outside the tary nature. In the US, 15% (range 17.3–47.7) of the
home including fast foods, greater consumption of population was described as physically inactive,
soft drinks and larger portion sizes. defined as not participating in any leisure-time
physical activities in the last month, while in the
Energy expenditure UK, 25% of people over the age of 16 years were
physically inactive, defined as taking less than
Although it is difficult to quantify, it seems likely 30 minutes of moderate-intensity physical activi-
that a major downward change in physical activ- ties per week. A cross-sectional study in South
ity and, thus, energy expenditure, plays a signifi- Carolina, US, suggested that obese children spent
cant role in the development of obesity in modern less time in moderate and vigorous physical activ-
society whether or not energy intake has increased. ity than their non-obese counterparts, and in a
This includes the level of activity required at work national US study, children who engaged in the
and in the home, reduced dependence on walking least vigorous physical activity or the most televi-
and cycling for transportation, reduced physical sion viewing tended to be the most overweight.
 The obesity epidemic 21

Figure 2.27 Of the patients who have

Klinefelter’s syndrome (47,XXY karyotype), 26% Figure 2.28 Diabetes is present in around 60%
show diabetes on the oral glucose tolerance test, of young adults with Turner’s syndrome (45,XO
but overt symptomatic diabetes is unusual. The karyotype) and is usually type 2. A paradoxical
cause of the diabetes is not known, but may be rise in growth hormone to oral glucose may be
related to insulin resistance. the cause of the glucose intolerance.

Genetics and obesity the hedonistic aspects of food intake are the main
drivers of obesity in both monogenic and poly-
From a genetic viewpoint, obesity may be consid- genic obesity. The genes for leptin, a hormone pro-
ered either rare, early-onset and severe monogenic duced by fat which reduces energy intake, and its
obesity or polygenic (common obesity), although it receptor became candidates for obesity. In 1997,
is likely that there is overlap between the two phe- congenital leptin deficiency was identified lead-
notypes. Gene discoveries suggest that the central ing to obesity and this discovery was followed by
nervous system and neuronal pathways controlling identification of genes encoding the leptin receptor
22 Pathogenesis

Figure 2.29 The typical facies of myotonic dys-

trophy, with frontal balding and a smooth fore-
head, is associated, albeit rarely, with diabetes
mellitus. Impaired glucose tolerance with insulin
resistance is more commonly found.
Figure 2.31 Glucose intolerance occurs in
about 30% of cases of cystic fibrosis, although
only 1–2% of patients have frank diabetes. This
low-power view of the pancreas of a 14-year-old
child with cystic fibrosis complicated by dia-
betes shows complete atrophy of the exocrine
pancreas, but with survival of the islets. Some of
the islets (lower part of field) are embedded in
fibrous tissue. Haematoxylin and eosin stain.

Figure 2.30 This 13-year-old boy with Rabson– Figure 2.32 This is a coronal section of the tail
Mendenhall syndrome exhibits severe insulin resis- of the pancreas from a patient with haemochro-
tance (moderate hyperglycaemia associated with matosis. Note the brown colour of the pancreas
gross elevation of plasma insulin levels). Typically compared with the surrounding fat. Normal
associated features include stunted growth and pancreas tissue appears pale. The smaller piece
acanthosis nigricans, affecting the neck, axillae and of pancreas has been stained with Prussian blue
antecubital fossae, and a characteristic facies. to show the presence of iron deposits.
 The obesity epidemic 23

Figure 2.35 This endoscopic retrograde cholan-

giopancreato-gram shows the typical appear-
ances of chronic pancreatitis. There is a dilated
pancreatic duct with amputation and beading of
Figure 2.33 Haemochromatosis. Haemosiderin the side branches.
deposits in this low-power view of pancreas are
stained blue. Note the accumulation of iron in the
endocrine cells of the islet (centre) as well as in
the acinar cells of the exocrine pancreas. Prussian
blue staining was used.

Figure 2.36 Plain abdominal radiograph show-

ing pancreatic calcification due to chronic
pancreatitis. Diabetes occurs in around 45%
of cases of chronic pancreatitis and is usually
mild. Approximately one-third of patients will
Figure 2.34 This endoscopic retrograde cholangi- ultimately require insulin treatment to maintain
opancreato-gram shows a normal pancreatic duct. adequate glycaemic control.
24 Pathogenesis

Figure 2.37 This computed tomography scan

shows cancer of the pancreas. An association
between adenocarcinoma of the pancreas and
diabetes has long been recognized. Pancreatic
cancer may precede the diagnosis of diabetes,
but some epidemiological studies suggest that
there is an increased risk of pancreatic cancer
in diabetic patients. Unexplained weight loss or
back pain in a patient with type 2 diabetes melli-
tus must always raise the suspicion of underlying
pancreatic cancer.

as well as genes encoding multiple components

of the melanocortin pathway, all of which were
found to result in severe early-onset obesity. Other
monogenic obesity mutations have been identi-
fied. GWAS are ongoing, but variants in only six
genes show reproducible association with obesity
outcomes. Nevertheless, such studies are likely to Figure 2.38 Type 2 diabetes mellitus (T2DM) is
deliver knowledge about the relationship between strongly associated with obesity and this link has
been recognized for centuries. The risk of devel-
gene defects and the ‘obesogenic’ environment.
oping T2DM increases progressively with rising
body mass index. T2DM is the result of increased
Sequelae of obesity insulin resistance and insulin deficiency. Obesity
is strongly associated with insulin resistance and
Obesity is associated with an increased risk of heart high fasting insulin levels. It has been proposed
disease, hypertension, a variety of cancers, cere- that this may ultimately result in β-cell failure and
brovascular disease, gallstones and osteoarthritis; the emergence of T2DM; however, this theory
furthermore, it has also been associated with an is oversimplistic and the precise cause of T2DM
alarming increase in the prevalence of T2DM with remains unknown except in a few cases of identi-
fied genetic abnormalities.
adults presenting at an ever-earlier age and the dis-
turbing appearance of T2DM in adolescents and
children. The health and economic consequences PREVENTION OF DIABETES
of this are likely to be devastating, thus, the obe-
sity epidemic has to be considered a global issue of T1DM
major importance. Governments and their politi-
cians must address this issue and develop workable Prevention of the loss of β-cell mass is a major chal-
public health policies and legislation to reverse the lenge in T1DM research. On the basis of the theory
obesity trend (Figures 2.38 and 2.39). that immune-mediated T1DM is believed to result
 Prevention of diabetes 25

who have a high-risk genotype plus or minus the

presence of islet autoantibodies. Low-risk dietary
intervention trials in genetically susceptible indi-
viduals without autoantibodies have been largely
unsuccessful (NIP, DAISY, TRIGR, FINDIA,
BABYDIET, Diabetes TrialNet).
Trials using the administration of nicotinamide,
which can prevent T1DM in animal models, have
failed to prevent diabetes as have trials of insulin
administration using the oral, nasal or subcutane-
ous route. Immunotherapy with monoclonal anti-
bodies (for example, teplizumab which targets CD8
lymphocytes) holds the greatest promise in T1DM
prevention. The T1DM TrialNet Study Group trial
demonstrated for the first time that treatment with
teplizumab delayed the onset of T1DM in a high-
risk group by a median of 2 years. Teplizumab has
also been trialled in patients with established T1DM
where is has been shown to be effective in preserv-
ing C-peptide secretion when administered early
in the course of the disease. Other agents that have
been used in tertiary prevention are cyclosporine A
and azathioprine with glucocorticoids. These have
shown an effect on preservation of insulin secretion
Figure 2.39 This young child has morbid obe-
in some individuals but, unfortunately, the effect
sity. As the age of peak incidence of diabetes was not prolonged. Treatment of new-onset T1DM
declines, cases of type 2 diabetes mellitus are patients with a class of immunosuppressive lym-
now being identified in such children and in phocytes known as regulatory T cells (Tregs) can
young adolescents, especially in highly suscep- delay β-cell destruction. Monoclonal antibodies
tible ethnic groups. The health consequences of and other immune-modifying agents would seem
this phenomenon are likely to be immense. to hold out the best promise as preventative agents
in T1DM. There may be a role for vaccines but such
from immunological destruction of islet β-cells as research is at an early stage.
a consequence of an interplay between genetic sus-
ceptibility and a triggering environmental agent or T2DM
agents, it would seem possible to identify potential
targets for prevention of the disease, although we Expanding prevalence rates of T2DM diabetes
know that the previously discussed theory is very both in developed and developing nations dictate
much an oversimplification of the true pathological that the prevention of T2DM is an issue of global
mechanism. The development of T1DM is a slow importance. Clearly the prevention of T2DM is
process with the best prospect of preventive strate- closely related to the prevention of obesity. T2DM
gies occurring early in the disease process. At that lends itself to potential preventative action because
stage, disease prediction is less accurate and any of the long delay between development of the ear-
treatment would need to be safe, otherwise, indi- liest metabolic defects and full expression of the
viduals may be harmed by a treatment who were disease. Lifestyle modification (weight loss and
never going to develop the disease. Strategies to increased physical activity) is without doubt the
prevent T1DM would include (a) identification and most effective way to prevent progression to frank
elimination of environmental triggers, (b) identifi- diabetes. Lifestyle modification or pharmacologi-
cation and promotion of environmental protective cal intervention that can improve insulin sensi-
factors and (c) interruption of the immunologi- tivity (reduce insulin resistance) or improve or
cal process leading to β-cell destruction. A target preserve β-cell function would be expected to have
population for preventative trials would be those an impact on the future development of T2DM.
26 Pathogenesis

The first major trial to show the effect of lifestyle The multinational Study to Prevent Non-Insulin
change on the development of diabetes was the Da Dependent Diabetes Mellitus (STOP-NIDDM
Qing Study in China where patients with IGT were Trial) used acarbose to prevent progression to
randomised to a control group and one of three diabetes in IGT subjects. Patients who were ran-
active treatment groups (change in diet, exercise or domised to acarbose were 25% less likely to
change in diet plus exercise). The diet group expe- develop diabetes, and when the data were cor-
rienced a relative risk reduction of progression to rected to the current ADA criteria for the diagnosis
frank diabetes of 31%, the exercise group of 46% of diabetes, there was an even greater relative risk
and the combined group of 42%. Follow-up data reduction of 32%. Treatment with a glitazone has
revealed a 39% reduction in diabetes at 30 years. also been shown to reduce the number of patients
This study was followed by the Finnish Diabetes who develop diabetes 30 months after gestational
Prevention Study, which compared lifestyle inter- diabetes with a 55% relative risk reduction in the
vention to a control group in overweight patients Troglitazone in Prevention of Diabetes (TRIPOD)
with IGT. The lifestyle intervention group received study, although troglitazone is no longer available,
detailed dietary advice and individualised advice and the use of pioglitazone in subjects with IGT in
on physical activity with supervised training ses- the Assessing the Effectiveness of Communication
sions. During the first year of the study, the inter- Therapy in the North West (ACTNOW) study
vention group achieved a significant loss of 4.2 kg reduced the conversion to T2DM by 72%, while
with minimal change in the control group and 42% of the pioglitazone subjects reverted to nor-
after 2 years, the cumulative incidence of progres- mal glucose tolerance.
sion to diabetes was reduced by 58%. Whether such Several other T2DM pharmacological preven-
an intensity of lifestyle intervention could be pro- tion trials have been conducted. In the Trial of
vided, funded and adhered to outside the context Prevention of Cardiovascular Complications and
of a clinical trial remains open to debate. However, Type 2 Diabetes with Valsartan and/or Nateglinide
the investigators reported a 43% reduction in new (NAVIGATOR) study, the use of nateglinide was
diabetes cases after 7 years of follow-up. not associated with any reduction in diabetes
In the US, the investigators in the Diabetes incidence or cardiovascular outcomes. Subjects
Prevention Program randomly assigned patients in the DREAM (Diabetes Reduction Assessment
with IGT to one of three arms: placebo, lifestyle with Ramipril and Rosiglitazone Medication)
modification or metformin (850 mg twice daily). study with IFG or IGT were treated with ramipril
Patients in the lifestyle intervention group were for 3 years with no significant decrease in diabe-
asked to achieve and maintain a reduction of at tes incidence or death (although there was a sig-
least 7% in body weight through a healthy diet and nificant increase in the number of individuals
to engage in moderate physical activity for at least regressing to normoglycaemia). In the Outcome
150 minutes per week. Patients received intensive Reduction with Initial Glargine (ORIGIN) study,
support and, as for the Finnish study, such a level of people with cardiovascular risk factors and IFG,
support is unlikely to be available in routine clini- IGT or T2DM were treated with an injection of
cal practice. The lifestyle group achieved a greater basal insulin glargine. This had a neutral effect
weight loss (5.6 kg) and a greater increase in physi- on cardiovascular outcomes and cancer cases but
cal activity than the other groups. At 3 years, the reduced new onset diabetes (30% vs. 35% 3 months
prevalence of T2DM was reduced by 58% with after glargine stopped) but with an increase in
lifestyle change and by 31% in the metformin hypoglycaemia and an increase in weight.
group. After 15 years of follow-up, diabetes inci- Thus, it has been conclusively shown that life-
dence was reduced by 27% by lifestyle intervention. style modification and drug therapy can delay
Accordingly, The American Diabetes Association the onset of T2DM. Whether there has been true
(ADA) recommends intensive lifestyle modification ‘prevention’ in those subjects who did not develop
for the prevention of diabetes in patients with ‘pre- diabetes is a different matter, and it may seem coun-
diabetes’ and states that metformin therapy should terintuitive to prevent diabetes by the use of agents
be recommended for those at high risk of develop- to treat diabetes. Cost-effective analyses would
ing T2DM (previous history of gestational diabetes also have to be taken into consideration, although
mellitus or BMI greater than or equal to 35). individual health benefit is likely to ensue.
 Prevention of diabetes 27

Reversal of T2DM Bottazzo GF. Death of a beta cell: homicide or

suicide? Diabetic Med. 1986; 3: 119–30
Prolonged excess calorie intake leads to fat accumu- Chiasson JL, Gomis R, Hanefeld M, et al. The
lation in the liver. Increased liver fat causes relative STOP-NIDDM trial: an international study on
resistance to hepatic glucose production by insulin. the efficacy of an alpha-glucosidase inhibitor
The resultant increase in FPG leads to hyperinsu- to prevent type 2 diabetes in a population
linaemia, which further increases the conversion of with impaired glucose tolerance: rationale,
excess calories into liver fat. A fatty liver results in design, and preliminary screening data. Study
excess export of very low-density-lipoprotein (VLDL) to prevent non-insulin-dependent Diabetes
triacylglycerol increasing fat delivery to the pancre- Mellitus. Diabetes Care. 1998; 21: 1720–5
atic islets, which impairs the acute insulin secretion DeFronzo R. The triumvirate: β-cell, muscle, liver.
to ingested food resulting in postprandial hypergly- a collusion responsible for NIDDM. Diabetes.
caemia. This results in a further increase in insulin 1988; 37: 667–75
secretion and further augmentation of liver and pan- DeFronzo RA. Pathogenesis of type 2 diabetes
creatic islet fat deposition in a vicious cycle, the end mellitus. Med Clin North Am. 2004; 88: 787–835
result being the emergence of diabetes. This is known Ebbeling CB, Pawiak DB, Ludwig DS. Childhood
as the twin cycle hypothesis. The Counterpoint study obesity: public-health crisis, common sense
showed that patients diagnosed with T2DM within cure. Lancet. 2002; 360: 473–82
4 years who adhered to a very low-calorie liquid diet Froguel P, Velho G. Genetic determinants of type
(600 kcal) for 8 weeks while carrying on a normal 2 diabetes. Recent Prog Horm Res. 2001; 56:
life and who lost on average 15 kg in weight, exhib- 91–105
ited a fall to normal levels of previously high levels of Fujimoto WY. The importance of insulin resistance
liver and pancreatic fat and decreased their hepatic in the pathogenesis of type 2 diabetes mel-
glucose output and improved their β-cell function. litus. Am J Med. 2000; 108(Suppl 6a): 9s–14s
Seventy-three percent achieved remission of T2DM. Giwa AM, Ahmed R, Omidian Z, et al. Current
Subsequent studies (Counterbalance, Diabetes understandings of the pathogenesis of
Remission Clinical Trial [DiRECT]) confirmed type 1 diabetes: genetics to environment.
these findings, although remission rates are lower for World J Diabetes. 2020 Jan 15; 11(1): 13–25.
patients with longer duration of diabetes. The impor- Doi: 10.4239/wjd.v11.i1.13
tance of these studies is the knowledge that, for some Hitman GA. The major histocompatibility com-
people, T2DM may be reversible even when severe plex and insulin dependent (type I) diabetes.
calorie restriction is relaxed. Autoimmunity. 1989; 4: 119–30
Inzucchi SE, Sherwin RS. The prevention of type
BIBLIOGRAPHY 2 diabetes mellitus. Endocrinol Metab Clin
North Am. 2005; 34: 199–219
Andersen RE, Crespo CJ, Bartlett SJ, et al. Kahn SE. The importance of the beta-cell in the
Relationship of physical activity and television pathogenesis of type 2 diabetes mellitus. Am
watching with body weight and level of fat- J Med. 2000; 108(Suppl 6a): 2s–8s
ness among children: results from the third Krischer JP, Liu X, Lernmark A, et al. The influ-
national health and nutrition examination ence of type 1 diabetes genetic susceptibility
survey. JAMA. 1998; 279: 938–42 regions, age, sex and family history to the pro-
Atkinson MA, Eisenbarth GS. Type I diabetes: gression from multiple autoantibodies to type
new perspectives on disease pathogenesis 1 diabetes: a TEDDY study report. Diabetes.
and treatment. Lancet. 2001; 358: 221–9 2017.66 3122–29. Doi: 10.2337/db17-0261
Beik P, Ciesielska M, et al. Prevention of type 1 Paschou SA, Papadopoulou-Marketou N,
diabetes: past experience and future oppor- Chrousos GP, et al. On type 1 diabetes mel-
tunities. J Clin Med. 2020 Sep; 9(9): 2805. litus pathogenesis. Endocr Connect. 2018
Doi: 10.3390/jcm9092805 Jan; 7(1): R38–R46. Doi: 10.1530/EC-17-0347
Besser R, Ng SM, Robertson EJ. Screening Redondo MJ, Fain PR, Eisenbarth GS. Genetics
children for type 1 diabetes. BMJ 2021; 375: of type IA diabetes. Recent Prog Horm Res.
e067937. Doi: 10.1136/bmj-2021-067937 2001; 56: 69–89
28 Pathogenesis

Riddle MC, Philipson LH, Rich SS, et al. in obese and non-obese children. Int J Obes
Monogenic diabetes: from genetic insights Relat Metab Disord. 2001; 25: 822–9
to population-based precision in care. Taylor R. Calorie restriction for long-term
Reflections from a diabetes care Editors’ remission of type 2 diabetes. Clin Med
expert forum. Diabetes Care. 2020; 43(12): (Lond). 2019 Jan; 19(1): 37–42. Doi: 10.7861/
3117–28. Doi.org/10.2337/dci20-0065 clinmedicine.19-1-37
Skyler JS. Immunotherapy for interdicting the Undlien DE, Lie BA, Thorsby E. HLA complex
type 1 diabetes disease process. In Pickup J, genes in type I diabetes and other autoim-
Williams G, eds. Textbook of Diabetes, 3rd mune diseases. Which genes are involved?
edn. Oxford: Blackwell Scientific Publications, Trends Genet. 2001; 17: 93–100
2003: 74.1–74.12 Zimmet PZ. The pathogenesis and prevention of
Trost SG, Kerr LM, Ward DS, Pate RR. Physical diabetes in adults. Genes, autoimmunity, and
activity and determinates of physical activity demography. Diabetes Care. 1995; 18: 1050–64
 3
Treatment of type 1 diabetes mellitus

INTRODUCTION ‘conventional’ regime based on standard practice at

the time (typically one or two daily injections) or an
Effective treatment of type 1 diabetes mellitus ‘intensive’ treatment regime comprising three or more
(T1DM) first became possible with the introduc- insulin injections a day and four times daily blood
tion of insulin to clinical practice in 1922. Initial glucose testing. A subgroup of the ‘intensive’ treat-
insulin preparations were variable in strength and ment arm used the then-new technology of continu-
were short acting, requiring repeated dosing with ous subcutaneous insulin delivery by insulin pump.
meals. In 1936, the first long-acting insulin was The difference in outcomes were striking. After
produced combining insulin with protamine and 6.4 years of follow-up, the intensive group achieved a
zinc to create a product that was absorbed slowly mean HbA1C of 7% (53 mmol/mol) compared to 9%
after subcutaneous injection to enable mainte- (76 mmol/mol) in the conventional group. This dif-
nance of blood insulin levels over the course of the ference was associated with a 76% reduction in new
day. As a result, it became possible to offer more retinopathy and a 50–60% reduction in onset or pro-
physiological insulin replacement combining a gression of diabetic nephropathy and neuropathy.
long-acting ‘basal’ insulin to replace basal insu- Long-term follow-up of the cohort of patients who
lin secretion with a mealtime ‘bolus’ to mimic the participated in the DCCT has shown that the benefits
rise in insulin occurring in the postprandial state. observed were sustained for more than 20 years with
Various pre-mixed insulins were produced, com- substantially lower rates of nephropathy and reti-
bining variable proportions of short- and long- nopathy in the intensively managed group and with
acting insulins, and the majority of people with one-third lower mortality in these patients when com-
T1DM were managed on two injections a day with pared to those who received conventional treatment.
occasional urine or blood glucose testing, with the On the basis of these results, subsequent T1DM
aim of maintaining moderate control of glucose guidelines have evolved to recommend very tight
and avoiding acute metabolic decompensation. blood glucose control and to aim for near normo-
Challenges with early insulin treatment included glycaemia with recommended targets for HbA1C
local issues at injection sites including lipoatrophy, ranging from 48 to 53 mmol/mol (6.5% to 7.0%).
which was more commonly observed with animal Despite such guidance and advancements in the
sequence insulin than with modern insulins. management of diabetes, the majority of patients
The need for a more intensive approach and the continue to have suboptimal control. In the UK,
importance of maintaining tight blood glucose con- only 9.8% of adults with T1DM achieved a HbA1C
trol in T1DM was established beyond doubt fol- under 48 mmol/mol and only 19.5% achieved a
lowing the publication of the Diabetes Control and value under 53 mmol/l, with some 14.4% having
Complications Trial (DCCT) in 1993. This study values above 86 mmol/mol, a cut-off selected to
enrolled more than 1400 patients with T1DM aged identify a very high-risk population.
between 13 and 39 years of which half had no diabetes These data reflect the challenges of managing
complications and half had evidence of retinopathy diabetes in adults with T1DM. Significant bar-
or microalbuminuria. Patients were randomised to a riers remain to optimising control, particularly

DOI: 10.1201/9781003342700-3 29
30 Treatment of type 1 diabetes mellitus

Figure 3.1 The structure of human proinsulin. Insulin is produced in the β-cells of the islets of
Langerhans by cleavage of the precursor proinsulin into insulin and C-peptide. Measurement of
C-peptide, especially following intravenous injection of 1 mg of glucagon, is a useful indicator of
β-cell function, as C-peptide and insulin are secreted in equimolar amounts and the former is mini-
mally extracted by the liver. This test can be used to differentiate between types 1 and 2 diabetes
mellitus in cases of diagnostic confusion.

in relation to avoidance of hypoglycaemia and to

managing the burden of living with T1DM on a
continuing basis. However, there are ongoing devel-
opments that continue to improve the management
of T1DM (Figures 3.1–3.7).

DEVELOPMENT OF INSULIN
PREPARATIONS
At the time of the DCCT, the range of available
insulins was limited and there have been signifi-
cant advances in insulin biochemistry since then
with the development of insulin analogues with Figure 3.2 Insulin crystals. Insulin is stored in
β-cells as hexamers complexed with zinc. Insulin–
different rates of absorption from subcutaneous
zinc hexamers readily form crystals, which are
tissue which can allow for differing durations of stored in the pancreatic granules. Following sub-
actions and properties. cutaneous injection, insulin similarly tends to self-
For mealtime bolus delivery, the only avail- aggregate into hexamers but needs to dissociate
able insulins then were soluble human or porcine into its monomeric form to enter the blood.
 Development of insulin preparations 31

Figure 3.4 Escherichia coli distended by biosyn-

thetic human proinsulin before lysis.

insulin molecules to combine to form hexamers;

following subcutaneous injection, these hexamers
need to dissociate into monomers to enable absorp-
tion into the circulation and this occurs at a vari-
able rate. Since then, two new insulin analogues
insulin aspart and insulin lispro have been devel-
oped with amino acid substitutions that result in
the insulin mainly existing as dimers rather than
hexamers, resulting in more rapid insulin absorp-
tion into the circulation and a more predictable
postprandial glucose response.
Figure 3.3 Insulin for therapeutic use was previ-
ously produced solely from porcine or bovine For basal insulin replacement, the DCCT patients
sources. Nearly all insulin now used is produced predominantly used isophane insulins. These have
by biosynthesis of human sequence insulin and an effective duration of action of 12–16 hours, but
analogues created by further amino acid substi- a pronounced peak in insulin levels occurring at
tution and in some cases, addition of fatty acid around 6–8 hours, which, for some patients, could
chains to prolong action. Porcine and human insu- lead to hypoglycaemia between meals or overnight.
lin differ only in a single residue at the C terminus In T1DM treatment, these have now largely been
of the β chain. Enzymatic conversion involves replaced by long-acting insulin analogues with more
substitution of the porcine B30 alanine residue by
predictable absorption and absence of peaks. The
threonine to produce the semisynthetic human
insulin enzymatically modified porcine (‘emp’). first-generation basal analogues insulin glargine
The biosynthesis of human insulin using recom- (marketed as Lantus and its biosimilar Abasaglar)
binant-DNA technology involves insertion of a and insulin detemir (Levemir) were introduced
synthetic gene coding for human proinsulin into a shortly after the millennium and were associated
bacterial plasmid, which is then introduced into a with less hypoglycaemia (particularly nocturnal
bacterium such as Escherichia coli. Ultimately, the hypoglycaemia) compared to isophane insulin
synthetic gene is transcribed in quantity and its preparations. However, they still required twice-
messenger RNA translated into proinsulin. daily dosing for optimal basal insulin replacement.
A second generation of basal insulin analogues
sequence insulin, which, while similar to native has since appeared, comprising insulin degludec
insulin in amino acid structure, did have signifi- (Tresiba) and Toujeo, a concentrated preparation of
cant variability in absorption after subcutaneous insulin glargine. Both of these insulins have effec-
injection. This is due to the natural properties of tive actions greater than 24 hours and, as a result,
32 Treatment of type 1 diabetes mellitus

Figure 3.5 Almost all conventional insulin treatment is provided by the use of insulin ‘pens’. These
were first introduced in the mid-1980s and include fully disposable devices such as the Lilly Kwikpen®
and Novo Nordisk ‘Flexpen®’ (a) and reusable robust devices that take 3 ml pre-filled insulin car-
tridges such as the Lilly Humapen® and Novo Nordisk Novopen® (b). Recently, new ‘smart’ insulin
pens have been introduced that record data on insulin dose administration with the potential to link
via Bluetooth technology to diabetes management apps.

Figure 3.7 Insulin injection technique: The

modern practice is to insert the needle vertically
into the subcutaneous tissue. Needles of 8 mm
in length are used with a pinch-up technique
except in obese patients, in whom the standard
12 mm needle should be used. When insulin is
Figure 3.6 Usual sites of insulin administration being injected without pinch-up into the arms,
are the outer thighs, buttocks, upper arms and 6 mm needles are recommended. It is no longer
abdomen, and should be rotated within each considered necessary to swab the skin with
anatomic area as injection into exactly the same alcohol or to withdraw the skin plunger to check
site may cause lipohypertrophy), which may for blood. Care must be taken in thin patients to
hinder insulin absorption. Insulin absorption may avoid intramuscular injection as this will result in
vary from one site to another. more rapid absorption of insulin.
 Dietary management and patient education 33

in a more formalised approach to adjustment of

insulin for carbohydrates and this approach was
developed and refined in Dusseldorf, Germany, as
the basis for a five-day residential structured edu-
cation programme in which patients were taught
the basic principles of insulin adjustment based
on ratios of insulin to carbohydrate. Audit data
from this programme showed very good attain-
ment of HbA1C targets but with less hypoglycaemia
than seen for similar levels of glycaemic control in

Figure 3.8 Physiologic plasma insulin and glucose

profiles: In non-diabetic subjects, basal fasting
insulin secretion is very low and suppresses hepatic
glucose production, but meal ingestion results in a
rapid increase in insulin secretion (shown here). This
tight regulation keeps plasma glucose concentra-
tions within a narrow range of about 3.5–7.5 mmol/l
(63–135 mg/dl). It is this pattern which exogenous
insulin therapy attempts to emulate.

provide very stable insulin concentrations when

given in once-daily dosing. In the case of Tresiba,
this is achieved as the insulin aggregates into long
polymeric chains in the subcutaneous space with
slow dissociation to release insulin monomers. In
the case of Toujeo, insulin glargine is standardised
to 300 u/ml rather than the more usual 100 units/
ml, and the increased concentration results in lower
solubility and slower absorption into the circula-
tion. Both Toujeo and Tresiba have been shown to
be associated with less hypoglycaemia in clinical
trials when compared to the first-generation insulin
analogues (Figures 3.8–3.11).

DIETARY MANAGEMENT AND

PATIENT EDUCATION
Figure 3.9 Insulin lipoatrophy manifests as
There has been little consensus over time on opti- depressed areas of skin owing to underlying fat
mal dietary advice for patients with T1DM. General atrophy. This was common before the advent
principles have been to maintain a moderate of purified porcine and, more especially, human
insulin. Several rare syndromes of lipoatrophy
restriction in carbohydrates and a low-fat content
associated with diabetes have been described
in the diet. In the DCCT, only broad dietary advice and are characterized by insulin-resistant diabe-
was provided but it was noted that the regularity of tes and absence of subcutaneous adipose tissue,
the diet and some adjustment of insulin for carbo- either generalized or partial. These syndromes
hydrates were associated with better outcomes. At constitute a heterogeneous group, some of which
the same time in Europe, interest was developing are congenital and others of which are acquired.
34 Treatment of type 1 diabetes mellitus

Figure 3.11 This patient has areas of lipohyper-

trophy on both elbows. This is a highly unusual
site to encounter lipid hypertrophy and a highly
unusual site for insulin injection. His glycemic
control, as a consequence, was very unstable
but improved when he was persuaded to inject
elsewhere on a rotational basis.

measures other than general advice on healthy

eating. Participants are taught to adjust mealtime
insulin on a meal-by-meal basis using a ratio of
insulin to carbohydrate portions (1 portion being
10 g) and to adjust basal insulin replacement
according to overall glucose patterns observed
over time. In a randomised controlled trial, the
DAFNE programme was shown to be associated
with improved HbA1C and perceived quality of life,
and this has since been confirmed in real-world
audit data collected at scale across the UK with
Figure 3.10 This patient has both insulin lipid additional evidence being observed of a reduc-
hypertrophy and lipoatrophy. The lipid hyper- tion in severe hypoglycaemia and improvement
trophy is seen in the lateral thigh and buttock in hypoglycaemia awareness. On the basis of these
regions where insulin has been injected. If the results, DAFNE and similar-structured education
same injection site is used over many years, a soft programmes have been made a standard of care for
fatty dermal nodule, often of considerable size, type 1 management in national guidelines and var-
develops, possibly owing to the lipogenic action ious tools including carbohydrate tables and apps
of insulin. Patients should be discouraged from
have been developed to support self-management.
using such sites as variation in insulin absorption
may occur, leading to erratic control.
GLUCOSE MONITORING
the DCCT. In the UK, the Dusseldorf model was A limiting factor in the management of T1DM has
adapted to form the basis of the Dose Adjustment been the need for frequent blood glucose monitor-
for Normal Eating (DAFNE)-structured education ing with many patients needing to test glucose more
programme, and this and similar programmes than eight times a day to achieve optimal glucose
have now formed the basis of T1DM self-manage- control. The challenges of performing large num-
ment education. DAFNE advocates adjustment of bers of finger-prick blood tests have meant that
insulin for a ‘normal’ diet and imposes no specific many patients found the practice difficult to sus-
advice on carbohydrate intake or other dietary tain. In recent years, the widespread deployment
 Insulin pump treatment and closed-loop insulin delivery 35

of subcutaneous continuous glucose monitor-

ing systems has transformed the lives of people
with diabetes, reducing the burden of testing and
improving outcomes. These systems are based pri-
marily on the use of the glucose oxidase reaction to
measure glucose in subcutaneous fluid via a subcu-
taneous filament. Glucose data are updated every
5 minutes and transmitted to a smartphone or
dedicated monitoring device either intermittently
using near-field connection technology (described
as ‘Flash’ glucose monitoring) or continuously via
a Bluetooth connection.
The use of either intermittently scanned or con-
tinuous glucose monitoring has now been endorsed
as the standard of care for T1DM patients by NICE Figure 3.12 Traditional blood glucose self-mon-
in the UK, by the American Diabetes Association itoring based on the glucose oxidase reaction
and in many other management guidelines. This creating an electrical current proportional to its
glucose concentration. Frequent self-monitoring
follows demonstration of efficacy in clinical tri-
has now been superseded by the widespread use
als and particularly in large-scale real-world data of continuous glucose monitoring systems, but
reviews. Of particular note, the UK ABCD audit is still required to confirm an abnormal glucose
of the use of the Abbott Freestyle Libre, the first and, in some countries, to comply with legal
‘Flash’ monitoring system, included data on more requirements for driving.
than 10,000 people living with diabetes who
started using the Freestyle Libre. For patients with
more than 7 months of available data, there was a of glucose data over a standardised 24 hours along-
significant reduction in HbA1C from 67.5 mmol/l side data on time in range, with an accepted stan-
to 62.3 mmol/l (8.3% to 7.9%) and a more marked dard definition of time in range of 3.9–10 mmol/l
reduction among those who had higher HbA1C at for this purpose. Continuous glucose data can also
entry. In addition, significant reductions were seen be used to estimate HbA1C with the term ‘glucose
in hypoglycaemia frequency and hospital atten- management indicator’ being used for this pur-
dance for hypoglycaemia or ketoacidosis. pose. Where data are available for greater than 60
Continuous glucose sensing technology con- days, the calculated glucose management indicator
tinues to develop with increasing accuracy, longer is closely correlated to the laboratory HbA1C and is
duration of individual sensor life and the avail- increasingly used as a measure of control in clini-
ability of sensors that do not require calibration cal practice (Figures 3.12–3.16).
by blood glucose measurements. While most
systems used in the management of T1DM are INSULIN PUMP TREATMENT AND
based on a subcutaneous filament, a transcuta- CLOSED-LOOP INSULIN DELIVERY
neous needle-free system (My Sugar Watch) has
recently been launched. This device can record Insulin pumps were first introduced in the 1980s to
glucose for up to 14 hours and may offer an alter- enable continuous subcutaneous insulin infusion
native for patients who have had recurrent issues (CSII), but early experience was variable and was
with placement of the more conventional sensors hampered by the limitations of the technology avail-
and those where intermittent glucose monitoring able at the time. A particular issue in early pump
to guide insulin titration may be sufficient to sup- experience was an increased risk of diabetic ketoaci-
port diabetes management. dosis due to failure of subcutaneous insulin delivery;
With the rise in continuous glucose monitor- this is a greater risk for pump users as there is no sub-
ing, a need has arisen for standardised presenta- cutaneous buffer of insulin to enter the circulation
tion of continuous glucose data, and this has been if delivery fails. Through the 1990s, insulin pumps
fulfilled by the development of the ambulatory evolved with improvements in microelectronics and
glucose profile which shows a statistical summary started to enter mainstream diabetes care.
36 Treatment of type 1 diabetes mellitus

CSII has the advantage over basal bolus insulin

delivery by being able to more closely mimic physi-
ological insulin levels and allow for variation in
basal insulin delivery rates over the course of the
day to match diurnal variations in insulin sensitiv-
ity and the effects of exercise. Bolus doses can be
precisely matched to carbohydrates and the timing
of bolus insulin delivery can be adjusted for differ-
ent types of meals and to allow for delayed gastric
emptying in patients with autonomic dysfunction
and gastroparesis.
These advantages have translated into better
overall blood glucose control and a reduction in
hypoglycaemia burden, including a reduction in
severe hypoglycaemia. With the advent of glucose
sensor technology, closed-loop insulin pump sys-
tems have been developed that modulate insulin
delivery based on changes in glucose. While still
requiring input of carbohydrate data to optimise
Figure 3.13 The MiniMed continuous glucose mealtime insulin delivery, these systems can
monitoring system was the first widely available
system to monitor glucose levels in interstitial
fluid. In this system, the sensor is inserted under
the skin of the anterior abdominal wall and inter-
stitial glucose levels are sensed every 10 sec-
onds and averaged over 5 minutes. The original
glucose sensors lasted a maximum of 3 days and
required calibration on the basis of four or more
capillary glucose readings each day.

  

Figure 3.14 The Freestyle Libre 2 flash glucose monitoring system comprises a small glucose sen-
sor with a subcutaneous filament placed on the arm and measures interstitial fluid glucose for up to
14 days (a). In contrast to earlier continuous glucose monitoring systems, the Libre 2 system does not
provide a continuous display of glucose data but blood glucose is measured when desired by ‘scan-
ning’ the sensor with a reader device or with a smartphone equipped with near-field connectivity (b).
The relative simplicity and lower cost of the Libre has allowed for very wide uptake and transforma-
tion in monitoring in type 1 diabetes such that the use of continuous monitoring is now accepted as
the standard of care for type 1 diabetes in the UK.
 Psychological aspects of type 1 diabetes management 37

Figure 3.17 Two examples of current insulin

pumps; the Medtronic 780 G, a conventional
tubed pump, and the Omnipod tubeless insulin
delivery system. The Omnipod has a smaller
form factor and the infusion site is directly in line
with the body of the pump and is controlled by a
Figure 3.15 The MySugarWatch® glucose sensor separate handheld controller. The Medtronic 780
system is the first marketed needle free con- G delivers insulin through a length of tubing and
tinuous glucose monitor. The sensor comprises cannula and the controller is integral to the body
a hydrocolloid patch placed over an area of of the pump.
prepared skin on the arm and provides continu-
ous glucose data for up to 14 hours. This may
provide a simpler solution for glucose monitoring minimise glucose excursions and enable remark-
for those who do not wish to use a sensor on a ably tight blood glucose control with very low risks
continuous basis and for intermittent use to sup-
of hypoglycaemia (Figures 3.17–3.19).
port insulin titration in type 2 diabetes.

PSYCHOLOGICAL ASPECTS
OF TYPE 1 DIABETES
MANAGEMENT
Despite the advances in medical management
that have occurred over recent years, many peo-
ple with T1DM still struggle to maintain optimal
diabetes control and the complexity of manage-
ment can in itself create a significant psychologi-
cal burden. There is increasing recognition of the
psychological impact of diabetes and a specific
concept of ‘diabetes distress’ has emerged, reflect-
ing feelings of being overwhelmed or failing with
Figure 3.16 With the increased use of wearable diabetes management. Furthermore, a state of
technology in type 1 diabetes, there has emerged ‘diabetes burnout’ has been identified which can
a small subset of patients who experience sig-
make it hard for an individual to sustain the high
nificant skin reactions to adhesive used to hold
sensors and pump cannulae in place. Here, there
level of self-motivation needed for optimal self-
is marked erythema at the site of a Freestyle Libre management. Incorporating consideration of the
sensor that persisted for more than 48 hours after psychological impact of diabetes care into routine
removal. Although rare, such reactions can limit clinical management is now being recognised as a
the use of technology for some individuals. core element of service provision and consultation
38 Treatment of type 1 diabetes mellitus

Figure 3.18 The ambulatory glucose profile has been developed as a standard way of summarising
data over time from continuous glucose monitoring (CGM) systems and is now used across many
platforms. The dark blue line shows the median glucose and this is superimposed on a representa-
tion of the interquartile range for glucose. In this case based on continuous data collected over
60 days, there is a pattern of high glucose excursions after breakfast despite otherwise good
overall glucose control.

Figure 3.19 With the advent of closed-loop technology, it has proved possible to obtain
very consistent blood glucose control with minimal prandial variation and absence of
hypoglycaemia as seen in this ambulatory glucose profile trace from a patient using a
closed-loop system.

tools that include consideration of diabetes distress diabetes care, the development of effective man-
and other patient-reported outcome and experi- agement pathways to manage the psychological
ence measures have been developed, with evidence demands of diabetes will be essential to achieve
that their deployment is associated with improve- optimal outcomes and help avoid the morbidity
ments in both psychological well-being and glycae- that can be associated with suboptimally managed
mic control. With the ever-growing complexity of T1DM (Figure 3.20).
 Psychological aspects of type 1 diabetes management 39

Figure 3.20 With the increased recognition of the impact of psychological factors in diabetes, care
tools have been advised to provide simple feedback on a patient’s control across various dimensions
of care and experience. This type 1 diabetes consultation tool was devised by the SE London Health
Innovation Network and presents data on hypoglycaemia awareness, diabetes distress and glycaemic
control on a ‘dart board’ diagram. Use of the tool has been shown to be associated with improved
patient satisfaction in consultation and an improvement in distress and HbA1C on follow up.
(From Todd PJ, Edwards F, Spratling L, et al. Evaluating the relationships of hypoglycaemia and
HbA1C with screening-detected diabetes distress in type 1 diabetes. Endocrinol Diab Metab.
2018; 1:e3. https://doi.org/10.1002/edm2.3.)

BIBLIOGRAPHY adjustment for normal eating (DAFNE) ran-

domised controlled trial. BMJ 2002; 325. doi:
Bode BW, Steed RD, Davidson PC. Reduction https://doi.org/10.1136/bmj.325.7367.746
in severe hypoglycemia with long-term DeVries JH, Snoek FJ, Heine RJ. Persistent poor
continuous subcutaneous insulin infusion in glycaemic control in adult type 1 diabetes.
type I diabetes. Diabetes Care. 1996; 19(4): A closer look at the problem. Diabetic Med.
324–7. doi: 10.2337/diacare.19.4.324 2004; 21: 1263–8
Da Silva J, et al. Real-world performance of the Hopkins D, Lawrence I, Mansell P, et al. Improved
MiniMed™ 780G system: First report of biomedical and psychological outcomes
outcomes from 4120 users. Diabetes Technol 1 year after structured education in flexible
Ther. 2021. doi: 10.1089/dia.2021.0203 insulin therapy for people with type 1 diabe-
DAFNE study group. Training in flexible, inten- tes: The U.K. DAFNE experience. Diabetes
sive insulin management to enable dietary Care. 2012 Aug; 35(8):1638–42. doi: 10.2337/
freedom in people with type 1 diabetes: Dose dc11-1579
40 Treatment of type 1 diabetes mellitus

Khan A, Choudhary P. Investigating the asso- National Institute for Health and Care Excellence.
ciation between diabetes distress and Type 1 diabetes in adults: diagnosis and
self-management behaviors. J Diabetes management. Evidence reviews for long
Sci Technol. 2018 Nov; 12(6): 1116–24. acting insulins in type 1 diabetes. Published
doi: 10.1177/1932296818789721 online https://www.nice.org.uk/guidance/
Leelarathna L, Little SA, Walkinshaw E, et al. ng17/evidence/a-longacting-insulins-in-type-
Restoration of self-awareness of hypoglyce- 1-diabetes-pdf-9196139918
mia in adults with long-standing type 1 dia- NHS Digital. National Diabetes Audit 2020–21,
betes: Hyperinsulinemic-hypoglycemic clamp England & Wales. Published online 16th June
substudy results from the HypoCOMPaSS 2022 at https://files.digital.nhs.uk/56/9D4E2F/
trial. Diabetes Care. 2013 Dec; 36(12): NDA%202020-21%20Type%201%20
4063–70. doi: 10.2337/dc13-1004 Diabetes%20Report.pdf
Mühlhauser I, Jörgens V, Berger M, et al. Russell-Jones D, Gall MA, Niemeyer M, et al.
Bicentric evaluation of a teaching and treat- Insulin degludec results in lower rates of
ment programme for type 1 (insulin-depen- nocturnal hypoglycaemia and fasting plasma
dent) diabetic patients: Improvement of glucose vs. insulin glargine: A meta-analysis
metabolic control and other measures of dia- of seven clinical trials. Nutr Metab Cardiovasc
betes care for up to 22 months. Diabetologia. Dis. 2015 Oct; 25(10): 898–905. doi: 10.1016/j.
1983 Dec; 25(6): 470–6. doi: 10.1007/ numecd.2015.06.005
BF00284453 The Diabetes Control and Complications
Nathan DM. Realising the long-term promise Trial Research Group. Progression of long-
of insulin therapy: The DCCT/EDIC study. term complications in insulin-dependent
Diabetologia. 2021; 64: 1049–58. https://doi. diabetes mellitus. N Engl J Med 1993;
org/10.1007/s00125-021-05397-4 329: 977–86. doi: 10.1056/
NEJM199309303291401
 4
Treatment of type 2 diabetes mellitus

In the early years of insulin management of diabetes, Diabetes Study (UKPDS) study in 1998. This large,
it was recognised that there was a subset of patients long-term intervention study recruited a cohort of
who had less severe metabolic derangement and more than 5000 people with T2DM from the point
who could be managed by dietary measures without of diagnosis with randomisation to standard con-
insulin, particularly with weight loss. These indi- trol based on symptomatic management of diabe-
viduals generally developed diabetes at an older age tes versus a regime of ‘tight blood glucose control’
and, thus, the term ‘maturity onset diabetes’ became based on achieving near normal glucose levels. In
prevalent. Studies performed in the late 1940s and a substudy, 1148 patients were also randomised
early 1950s using insulin bioassays showed that these into ‘tight’ versus standard blood pressure control
individuals had preserved circulating insulin, albeit groups. Given the limitations of glucose medica-
at a lower level than in healthy control subjects. Out tion at the time of onset of the study, management
of this work, the concept emerged that this type of was based first on sulphonylurea for the majority
diabetes was due to insulin resistance and a relevant of patients and on metformin for a subset of those
impairment in insulin secretion in contrast to the who were overweight at recruitment.
absolute insulin deficiency of the classical syndrome After a median of 10 years of follow-up, there
of what we now consider as type 1 diabetes mellitus was a 0.9% difference in HbA1C between the two
(T1DM). This syndrome was variously described as groups (7.0% for the intensive arm and 7.9% for the
‘maturity onset diabetes’ and ‘non-insulin depen- conventional arm). This difference was associated
dent diabetes’ until standardised terminology was with significantly lower rates of development and
adopted following a World Health Organization progression of microvascular disease in the inten-
(WHO) consensus report in 1999, when the current sive management arm with a risk reduction of
classifications of T1DM and type 2 diabetes mellitus microvascular endpoints of 25% and a non-signifi-
(T2DM) were adopted. cant trend to lower cardiovascular events. In those
Historically, what we now call T2DM was con- starting with metformin as a first-line treatment,
sidered to be a less-severe form of diabetes than the overall risk reduction was greater. In the blood
T1DM on the basis that acute metabolic decompen- pressure substudy, a difference in attained BP of
sation was rare. Many patients were treated only on 12/7 mmHg (142/82 mmHg versus 154/87 mmHg
the basis of avoiding osmotic symptoms associated over a median of 8.4 years) achieved with the use
with marked hyperglycaemia. However, epidemio- of ACE inhibitors or beta blockers reduced the risk
logical data emerged to show that far from being a of both microvascular and macrovascular disease.
mild disease, T2DM was associated with significant Following the completion of the randomised
morbidity and mortality and with a similar range UKPDS study, participants continued to be fol-
of diabetes complications to those seen in T1DM. lowed for a further 10 years. During this time, the
This led to studies being carried out to assess difference in blood glucose control between the
the impact of glucose control on diabetes compli- two arms was lost with intensification of manage-
cations and conclusive evidence of this came with ment in the control subjects. However, the separa-
the publication of the United Kingdom Prospective tion between the two groups in outcomes persisted

DOI: 10.1201/9781003342700-4 41
42 Treatment of type 2 diabetes mellitus

with a 24% reduction in microvascular endpoints. in the early years after diagnosis. This was the
In addition, significant relative risk reductions approach of the DIRECT study which used an 800
emerged for myocardial infarction (15%) and all- kCal meal-replacement programme followed by a
cause mortality (12%). These results indicated a ‘leg- gradual reintroduction of a normal diet, with the
acy effect’ of early, tight blood glucose control that aim of achieving and sustaining a 15 kg weight
persisted for many years. A similar legacy effect was loss. In an initial cluster randomised study of the
also seen in other, smaller outcome studies, but, in intervention, a mean weight reduction of 10 kg was
contrast, studies of intensification of control later in observed and 46% of participants achieved remis-
the course of diabetes have shown less benefit and, sion of diabetes, with greater rates of remission
in one case, an increase in cardiovascular events. among those with the greatest achieved weight loss.
These results had a profound impact on the devel- In most clinical services, dietary self-man-
opment of T2DM management in the early years agement guidance is provided as part of a struc-
of the 20th century, aided by the appearance of an tured education programme such as the Diabetes
extended range of drugs for the management of Education and Self -Management for Ongoing
T2DM. Current guidelines now recommend aim- and Newly Diagnosed diabetes (DESMOND) pro-
ing for near normoglycaemia following diagnosis, gramme which aims to provide general advice on
with an ideal target HbA1C of 48 mmol/mol (6.5%) for living with diabetes and support the development
patients on drugs with a low risk of hypoglycaemia of self-efficacy. In randomised studies, this and
and of 53 mmol/mol (7.0%) for those on other agents. similar interventions were shown to be associated
with greater weight loss and greater understand-
DIETARY TREATMENT FOR T2DM ing of diabetes, but in contrast to programmes in
T1DM, observed impact on HbA1C has been lim-
Although the majority of people with T2DM will ited, reflecting the difficulty sustaining control in
begin pharmacotherapy early after the diagnosis of T2DM without achieving significant weight loss or
diabetes, diet remains a pivotal aspect of manage- the introduction of pharmacotherapy.
ment. Over 80% of people with T2DM are over-
weight or obese at diagnosis, and targeting weight DRUG TREATMENT FOR T2DM
loss should be a key aspect of dietary management.
In a recent review of the literature, weight loss of Oral alternatives to insulin for the management
approximately 5% of body weight was required to of T2DM first emerged with the introduction
achieve a significant effect on blood glucose con- of sulphonylureas and metformin in the 1950s.
trol and this was associated with a 7 mmol/mol fall These remained the mainstay of diabetes manage-
in HbA1C in patients with established diabetes and ment until the 1990s when rapid advances in the
up to 13 mmol/mol reduction in those with newly understanding of T2DM led to the appearance of a
diagnosed diabetes. Furthermore, patients who range of new medications with novel mechanisms
succeeded with weight loss were more likely to sus- of action. The past 20 years have seen progressive
tain target HbA1C over a longer period. improvement in the pharamacotherapy of T2DM,
Simple initial advice for calorie restriction and incorporating learning from large scale clinical
avoidance of sweet foods and drinks can lead to trials of these newer agents (Figure 4.1).
symptomatic improvement and a reduction in
blood glucose levels before any reductions in body SULPHONYLUREAS
weight are detectable, but ongoing support and a
strategic approach to supporting weight manage- The first commercially available sulphonylurea was
ment are required for effective intervention. There launched in 1956, and this class of drugs became
remains little consensus over dietary constitu- the mainstay of diabetes treatment until the start
ency other than for a need for caloric restriction. of the 21st century. Sulphonylureas stimulate insu-
Moderate carbohydrate restriction and an overall lin secretion from the beta cell (β-cell) by binding
reduction in fat (particularly saturates) is generally to and inducing closure of ATP-sensitive potas-
recommended. sium channels that play a key role in the regulation
There is increased interest in more marked of insulin secretion. As a result of their mecha-
dietary measures aiming at achieving higher levels nism of action, sulphonylureas are only effective
of weight loss and remission of diabetes altogether in patients with preserved insulin secretion and,
 Biguanides (metformin) 43

Figure 4.1 A timeline of the introduction of drugs for the treatment of type 2 diabetes.

thus, their effect declines over time as progressive lethal acute metabolic derangement. A sec-
β-cell failure is a characteristic of T2DM. As they ond biguanide, metformin, remained available
stimulate insulin secretion across a wide range of in Europe, but was only approved in the US in
glucose levels, they carry some risk of hypogly- 1994. Metformin lowers plasma glucose primar-
caemia, particularly in situations where the drug ily by inhibiting hepatic glucose production and
and active metabolites may accumulate, such as in increasing the sensitivity of peripheral tissue to
renal failure. There has been a gradual evolution insulin. It does not usually cause hypoglycae-
of sulphonylureas with older agents (chlorprop- mia but, as it is renally excreted, it can accumu-
amide and glibenclamide) having a long duration late and its use is relatively contraindicated in
of action and predominant renal excretion, result- patients with renal and hepatic impairment due
ing in a greater hypoglycaemia risk. Newer agents to an associated risk of lactic acidosis. It is weight
such as glimepiride and gliclazide are predomi- neutral and on this basis was used as a first-line
natly metabolised in the liver and are associated treatment in a subgroup of overweight patients in
with less hypoglycaemia. the UKPDS study. The overall results in terms of
While there is a strong evidence base for the risk reduction in this group were slightly better
efficacy of the sulphonylureas (which were a first- than for those starting with sulphonylurea and,
line treatment for the majority of patients in the as a result, metformin has become a mainstay of
UKPDS), their use is declining due to their asso- diabetes management, remaining as the first-line
ciation with weight gain and hypoglycaemia and oral agent for the majority of patients.
the lack of specific cardiovascular benefits in com- Gastrointestinal side-effects are common,
parison to newer agents. including bloating, dyspepsia and altered taste.
These effects are dose dependent and can generally
BIGUANIDES (METFORMIN) be minimized by gradual dose titration. To mini-
mize the occurrence of side-effects, patients should
The first biguanide phenformin entered clini- start on a low dose. Weight gain is usually not a
cal use in 1958, but was later withdrawn due to problem with metformin, possibly because it has a
an association with lactic acidosis, a potentially slight anorectic effect.
44 Treatment of type 2 diabetes mellitus

α-GLUCOSIDASE INHIBITORS with marked insulin resistance and, at the time of

their initial launch, there was considerable inter-
These drugs, which include acarbose (Glucobay®, est in their potential to influence cardiovascular
Bayer) were introduced in the mid-1990s and have outcomes due to an apparently favourable effect on
been widely used as a first-line treatment in some lipids and other potential risk markers.
countries. They delay the absorption of complex However, the promise of these agents was not
carbohydrates from the gastrointestinal tract and borne out in clinical practice. The first agent to
are of value in controlling postprandial hyper- reach market, Troglitazone, was found to have sig-
glycaemia; however, their blood glucose lowering nificant hepatoxicity in some users and was rapidly
effect is modest and lower than those of metformin withdrawn. Two other agents, Rosiglitazone and
or the sulphonylureas, and the side-effects of flatu- Pioglitazone, were widely used in the early 2000s,
lence and diarrhoea often limit their tolerability. but Rosiglitazone was later withdrawn from the
As a result, their use has declined with the emer- market after concerns of a possible data signal of
gence of newer agents. increased cardiovascular mortality. Pioglitazone
remains available, but its use has declined. While
MEGLITINIDES an effective drug for lowering blood glucose, its
use is associated with weight gain and fluid reten-
This class of agents comprises two drugs, repa- tion, which can exacerbate heart failure in some
glinide and nateglinide. They were first introduced patients. A study designed to determine if piogli-
in the late 1990s and are similar in their action to tazone had cardiovascular benefit over other avail-
sulphonylureas, acting via closure of K-ATP chan- able drugs (PROACTIVE) was inconclusive, with
nels in the β-cells, although their receptor-binding no benefit seen in the prespecified composite pri-
characteristics are different. Compared to sulpho- mary endpoint, though some secondary endpoint
nylureas, their effect on insulin is short lived and is data did suggest possible benefits.
dependent on the concentration of glucose. Thus,
taken before meals, they restore towards normal INCRETIN-BASED TREATMENTS
the impaired insulin response to meals seen in
T2DM, with a lower overall risk of hypoglycae- The first major advance in treatment of T2DM in
mia than seen with sulphonylureas. However, as a the 21st century was the launch of incretin-based
result of their short duration of action, they need therapies, firstly with the glucagon-like peptide-1
to be taken with each meal to be effective. While (GLP-1) agonist drug exenatide in 2005 and the
they offer an alternative to sulphonylureas, for first dipeptidyl peptidase-4 (DPP-IV) inhibitor
some patients, their use has been limited and has sitagliptin in 2006. The development of these drugs
declined with the arrival of newer agents. resulted from the identification of incretins, gut-
derived peptides that enhance glucose-mediated
THIAZOLINEIDIONES (GLITAZONES) insulin secretion and have a range of additional
effects, notably slowing of gastric emptying that
These drugs work by activating the nuclear recep- enhances postprandial glucose control. The two
tor peroxisome proliferator-activated receptor- major incretins are GLP-1 and gastric inhibitory
gamma (PPARγ), which is found predominantly in polypeptide (GIP). GLP-1 was the initial target of
adipose tissue, but also in skeletal muscle and liver. pharmacological research, as GLP-1 levels are low in
This leads to the upregulation of expression of T2DM and early studies demonstrated that GLP-1
several proteins in the insulin signalling pathway, infusion was effective at stimulating insulin secre-
effectively sensitizing target tissues to insulin and tion and lowering glucose. However, native human
resulting in a reduction of hepatic glucose produc- GLP-1 has a plasma half-life of less than 5 minutes,
tion and an increase in peripheral glucose uptake. limiting its therapeutic potential and leading to
Thiazolidinediones act to increase fatty-acid the need to develop stable agonists. Two principal
uptake into adipocytes, thus, lowering triglyceride groups of injectable GLP-1 agonist drugs have now
and non-esterified fatty-acid levels which also con- been developed based on Exendin, a more stable
tribute to the favourable effects of the drugs on glu- lizard-derived GLP-1-like molecule (e.g. exena-
cose metabolism outlined previously. These agents tide and lixisenatide) and based on modification
can be very effective at lowering glucose in patients of the sequence of human GLP-1 (e.g. liraglutide,
 Incretin-based treatments 45

semaglutide and dulaglutide) to enhance protein- generation GLP-1 agonists (semaglutide, dulaglutide
binding in the circulation from degradation. and extended release exenatide) have been developed
A second therapeutic approach has been the that allow the convenience of once daily administra-
development of inhibitors of DPP-IV, a ubiquitous tion, reducing the treatment burden associated with
protease enzyme that is primarily responsible for injectable treatments.
the degradation of circulating native GLP-1. A series The DPP-IV inhibitors are less potent than
of potent DPP-IV inhibitors have now been devel- GLP-1 agonists, reflecting the fact that they elevate
oped which indirectly stimulate insulin secretion by circulating GLP-1 levels to high physiological con-
potentiating the levels of circulating GLP-1. centrations compared to the supraphysiological
The GLP-1 agonists are potent glucose-lowering effect of the agonist drugs. They are effective at
agents that also have a significant impact on weight; lowering blood glucose and carry a lower risk of
indeed, several agents in the class are now licensed for hypoglycaemia than sulphonylureas, but do not
the treatment of obesity outside of the context of dia- have any significant effect on weight. They are
betes management. As their primary glucose-lower- increasingly used in place of sulphonylureas in the
ing effect is through stimulation of insulin secretion, oral treatment of T2DM.
they rely on the presence of residual β-cell function A new development in the incretin field is the
and become less effective late in the course of diabetes launch of the first dual incretin agonist, tirzepa-
when β-cell failure has become prominent. In contrast tide, which entered clinical practice in the US in
to sulphonylureas, their effect on insulin secretion late 2022. Tirzepatide has actions at both the GLP-1
is glucose dependent and attenuated at low glucose and GIP receptor and, in clinical trials, was shown
concentrations. As a result, they are associated with to have very high potency in glucose lowering and
a low risk of hypoglycaemia compared to sulphonyl- particularly in supporting weight loss. It is likely to
ureas and insulin. While the original GLP-1 drugs assume a major role in the management of T2DM,
required once or twice daily administration, second particularly in obese subjects (Figure 4.2).

Figure 4.2 Actions of GLP-1 receptor agonists relevant to glucose homeostasis. The primary action of
GLP-1 is to promote glucose-dependent insulin secretion in pancreatic β-cells. In addition, GLP-1 RA
treatment is associated with a slowing of gastric emptying and a reduction in glucagon secretion from
pancreatic alpha cells. This results in a reduction in peak postprandial glucose absorption and hepatic
glucose output, which, together with the increase in insulin secretion, leads to a reduction in post-
prandial hyperglycaemia. In addition to the effect on gastric emptying, GLP-1 RA has direct but as yet
not fully elucidated effects on appetite control in the central nervous system and the promotion of
satiety is a major contributor to the weight loss observed following GLP-1 RA treatment.
46 Treatment of type 2 diabetes mellitus

SGLT-2 INHIBITORS be highly effective at lowering blood glucose and to

be generally weight tolerant. In addition, they were
The first SGLT-2 (Sodium-Glucose Co-transporter) shown to have multiple additional effects of poten-
inhibitor entered clinical practice at the end of 2013 tial benefit, including lowering blood pressure and
and, since then, this class of drugs has become a reducing proteinuria in patients with established
mainstay of T2DM treatment, with three agents diabetic kidney disease. There are some potential
(canagliflozin, dapagliflozin and empagliflozin) in adverse effects; the high urinary glucose load pre-
widespread use. The principle behind their action disposes to genito-urinary infection, particularly
is that glucose is filtered freely in the glomerulus of genital candidiasis, and this can be a limiting fac-
the kidney, but most of the filtered glucose is reab- tor for some patients. In addition, in patients with
sorbed from the renal tubular system by sodium- significant insulin deficiency, SGLT-2 treatment
glucose co-transporters. There are two principal can predispose to the development of ketoacidosis
types of transporter in the kidney—SGLT-1 and and a specific phenomenon of ketoacidosis occur-
SGLT-2—with the latter present primarily in the ring without marked elevation of glucose (eug-
proximal tubule and being responsible for reab- lycaemic ketoacidosis). For this reason, ketone
sorption of approximately 90% of the filtered glu- monitoring should be considered for patients who
cose. Inhibition of SGLT-2 results in significant are also on insulin treatment and SGLT-2 inhibi-
renal glucose excretion with a concomitant reduc- tors should be stopped during intercurrent illness
tion on blood glucose and potential for weight loss. that may predispose to metabolic decompensation
In clinical trials, SGLT-2 inhibitors were found to (Figure 4.3).

Figure 4.3 Role of SGLT-1 and -2 in renal glucose handling. Glucose is filtered freely in the glomerulus
but in health is completely reabsorbed, resulting in minimal renal glucose loss. Reabsorption is medi-
ated in conjunction with reabsorption of sodium by sodium glucose co-transporters (SGLTs) with around
90% of the reabsorption being mediated by SGLT-2 in the proximal tubule. The remaining 10% is then
reabsorbed more distally in the tubule by the SGLT-1-mediated transport. In healthy individuals, about
160–180 g of glucose are filtered over a 24 h period. With SGLT-2 inhibition, there is a marked reduction
of glucose reabsorption, resulting in about 60–80 g of glucose excretion per day.
 Treatment strategies and guidelines 47

INSULIN US Food and Drug Administration for approval

of all new glucose-lowering medications, and this
If glycaemic control is not sustained despite opti- led to the development of very large-scale out-
mal oral drug treatment or GLP-1 agonist treat- come studies which were designed to show non-
ment, insulin therapy may be indicated. Insulin is inferiority over comparator in cardiovascular
the only effective therapy in T2DM once signifi- safety parameters.
cant β-cell failure has supervened. Oral agents fail The first of these to report positively was
to lower blood glucose levels adequately once the EMPA-REG, a study of empagliflozin, followed
β-cell reserve falls below about 15% of normal. by the Liraglutide Effect and Action in Diabetes:
Approximately half of all T2DM will require Evaluation of Cardiovascular Outcome Results
insulin therapy because of a progressive decline (LEADER) study of the cardiovascular safety of
in β-cell function. Insulin therapy may be associ- liraglutide. In both studies, significant benefits
ated with an increase in weight and increased risk were seen in terms of a reduction in a composite
of hypoglycaemia compared to other treatment cardiovascular endpoint. Since then, additional
regimes, and specific dietary management rein- studies have shown evidence of benefit for other
forcement is needed to minimize weight gain. GLP-1 receptor agonists (dulaglutide and sema-
There are many ways of giving insulin to glutide) and other SGLT-2 inhibitors (dapagliflozin
patients with T2DM and there is no universal con- and canagliflozin). The effects observed have been
sensus on the best way of delivering insulin. There variable between studies, reflecting differences in
is, however, growing evidence for an approach that design but, overall, show clear benefits of these
starts with once daily long-acting insulin with later newer classes of agents over earlier diabetes treat-
introduction of a rapid-acting mealtime insulin, if ments. Additional benefits have been seen with
required. There is also evidence that longer-acting SGLT-2 inhibitors in relation to heart failure and
insulin analogues (e.g. Tresiba [insulin degludec] progression of proteinuria in diabetic nephropathy
and Toujeo [insulin glargine 300 units/ml]) are and have led to these agents being used earlier in
associated with a lower risk of hypoglycaemia and the treatment pathway for T2DM, particularly in
a greater likelihood of achieving glucose-control patients with pre-existing cardiovascular disease
targets without hypoglycaemia. and high overall cardiovascular risk.
There is evidence that using a GLP-1 agonist
in combination with basal insulin replacement TREATMENT STRATEGIES
can be more effective than using basal insulin
AND GUIDELINES
alone, and two preparations combining a basal
insulin analogue and a GLP-1 agonist (Xultophy, The wealth of new information that has appeared
comprising degludec and liraglutide and over recent years has led to a comprehensive
Suliqua, comprising lixisenatide and glargine), review of guidance for the management of T2DM,
have now entered clinical practice and have been with particular emphasis on considering an indi-
shown to provide excellent glucose control with vidual’s cardiovascular risk and requirements for
less weight gain and hypoglycaemia, reflecting weight management in choosing initial and subse-
lower overall insulin dose requirements than for quent drugs.
insulin-only regimes. Metformin remains the first-line treatment
for the majority of patients in whom it is tolerated
CARDIOVASCULAR OUTCOME and in the absence of any contraindications (pri-
STUDIES marily in relation to renal function). However,
for those with high cardiovascular risk, current
A major change in diabetes management has been guidance now recommends the addition of an
the recognition that some of the newer agents have SGLT-2 inhibitor, either simultaneously as joint
advantages in terms of cardiovascular outcomes first-line treatment or immediately after start-
and reduction in mortality that are independent of ing metformin. For obese patients, consider-
their effects on lowering blood glucose. Following ation may be given to early use of GLP-1 agonists
concerns about the safety of rosiglitazone, cardio- (which are now also licenced in the management
vascular outcome studies were mandated by the of prediabetic hyperglycaemia). For those with
48 Treatment of type 2 diabetes mellitus

no specific reason to use either of these agents, be set for a young person with new onset T2DM,
then second-line treatment is at individual dis- whereas a target of 64 mmol/mol (8%) may be
cretion with a choice of any of the established acceptable at an older age. Once set, it is impor-
agents. For many, acquisition cost remains a tant that treatment is promptly escalated when
significant factor in the choice of drug, as the control is sustained above target, as real-world
newer agents are significantly more expensive data analyses have shown that there is a signifi-
than older diabetes treatments; in the UK GLP-1 cant issue with treatment inertia and individual
agonists remain relatively late in the NICE treat- patients often have poor control for many years
ment recommendations compared to other before treatment is escalated.
agents, reflecting their high cost. Furthermore, treatment of hyperglycaemia in
All current guidelines place a strong emphasis T2DM should be considered as only one aspect
on determining an individual glycaemic target of management. T2DM is a multifaceted syn-
based on factors including age and duration of drome with strong associations with hypertension,
diabetes and balancing the benefits of tight gly- hyperlipidaemia and cardiovascular disease, and a
caemic control with risks associated with hypo- comprehensive approach to managing these other
glycaemia, particularly in the elderly. While there risk factors is essential to optimise outcomes. The
is strong evidence that early intensive manage- importance of effective self-management should
ment reduces morbidity, the impact of diabetes is also be given due consideration, as treatment of
related to age at diagnosis with risks of compli- these various risk factors can carry a significant
cations being high in those diagnosed at a young emotional burden which needs to be addressed to
age while those diagnosed in their 70s and older help a person achieve good physical and psycho-
have a much lower risk. Hence, an ideal target logical health despite living with a long-term con-
HbA1C of under 48 or 53 mmol/mol (6.5–7%) may dition (Figures 4.4 and 4.5).

Figure 4.4 A simplified treatment algorithm for management of type 2 diabetes, based on the ADA/
EASD and NICE 2022 guidance. Treatment should be aimed at maintaining a HbA1C target of <53 mmol/
mol (7.0%) or to an individualised target based on a holistic assessment of the individual. A specific
evaluation of cardiovascular risk and the presence or absence of heart failure or other cardiovascular
disease should be made to guide treatment.
 Treatment strategies and guidelines 49

Figure 4.5 The management of type 2 diabetes often results in extensive polypharmacy, which
creates particular challenges in concordance and can create a significant burden for those living
with diabetes. Consideration of the psychological burden and support in self-efficacy are important
aspects of successful management.

BIBLIOGRAPHY https://diabetes-resources-production.s3.eu-
west-1.amazonaws.com/resources-s3/2018-
Bornstein J, Lawrence RD. Plasma insulin in 03/1373_Nutrition%20guidelines_0.pdf
human diabetes mellitus. Br Med J. 1951 Evans M, Morgan AR, Whyte MB, Hanif W, Bain
Dec 29; 2(4747): 1541–4. doi: 10.1136/ SC, Kalra PA, Davies S, Dashora U, Yousef
bmj.2.4747.1541 Z, Patel DC, Strain WD. New therapeutic
Davies MJ, Aroda VR, Collins BS, Gabbay RA, horizons in chronic kidney disease: The
Green J, Maruthur NM, Rosas SE, Del Prato S, role of SGLT2 inhibitors in clinical practice.
Mathieu C, Mingrone G, Rossing P, Tankova T, Drugs. 2022 Feb; 82(2): 97–108. doi: 10.1007/
Tsapas A, Buse JB. Management of hypergly- s40265-021-01655-2
cemia in type 2 diabetes, 2022. A consensus Holman RR, Farmer AJ, Davies MJ, Levy JC,
report by the American Diabetes Association Darbyshire JL, Keenan JF, Paul SK; 4-T Study
(ADA) and the European Association for the Group. Three-year efficacy of complex insulin
Study of Diabetes (EASD). Diabetes Care. regimens in type 2 diabetes. N Engl J Med.
2022 Nov 1; 45(11): 2753–86. doi: 10.2337/ 2009 Oct 29; 361(18): 1736–47. doi: 10.1056/
dci22-0034 NEJMoa0905479
Davies MJ, Heller S, Skinner TC, et al. Karagiannis T, Avgerinos I, Liakos A, et al.
Effectiveness of the diabetes education and Management of type 2 diabetes with the
self management for ongoing and newly dual GIP/GLP-1 receptor agonist tirzepa-
diagnosed (DESMOND) programme for tide: A systematic review and meta-analysis.
people with newly diagnosed type 2 diabe- Diabetologia. 2022 Aug; 65(8): 1251–61.
tes: Cluster randomised controlled trial. BMJ. doi: 10.1007/s00125-022-05715-4
2008 Mar 1; 336(7642): 491–5. doi: 10.1136/ Lean ME, Leslie WS, Barnes AC, et al. Primary
bmj.39474.922025.BE care-led weight management for remis-
Diabetes UK 2018 Nutrition Working Group. sion of type 2 diabetes (DiRECT): An open-
Evidence based nutrition guidelines for label, cluster-randomised trial. Lancet. 2018
the prevention and management of diabetes. Feb 10; 391(10120): 541–51. doi: 10.1016/
Published online March 2018 at S0140-6736(17)33102-1
50 Treatment of type 2 diabetes mellitus

Marso SP, Daniels GH, Brown-Frandsen K, cardiovascular outcomes trials. Postgrad Med
Kristensen P, Mann JF, Nauck MA, Nissen J. 2020 Mar; 96(1133): 156–61. doi: 10.1136/
SE, Pocock S, Poulter NR, Ravn LS, Steinberg postgradmedj-2019-137186
WM, Stockner M, Zinman B, Bergenstal Turner RC. The U.K. Prospective diabetes
RM, Buse JB; LEADER Steering Committee; study. A review. Diabetes Care. 1998
LEADER Trial Investigators. Liraglutide and Dec; 21(Suppl 3): C35–8. doi: 10.2337/
cardiovascular outcomes in type 2 diabetes. diacare.21.3.c35
N Engl J Med. 2016 Jul 28; 375(4): 311–22. Zinman B, Wanner C, Lachin JM, Fitchett D,
doi: 10.1056/NEJMoa1603827 Bluhmki E, Hantel S, Mattheus M,
Nauck MA, Quast DR, Wefers J, Meier JJ. Devins T, Johansen OE, Woerle HJ,
GLP-1 receptor agonists in the treatment Broedl UC, Inzucchi SE; EMPA-REG
of type 2 diabetes - state-of-the-art. Mol OUTCOME Investigators. Empagliflozin,
Metab. 2021 Apr; 46: 101102. doi: 10.1016/j. cardiovascular outcomes, and mortal-
molmet.2020.101102 ity in type 2 diabetes. N Engl J Med. 2015
Sheahan KH, Wahlberg EA, Gilbert MP. An Nov 26; 373(22): 2117–28. doi: 10.1056/
overview of GLP-1 agonists and recent NEJMoa1504720
 5
Treatment of children and adolescents
with diabetes

TYPE 1 DIABETES to take diabetes treatment at school. Historically,

some children with diabetes have been excluded
The importance of effective strategies for the treat- from some sports at school, but the current
ment of diabetes in children and adolescents is philosophy of management is to normalise diabetes
accentuated by the knowledge that time-trend in everyday activities and to avoid any restrictions.
data, for countries where it is available, have dem- In recent years, there has been increased
onstrated a clear increase in incidence of type 1 emphasis on early optimization of blood glucose
diabetes mellitus (T1DM) in these age groups. control, provided this can be achieved without
Such an increase suggests changes in environ- problematic hypoglycaemia. As a result, there has
mental factors, with the larger increase in children been a gradual shift away from pre-mixed insu-
<5 years of age, in early life. lin regimes (which were often used in paediat-
Treatment strategies must incorporate knowl- ric practice in the interest of simplicity) to basal
edge of developmental milestones and the behav- bolus insulin regimes and insulin pump treat-
ioural, physiological, psychological and social ment. In the UK, insulin pump treatment is now
factors that operate in this age group and impact recommended as a primary option for children
so strongly on any chronic disease management under the age of 12 years and for older children
programme in children. Emotional problems are where there is sustained poor glucose control or
common and some studies have suggested that the HbA1C >72 mmol/mol (8.5%). Total daily insulin
onset of diabetes is associated with adjustment dis- requirements in children with T1DM are around
orders, which seemed to confer an increased risk of 0.8 units/kg/24 hours, increasing to 1.0–1.5 units/
psychiatric problems later in life. A recent prospec- kg/24 hours in mid-puberty.
tive study of adolescents with T1DM from Australia The use of continuous glucose monitoring has now
documented the exhibition of a broad range of psy- become the standard of care for T1DM in children
chological morbidity 10 years after disease onset, and young people and has the additional advantage
with females and adolescents with pre-existing psy- in minors that most systems now have the facility for
chological problems being at particular risk. remote monitoring, allowing a parent to maintain
The management of diabetes in young people sight of a child’s blood glucose levels when at school.
needs a comprehensive multidisciplinary approach
comprising the paediatrician, specialist nurse, TYPE 2 DIABETES IN CHILDREN
dietitian and psychologist, with provision for pro- AND YOUNG PEOPLE
gressive transition to adult care, usually starting
at the age of 13 years. Close liaison with schools Early onset type 2 diabetes mellitus (T2DM)
is essential to ensure that appropriate adjustments appearing in children and adolescents started
are in place to enable a pupil to manage diabetes to emerge about 30 years ago as a rare phenom-
effectively and avoid any stigma related to having enon. Since then, the prevalence of this condition

DOI: 10.1201/9781003342700-5 51
52 Treatment of children and adolescents with diabetes

has increased progressively, mirroring a rise in young people; as in adult practice, metformin may
childhood obesity in the developed world. In be considered as a first-line treatment, but there is
the UK, estimates based on data from 2018 sug- a paucity of evidence in relation to other oral treat-
gested that there were about 800 children with ments and many children progress to insulin early
a diagnosis of T2DM and most paediatric dia- in the course of their condition. However, there is
betes services will now cater to several children increased use of GLP-1 receptor agonists and lira-
with this condition. Children with T2DM are glutide has now obtained a specific license for use
more likely to come from socially deprived fam- in the paediatric age group. Given the association
ily backgrounds, reflecting the impact of poverty with obesity, the use of GLP-1 agonists is likely to
and dietary factors in the aetiology of obesity and assume an increasingly important role in the man-
diabetes. In the US, the prevalence of childhood agement of childhood T2DM.
diabetes is higher, with a recent estimated popu-
lation prevalence of 0.67 cases per 1000 children BIBLIOGRAPHY
aged between 10 and 19 years.
The high rates of T2DM appearing in children Mortensen HB, Hougaard P, The Hvidore Study
is of particular concern, as evidence is emerging Group on Childhood Diabetes. Comparison
that the natural history of the disease is worse of metabolic control in a cross-sectional study
than in later onset T2DM, with very high rates of 2873 children and adolescents with IDDM
of early microvascular complications. A large from 18 countries. Diabetes Care. 1997; 20:
study, Treatment Options for Type 2 Diabetes in 714–20
Adolescents and Youth (TODAY), designed to Northam EA, Matthews LK, Anderson PJ, et al.
study the efficacy of treatment for T2DM in young Psychiatric morbidity and health outcome
people has provided considerable insight into the in type 1 diabetes – Perspectives from a
severity of the condition. In the TODAY study, the prospective longitudinal study. Diabet Med.
cumulative incidence of any microvascular com- 2005; 22: 152–7
plication was 50% by 9 years and 80% by 15 years Perng W, Conway R, Mayer-Davis E, Dabelea D.
of T2DM duration. Retinopathy was present in Youth-onset type 2 diabetes: The epidemi-
50% of TODAY participants by age 25 years, with a ology of an awakening epidemic. Diabetes
cumulative incidence of nephropathy of 35%. This Care. 2023 Mar 1; 46(3): 490–99. doi: 10.2337/
compares with a prevalence of microvascular com- dci22-0046
plications of around 25% after 10 years of T1DM. Williams RM, Dunger DB. Insulin treatment in
As yet, there is relatively little specific data to children and adolescents. Acta Paediatr.
guide the management of T2DM in children and 2004; 93: 440–6
 6
Diabetes and surgery: Inpatient
and perioperative diabetes care

About 15% of all people admitted to hospital will procedure. Furthermore, diabetes is associated
have diabetes as a comorbidity but, despite this, with a higher risk of critical-care admission in the
provision for inpatient management of diabetes is postoperative period and higher mortality rates.
often suboptimal, with poor understanding of dia- In part, this reflects the comorbidities associated
betes management by generalist hospital staff and with diabetes, particularly cardiovascular disease
variable provision of specialist support. Over the and nephropathy which may be exacerbated by
past decade, there have been improvements in this surgery. The incidence of perioperative acute kid-
area, with increased recognition of the importance ney injury is higher in patients with diabetes than
of optimising glucose management to improve in the general population and, in some cases, this
outcomes and reduce the length of inpatient stay. may reflect the presence of early and previously
In England, the quality of diabetes inpatient care silent diabetic nephropathy.
has been tracked by an annual National Diabetes Surgery can have a marked effect on blood
Inpatient Audit (NaDIA) conducted since 2010. glucose control and, without adequate manage-
The most recent report based on data from 2019 ment, can lead to acute decompensation of meta-
showed an increase in the proportion of people bolic control. The trauma associated with surgery
with diabetes seen by specialist teams and a reduc- results in an acute stress response, the magnitude
tion in inpatient hypoglycaemia, but drug errors of which depends on the severity of the surgery
(particularly in relation to insulin administration) and the underlying condition, in particular, the
were common and, alarmingly, 3.6% of those with presence of infection at the time of surgery (for
type 1 diabetes mellitus (T1DM) developed ketoac- example in a case of abdominal surgery for a perfo-
idosis during the course of their admission. There rated viscus). As part of the stress response, there is
have been delays implementing improvements in an increase in serum cortisol and catecholamines,
diabetes technology in inpatient care, and many which impact insulin sensitivity and promote
patients report frustration around the lack of sup- hyperglycaemia and ketone production which, if
port for insulin pump treatment and continuous unchecked, can lead to the development of diabetic
glucose monitoring, with many being obliged to ketoacidosis in patients with no or low endogenous
revert to traditional capillary glucose monitoring insulin secretion.
for the duration of their hospital stay.
Diabetes can have a significant impact on the PERIOPERATIVE MANAGEMENT
outcomes of surgical procedures. Recent data
have shown that people with diabetes continue to Factors to consider in the management of diabetic
have a significantly longer hospital stays and more patients are the severity of surgical trauma and
postoperative complications, with an estimated its duration, the pre-existing diabetes treatment
excess length of stay of up to 45% than expected and the extent of the patient’s endogenous insulin
for non-diabetic patients undergoing the same reserves. Patients with T1DM and, for practical

DOI: 10.1201/9781003342700-6 53
54 Diabetes and surgery: inpatient and perioperative diabetes care

purposes, those with type 2 diabetes mellitus SGLT-2 and metformin should only be restarted
(T2DM) treated with insulin, are assumed to have when normal oral fluid and dietary intake is
no endogenous insulin and, will therefore require established. For non-insulin-treated patients,
exogenous insulin administration to cover any glucose infusions should be avoided and blood
surgery. Other patients will only require insulin glucose checked hourly during surgery and the
therapy for major surgery procedures and may be early perioperative phase. In the event of a sus-
able to continue with oral agents alone for more tained glucose rise above the upper target limit of
minor procedures. 12 mmol/l, insulin and glucose substrate solution
Historically, patients with insulin-treated dia- should be started, as detailed later in the chapter,
betes have been admitted to hospital a day or more for patients on insulin treatment. Postoperatively,
before surgery for optimisation and preoperative oral agents may be recommenced at the time of
insulin management. While this may be required the next meal. When glycaemic control is poor or
for some patients with poor glycaemic control or major surgery is planned, it is desirable to admit
where prolonged fasting is required, most patients the patient before the day of operation to opti-
can be admitted on the day of surgery, and diabetes mise blood glucose control with short- or inter-
is no longer considered to be a contraindication to mediate-acting insulins. On the day of surgery,
day case surgical treatment. breakfast is omitted and the surgery covered with
The aim of management of diabetes during sur- intravenous (IV) insulin and glucose (discussed
gery is to maintain stable glucose levels close to later). Postoperatively, subcutaneous insulin is
the normal range, avoiding marked glucose excur- continued until blood glucose levels are stable
sions and, in particular, avoiding hypoglycaemia. when the patient can restart oral therapy.
There is consensus that an appropriate target glu-
cose range is 6–10 mmol/l (108–180 mg/dl), with PATIENTS ON INSULIN THERAPY
acceptance of upwards excursion to 12 mmol/l
(216 mg/dl). Glucose levels much above this should The principle behind insulin management dur-
be avoided, as they may impact wound healing, and ing surgery is to maintain near normoglycaemia
there is some evidence of an association between with avoidance of hypoglycaemia and to maintain
perioperative hyperglycaemia and postoperative normal electrolyte balance. To achieve this, cur-
infection rates. rent guidance recommends the use of a variable-
rate insulin infusion delivered by a syringe driver
PATIENTS ON NON-INSULIN infused alongside a balanced substrate solution
TREATMENT containing both sodium and glucose. This is in
contrast to older regimes which advocated add-
When pre-existing glycaemic control is accept- ing insulin and potassium to infusion bags of 5%
able on oral agents or glucagon-like peptide-1 or 10% glucose, as these regimes do not allow ade-
(GLP-1) agonist treatment and minor surgery is quate adjustment of insulin to maintain optimal
planned, patients can usually be managed safely glucose control, and the use of glucose as the sole
by fasting and the omission of the usual oral substrate risks causing hyponatraemia. The cur-
medication on the day of the procedure. For some rent recommended substrate solution for surgical
drugs, cessation in the days before surgery is management is 0.45% saline with 5% glucose and
desirable. Longer-acting sulphonylureas are best 0.15% to 0.3% potassium chloride (depending on
omitted on the day prior to surgery to reduce the baseline potassium levels). As an alternative, 4%
risk of any residual action and associated hypo- glucose in 0.18% saline and 0.15%/0.3% potassium
glycaemia. SGLT-2 inhibitors should also be dis- chloride is recommended when the former is not
continued to reduce the risk of ketosis associated available. For those patients on long-acting basal
with the use of this class of agents in the presence insulin analogues (e.g. insulin glargine, detemir or
of a stress response, and it is generally recom- degludec), it is recommended that the basal insu-
mended that these are stopped 3 to 4 days before lin is continued pre- and postoperatively, but at a
surgery. For procedures that involve the use of reduced dose calculated as 80% of the usual basal
contrast dye, it is also recommended that metfor- insulin requirement. Continuing the basal insulin
min is discontinued 24 to 48 hours before surgery. facilitates switching back to subcutaneous insulin
 Patients on insulin pump treatment 55

when normal feeding resumes and reduces the an IV insulin and substrate regime may be more
need for higher-dose IV insulin treatment in the appropriate.
perioperative period.
It is recommended that the regime is started BIBLIOGRAPHY
at the time of induction of surgery or at the time
of the first missed meal if there is any prolonga- Dhatariya K, Levy N. Perioperative diabetes care.
tion of preoperative fasting. IV insulin and glucose Clin Med (Lond). 2019 Nov; 19(6): 437–40.
substrate should normally be continued until oral doi: 10.7861/clinmed.2019.0226
intake is resumed. Diabetes Guideline Working Group, Centre
for Perioperative Care. Guideline for
PATIENTS ON INSULIN PUMP Perioperatieve Care for people with Diabetes
TREATMENT Mellitus Undergoing Elective and Emergency
Surgery. Published online March 2021 at:
Patients established on insulin pump treatment can https://www.cpoc.org.uk/sites/cpoc/files/
usually be managed effectively by continuing to use documents/2021-03/CPOC-Guideline for
this during surgery and the perioperative period Perioperative Care for People with Diabetes
to reduce the need for IV insulin, particularly for Mellitus Undergoing Elective and Emergency
more minor procedures. In preparation for surgery, Surgery.pdf
it is desirable to ensure optimisation of basal pump NHS Digital. National Diabetes Inpatient Audit
rates by assessing the response to performing a Report 2019. Published online at https://files.
limited fast a day prior to surgery and determin- digital.nhs.uk/F6/49FA05/NaDIA%202019%
ing that glucose remains stable on basal insulin 20-%20Full%20Report%20v1.1.pdf
in the absence of mealtime boluses. If there is any Partridge H, Perkins B, Mathieu S, et al. Clinical
tendency to a downward drift in glucose, consider- recommendations in the management of
ation should be given to reducing the basal rate to the patient with type 1 diabetes on insulin
around 80% of usual treatment dose. Continuing pump therapy in the perioperative period.
with subcutaneous insulin-pump treatment has Br J Anaesth. 2016: 116, 18–26. https://doi.
the advantage of allowing a more rapid return to org/10.1093/bja/aev347
usual treatment than switching to an IV regime. Sudhakaran S, Surani SR. Guidelines for peri-
However, there is less opportunity to make adjust- operative management of the diabetic
ments to treatment than with IV insulin treatment patient. Surg Res Pract. 2015; 2015: 284063.
and, thus, for more major procedures, switching to doi: 10.1155/2015/284063
 7
Acute complications of diabetes

HYPOGLYCAEMIA (Figures 7.1 and 7.2). Hypoglycaemia also occurs

in patients with type 2 diabetes mellitus (T2DM)
Hypoglycaemia is the greatest fear of diabetic treated with sulphonylureas or insulin, although
patients treated with insulin. Hypoglycaemia in to a lesser extent. The definition of hypoglycaemia
patients with type 1 diabetes mellitus (T1DM) is a reduction in the plasma glucose concentration
is a major source of disruption to their lives to a level that may induce symptoms or signs such

Figure 7.1 Hypoglycaemia is a major problem for insulin-treated diabetic patients; more than 30% of
such patients experience hypoglycaemic coma at least once. About 10% experience coma in any
given year and around 3% are incapacitated by frequent severe episodes. Hypoglycaemia is usually
due to an excessive dose of insulin, reduced or delayed ingestion of food, or increased energy expen-
diture owing to exercise. Identification of the cause and appropriate remedial action and education
are mandatory. Patients treated with sulphonylureas frequently experience hypoglycaemia.

56 DOI: 10.1201/9781003342700-7
 Hypoglycaemia 57

Figure 7.2 Hypoglycaemia is associated with regional brain activation. Here, CMG positron emission
tomography (PET) has been used to measure changes in global and regional brain glucose metabolism.
Hypoglycaemia has been shown to be associated with activation of the brain stem, prefrontal cortex
and anterior cingulate (yellow/orange indicates regions of increased glucose uptake and metabolism)
and with reduced neuronal activation in the midline occipital cortex and cerebellar vermis (blue).

as altered mental status and/or sympathetic system patients with T2DM, especially those treated with
stimulation. Numerically, there is no universal insulin. In a meta-analysis of studies incorporat-
agreement as to the actual glucose concentration ing 532,542 people with T2DM on oral therapies
below which hypoglycaemia exists (especially as and insulin, the prevalence of mild/moderate
the glucose concentration below which symptoms hypoglycaemia was 45% and severe hypoglycaemia
emerge varies from individual to individual), but, was 6%. The incidence of hypoglycaemic episodes
generally, hypoglycaemia is defined as a glucose per person-year for mild/moderate and for severe
level below 3.9 mmol/L (70 mg/dl). Acute hypo- was 19 and 0.80, respectively. The prevalence and
glycaemia produces autonomic symptoms (such incidence rates were higher for insulin-treated
as sweating, tremor, palpitations and hunger) or patients, while patients on sulphonylureas had
neuroglycopaenic symptoms (impaired cogni- higher rates than those not treated with a sulpho-
tive function, such as difficulty in concentrating nylurea. The main causes of hypoglycaemia are
and incoordination). If neuroglycopaenic symp- excessive doses of insulin or sulphonylureas, inad-
toms occur without prior warning of autonomic equate or delayed ingestion of food and sudden or
symptoms (hypoglycaemic unawareness), uncon- prolonged exercise.
sciousness and/or seizures may develop. Death Hypoglycaemia is usually self-treated by the
from hypoglycaemia is rare (estimated at 2–4% ingestion of glucose tablets (15–20 g) or carbohy-
of patients with T1DM) and is often associated drate or a meal. The 15-15 Rule is a useful guide
with the excessive use of alcohol or with deliber- (Figure 7.3). The patient should consume 15 g of
ate insulin overdose. Unexpected deaths, thought glucose or carbohydrate then wait 15 minutes
to be attributable to hypoglycaemia, are reported before testing their blood glucose again. If the glu-
in young people with T1DM who are usually found cose level is still <3.9 mmol/L (70 mg/dl), the exer-
dead in bed. Such deaths may be caused by hypo- cise should be repeated until the blood glucose rises
glycaemia-induced cardiac dysrhythmia, although to above 3.9 mmol/L (70 mg/dl). At that point, a
this remains unproven. The average individual snack or meal should be ingested. Some guidelines
patient with T1DM will experience one to two include the use of 40% glucose gel (Glucogel,
episodes of symptomatic hypoglycaemia per week Dextrogel, Rapilose) smeared into the mouth. If the
and may experience one or more temporarily dis- patient is unable to ingest glucose, then glucagon
abling hypoglycaemic events requiring third-party 1.0 mg in a powder for reconstitution (Glucagon
assistance per year. Hypoglycaemia also occurs in Emergency Kit, Eli Lilly; GlucaGen HypoKit,
58 Acute complications of diabetes

Figure 7.3 The 15-15 Rule for the treatment of hypoglycaemia.

Novo Nordisk) should be injected subcutaneously Patients experiencing recurrent hypoglycaemia

or intramuscularly. Glucagon enhances hepatic need to liaise with their medical or specialist nurs-
glucose production by promoting glycogenolysis ing advisors to determine the cause and to establish
and gluconeogenesis while inhibiting glycolysis. appropriate measures of prevention. When patients
Newer formulations of glucagon are now available experience hypoglycaemic unawareness, a strat-
in some countries and include a nasal preparation egy of loosening blood-glucose control with strict
of glucagon, Baqsimi Nasal Powder (Eli Lilly), and avoidance of low blood-glucose levels (<3.9 mmol/L,
pre-filled syringes and autoinjectors containing 70 mg/dl) is advised and has been shown to be
a liquid formulation of glucagon: Gvoke and associated with a resumption of awareness of
Gvoke HypoPen (US, Xeris Pharmaceuticals Inc) hypoglycaemia.
(Figure 7.4), Ogluo (UK/EU, Tetris Pharma Ltd) Recurrent hypoglycaemia and hypoglycaemic
and Zegalogue (dasiglucagon, Zealand Pharma). unawareness pose particular problems for drivers
These are useful adjuncts to the treatment of and for those engaged in certain high-risk occu-
hypoglycaemia for diabetic patients. Unconscious pations, e.g. operating heavy machinery. Patients
patients in hospital can be treated intravenously should be advised to avoid such activities until
with 75–100 ml of 20% glucose or 150–200 ml 10% these problems can be eliminated with the help of
glucose over 15 minutes followed by a 10% infusion. the diabetic team.

Figure 7.4 GvokeHypoPen, a pre-filled autoinjector containing a liquid formulation for the treatment
of hypoglycaemia (left). Glucagon as GlucaGen 1 mg (1 iu) for subcutaneous, intramuscular or intrave-
nous injection (right).
 Diabetic ketoacidosis and hyperosmolar hyperglycaemic state 59

DIABETIC KETOACIDOSIS a shift of potassium from the extracellular space to

AND HYPEROSMOLAR the intracellular space in exchange with extracel-
HYPERGLYCAEMIC STATE lular hydrogen ions.
DKA accounts for the majority of deaths in young
Biochemically, diabetic ketoacidosis (DKA) is pres- people with T1DM (while cardiovascular disease
ent when blood ketones are >5 mEq/L (or urinary and end-stage renal failure are largely responsible
ketones are greater than or equal to 3+), plasma glu- for deaths in people with longstanding T1DM). The
cose is >13.9 mmol/L (250 mg/dl), although it can most common cause of DKA is infection followed
be less in particular circumstances, and the blood by missed or disrupted insulin administration and
arterial pH is <7.3, associated with a low serum new, previously undiagnosed, T1DM (Figure 7.6).
bicarbonate of 18 mmol/L (18 mEq/L) or less and Most cases of DKA occur in young people. DKA
an increase in the anion gap. Thus, DKA is char- may occasionally be seen in patients with T2DM
acterized by hyperglycaemia, hyperketonaemia (especially in patients with ‘ketosis-prone’ T2DM),
with ketonuria and metabolic acidosis (Figure 7.5). and the usual precipitant is myocardial infarction
DKA occurs as a consequence of absolute or rela- or other major concomitant illness. DKA in preg-
tive insulin deficiency accompanied by an increase nancy is an even greater medical emergency as both
in counter-regulatory hormones (cortisol, glu- mother and fetus are at risk. Recurrent DKA is fre-
cagon, growth hormone, epinephrine) resulting quently seen in young women with T1DM where
in increased hepatic gluconeogenesis, glycolysis the causative factor is usually insulin omission. In
and lipolysis. Severe hyperglycaemia ensues while some instances, no clear discernible cause is found.
the breakdown of fat generates increasing levels DKA is characterised clinically by symptoms
of ketones and ketoacids which overwhelm the of nausea, vomiting, thirst, polyuria and, occa-
body’s ability to buffer them, leading to acidosis. sionally, abdominal pain accompanied by signs of
Glycosuria leads to osmotic diuresis, dehydration dehydration, acidotic respiration, ketones on the
and hyperosmolarity. Potassium loss is caused by breath, hypothermia and altered consciousness.

Figure 7.5 Diabetic ketoacidosis remains a significant cause of death in patients with type 1 diabetes
mellitus and is characterized by marked hyperglycaemia, hyperketonaemia (usually detected by the
presence of ketonuria), a low arterial pH and fluid and electrolyte depletion with prerenal uraemia.
Treatment involves rehydration with saline, low-dose intravenous insulin infusion, potassium replace-
ment, and therapy directed at the underlying cause, if apparent.
60 Acute complications of diabetes

Figure 7.6 Myocardial infarction and infection are the most common causes of death in diabetic ketoaci-
dosis. Cerebral oedema is an uncommon and poorly understood cause of death, and appears to have a
predilection for younger patients. Thromboembolic complications are an important cause of mortality.

Detailed biochemical assessment and monitoring potassium is >5.5 mmol/L (5.5 mEq/L). Thereafter,
(of renal function, electrolytes, glucose and arterial 40 mmol (40 mEq) of potassium should be added
gases) are mandatory in the management of this to each litre of the sodium chloride solution, usu-
condition, and a search should be undertaken for ally in a premixed bag, and adjusted accordingly.
the underlying cause (by chest radiography, urine Insulin is administered via a fixed-rate intrave-
and blood cultures, etc.). If a treatable underlying nous insulin infusion at a rate of 0.1 units/kg body
cause is found, it should be treated promptly. weight/hour (the patient’s body weight may need to
Successful treatment of DKA necessitates vig- be estimated). When the plasma glucose level falls
orous fluid replacement, correction of potassium below 14 mmol/L (252 mg/dl), an infusion of 10%
deficiency, continuous intravenous insulin infu- dextrose should be commenced, usually to run
sion, attention to acid–base status and treatment concurrently with the sodium chloride solution.
of the underlying cause where identifiable. Fluid The insulin infusion rate may need to be halved to
replacement is the vital first step in management, 0.05 units/kg/h to avoid the risk of hypoglycaemia.
followed by insulin treatment. Fluid replacement If the patient was on a long-acting insulin, then this
should be with 0.9% sodium chloride solution should be continued. Pump-treated patients should
(typical fluid replacement regimen 1 L in the first have their continuous subcutaneous insulin infu-
hour, 2 L next 4 hours, 2 L in next 8 hours for a sion stopped temporarily. The administration of
70 kg adult). If the initial systolic blood pressure bicarbonate (or phosphate) is not recommended
is <90 mm Hg, then 500 ml of 0.9% sodium routinely. The aim of treatment is to reduce blood
chloride solution should be administered over ketones by 0.5 mmol/L/h (5.0 mg/dl/h), the venous
10–15 minutes (this may need to be repeated). No bicarbonate by 3.0 mmol/L/h (3.0 mEq/L/h), the
potassium should be given if the initial plasma plasma glucose by 3.0 mmol/L/h (54 mg/dl/h)
 Diabetic ketoacidosis and hyperosmolar hyperglycaemic state 61

and to maintain the potassium between 4.0 and is found in fewer than 20% of patients with HHS,
5.5 mmol/L (4.0–5.5 mEq/L). To achieve this neces- hence, the abandonment of the term HONK. HHS
sitates frequent biochemical monitoring of glu- is characterised by hyperosmolarity, severe hyper-
cose, capillary ketones, venous pH or bicarbonate glycaemia and dehydration without significant
and potassium. Once the patient is stabilised, the ketoacidosis and is most commonly encountered
involvement of the specialist diabetic team should in patients with T2DM with concomitant illness.
be sought to commence or adjust the patient’s usual Patients may present with focal or global neuro-
insulin regime and to seek to determine what fac- logical deficits. The basic underlying problem with
tors led to DKA in the first place and how they HHS is a relative reduction in effective circulat-
could be prevented in future. The in-patient mortal- ing insulin with a concomitant increase in coun-
ity from DKA in the US and the UK is less than 1%. ter-regulatory hormones. Ketoacidosis does not
The overall mortality is approximately 0.2–2.0%, develop in HHS, as insulin levels remain adequate
but is 5% in those under 40 years of age and may be to inhibit lipolysis, thereby preventing the genera-
approaching 20% in the elderly or those with seri- tion of ketones. Hyperglycaemia-driven osmotic
ous concomitant illness. Cerebral oedema, espe- diuresis results in dehydration with loss of electro-
cially in children, is a rare (0.2–1% of cases), serious lytes such as sodium and potassium. Associated
and unexplained complication of DKA and may hyperosmolarity and hypotension may ultimately
respond to intravenous mannitol or dexametha- lead to renal shutdown, the end stage of which can
sone. Children with DKA should be treated accord- be coma and death. The potential causative factors
ing to paediatric DKA treatment protocols. in the development of HHS are multiple, but the
An important variant of DKA is euglycaemic majority of cases are due to infection. Any sig-
diabetic ketoacidosis (EDKA), characterised by nificant illness such as myocardial infarction or
euglycaemia (glucose <13.9 mmol/L, 250 mg/dl), pulmonary embolism may trigger HHS, as may
severe metabolic acidosis (pH <7.3, bicarbonate concomitant drug therapy, alcohol, withdrawal of
<18 mmol/L (18 mEq/L) and ketonaemia. The overall oral hypoglycaemic agents or insulin and neglect.
mechanism is based on a general state of starvation, Several different ethnic groups, such as African
resulting in ketosis while maintaining normogly- Americans, Hispanics and Native Americans,
caemia. Thus, it is associated with anorexia, gastro- are disproportionately affected by HHS, but this
paresis, fasting and alcohol misuse. Trigger factors may just reflect the prevalence of T2DM in these
may be pregnancy, pancreatitis, surgery, infection, groups. Patients presenting with HHS require
cocaine toxicity, cirrhosis and insulin-pump use. extensive investigations to assess their metabolic
The use of SGLT2 (sodium-glucose cotransporter-2) state as well as tests to look for the precipitating
inhibitors such as canagliflozin, dapagliflozin and illness, which may include brain imaging if there
empagliflozin can also result in EDKA. Treatment is is an altered conscious level, to exclude intra-
directed at fluid resuscitation, insulin infusion and cranial pathology. As the fluid deficit in patients
the co-administration of 5–10% dextrose. The nor- with HHS is of the order of 9 L, aggressive fluid
mal blood-glucose levels at presentation may delay resuscitation with 0.9% sodium chloride solution
the diagnosis of this serious acidotic condition. is the cornerstone of the initial treatment of HHS
at a rate of 15–20 mL/kg/h, together with potas-
Hyperosmolar Hyperglycaemic sium replacement as for DKA. Treatment with
State (HHS) 0.45% sodium chloride solution should only be
used if the serum osmolarity fails to decline. Once
Hyperosmolar Hyperglycaemic State (HHS) is fluid therapy has been initiated, an intravenous
also known as Hyperosmolar Hyperglycaemic insulin infusion can be commenced at a rate of
Nonketotic Syndrome (HHNS) and was previ- 0.5–0.1 units/kg/h. Insulin should not be admin-
ously known as Hyperglycaemic Hyperosmolar istered initially as it may cause a sudden precipi-
Nonketotic Coma (HONK). HHS is one further tous fall in osmolarity, leading to cardiovascular
life-threatening metabolic derangement which collapse. Further alterations in the administration
occurs in diabetes most commonly in patients with of fluids, insulin and potassium should be made
T2DM (Figure 7.7). The mortality rate for HHS far on the basis of subsequent frequent monitoring
exceeds that of DKA, reaching up to 5–10%. Coma and assessment, preferably undertaken in an ICU.
62 Acute complications of diabetes

Figure 7.7 Hyperosmolar Hyperglycaemic Syndrome usually affects middle-aged or elderly patients
with previously undiagnosed type 2 diabetes mellitus. It is characterized by marked hyperglycaemia
(usually >50 mmol/l; 900 mg/dl) and prerenal uraemia without significant hyperketonaemia and acidosis.
Treatment is by fluid replacement, attention to electrolyte balance and insulin therapy as for diabetic
ketoacidosis, and most patients will not ultimately require permanent insulin therapy. The condition has
a high mortality, owing to a high incidence of serious associated disorders and complications.

As there is an increased risk of venous thrombo- Frier BM, Fisher BM, eds. Hypoglycemia and
embolism in HHS, all patients should receive Diabetes. London: Edward Arnold, 1993
treatment with low molecular weight heparin Kitabchi AE, Umpierrez GE, Murphy MB, et al.
unless there is a contraindication. Management of hyperglycaemic crises in
patients with diabetes. Diabetes Care. 2001;
BIBLIOGRAPHY 24: 131–53
Munro JF, Campbell IW, MacCuish AC, Duncan
Cryer PE. The barrier of hypoglycemia in dia- LJ. Euglycaemic diabetic ketoacidosis. Br Med
betes. Diabetes. 2008 Dec; 57(12): 3169–76. J. 1973 Jun 9; 2(5866): 578–80. Doi: 10.1136/
Doi: 10.2337/db08-1084 bmj.2.5866.578
Cryer PE, Fisher JN, Shamoon H. Hypoglycemia. Schade DS, Eaton RP, Alberti KGGM, Johnston
Diabetes Care. 1994; 17: 734–55 DG. Diabetic Coma: Ketoacidotic and
Edridge CL, Dunkley AJ, Bodicoat DH, Rose TC, Hyperosmolar. Albuquerque: University of
Gray LJ, Davies MJ, Khunti K. Prevalence New Mexico Press, 1981
and incidence of hypoglycaemia in 532,542 Small M, Alzaid A, MacCuish AC. Diabetic hyper-
people with type 2 diabetes on oral therapies osmolar non-ketoacidotic decompensation.
and insulin: A systematic review and meta- Q J Med. 1988; 66: 251–7
analysis of population based studies. PloS Umpierrez GE, Murphy MB, Kitabchi AE.
One. Doi: 10.1371/journal.pone.0126427 Diabetic ketoacidosis and hyperglyce-
Evans K. Diabetic ketoacidosis: Update on man- mic hyperosmolar syndrome. Diabetes
agement. Clin Med. 2019 Sep; 19(5): 396–8. Spectr. 2002; 15(1): 28–36. Doi: 10.2337/
Doi: 10.7861/clinmed.2019-0284 diaspect.15.1.28
 8
Chronic complications of diabetes

Although the acute complications of diabetes because they have had previously unrecognised
impact significantly the day-to-day life of people T2DM for many years. The prevalence of retinop-
with diabetes, especially type 1 diabetes melli- athy increases with the duration of diabetes. In
tus (T1DM), the knowledge of the potential risk general, significant visual impairment is usually
of chronic complications is ever present. Results caused by proliferative retinopathy in T1DM and
from the Diabetes Control and Complications by maculopathy in T2DM. Diabetic retinopathy is
Trial (DCCT) established unequivocally the the leading cause of new blindness in persons aged
relationship between glycaemic control and the 25–74 years in the US. The estimated prevalence
incidence and progression of diabetic microvas- of diabetic retinopathy is 28.5% among those with
cular complications. Such complications occur in diabetes aged 40 years and over.
both T1DM and type 2 diabetes mellitus (T2DM) Background diabetic retinopathy (Figures 8.1–
patients, although the latter patients often suc- 8.8) is characterised by capillary dilatation and
cumb to major cardiovascular disease before occlusion, microaneurysms, ‘dot and blot’ haem-
microvascular complications become advanced. orrhages, flame-shaped haemorrhages, retinal
Although life expectancy for T1DM patients is
undoubtedly reduced, more than 40% of such
patients will survive for more than 40 years, half
of them without developing significant micro-
vascular complications. The United Kingdom
Prospective Diabetes Study (UKPDS) also pro-
vided pivotal information on the relationship
between glucose control and complications in
T2DM patients. It demonstrated, in a significant
way, the beneficial effect of an improvement in
blood glucose control on subsequent risk of devel-
oping specific diabetic complications.

DIABETIC RETINOPATHY
Both the incidence and prevalence of diabetic
retinopathy are highest in T1DM patients with
an early age of onset of diabetes. However, T1DM
patients do not exhibit retinopathy at presenta-
tion, and the likelihood of developing significant Figure 8.1 Normal fundus of the eye. Appreciation
diabetic eye disease in the first 5 years of the dis- of the fundal abnormalities seen in diabetes must
ease is small. In contrast, T2DM patients may be based on a sound knowledge of the normal
have retinopathy at presentation, presumably appearance.

DOI: 10.1201/9781003342700-8 63
64 Chronic complications of diabetes

Figure 8.2 Optic atrophy in diabetes insipidus, Figure 8.4 The fluorescein angiogram of the
diabetes mellitus, optic atrophy and deafness same area as in Figure 8.3 reveals many more
(DIDMOAD) syndrome, a rare condition that is abnormalities than can be seen on the fundal
usually diagnosed when type 1 diabetes mellitus photograph. Widespread microaneurysms
(T1DM) presents in childhood. The inheritance is appear as white dots.
autosomal recessive and diabetes insipidus tends
to develop after the diagnosis of T1DM.

Figure 8.5 Severe background diabetic retinopa-

thy includes venous changes, clusters and large
blot haemorrhages, intraretinal microvascular
abnormalities (IRMA), an early cottonwool spot
Figure 8.3 Background diabetic retinopathy with and a generally ischaemic appearance. This type
occasional scattered microaneurysms and dot of retinopathy is usually a prelude to prolifera-
haemorrhages. tive change.
 Diabetic retinopathy 65

Figure 8.6 A fluorescein angiogram of the same Figure 8.8 Circinate exudative retinopathy. The
area as in Figure 8.5 shows the blind ends of two hard exudate rings (lateral to the macula)
occluded small vessels, widespread capillary are true exudates due to leakage from abnormal
leakage and areas of non-perfusion. vessels and are associated with retinal oedema.
When hard exudates and retinal oedema affect
the macular area, the fovea may become involved,
which may threaten central vision. Laser photoco-
agulation helps to prevent such loss of vision.

retinopathy and is not associated with visual

loss unless hard exudates become extensive and
involve the fovea. Preproliferative lesions, a har-
binger of impending new vessel formation, include
cottonwool spots (nerve-fibre layer infarctions
caused by occlusion of precapillary arterioles),
venous loops and beading, arterial narrowing and
occlusion and intraretinal microvascular abnor-
malities. The latter consist of abnormal dilated
capillaries, which are often leaky.
The importance of the recognition of prepro-
liferative retinopathy is that it indicates the need
for urgent referral to an ophthalmologist. In
proliferative retinopathy (Figures 8.9–8.12) new
Figure 8.7 Serious diabetic retinopathy with vessels originate from a major vein (occasionally
venous irregularities, blot haemorrhages, intraret- from arteries) and appear in the retinal periphery
inal microvascular abnormalities, large cottonwool or on the optic disc. They are much less common
spots and extensive areas of hard exudates. in T2DM than in T1DM. New vessels have a dev-
astating impact on vision when they burst and
oedema and hard exudates (which are true exu- produce sudden preretinal or vitreous haemor-
dates of lipid-rich material from abnormal ves- rhage. Contraction of associated fibroglial tissue
sels). This picture represents non-proliferative may result in retinal detachment with resultant
66 Chronic complications of diabetes

Figure 8.11 Leashes of peripheral new vessels

with associated haemorrhage. These lesions are
amenable to laser photocoagulation.
Figure 8.9 Serious gross peripheral proliferative
diabetic retinopathy includes marked venous
changes such as dilatation and beading.

Figure 8.12 Fluorescein angiogram (A) and fundal

photograph (B) of new vessels at the optic disc,
which lead rapidly to visual loss. If haemorrhage
has already occurred, then visual loss is immi-
nent and urgent laser treatment is indicated.
Fluorescein angiography reveals the gross leakage
from the abnormal vessels.

Figure 8.10 Extensive peripheral prolifera-

tive retinopathy with venous beading and blot loss of vision, which may be profound if it affects
haemorrhages. New vessels usually originate the macula (Figures 8.13, 8.14).
from a major vein and adopt a branching pattern. Diabetic maculopathy is the most common
Proliferative retinopathy is the most common cause of visual loss in T2DM and may be exudative,
sight-threatening complication of type 1 diabetes oedematous or ischaemic. If left untreated, prep-
mellitus, with visual loss being due to break-
roliferative retinopathy, proliferative retinopathy
age of vessels leading to preretinal or vitreous
haemorrhage. It is always accompanied by other
and maculopathy will all have an appalling prog-
diabetic lesions and is treatable by laser photo- nosis for the patient’s eyesight. All diabetic patients
coagulation. It is less common in type 2 diabetes should be regularly screened for such changes and
mellitus (where exudative maculopathy is the referred, where appropriate, for specialised oph-
most common cause of visual loss). thalmic assessment.
 Diabetic retinopathy 67

Figure 8.15 A patient undergoing laser photo-

Figure 8.13 End-stage diabetic retinopathy is coagulation for diabetic retinopathy. A high-
characterised by gross distortion of the retina energy light beam is focused through a corneal
with extensive fibrous bands. Uncontrolled new contact lens onto the target area of the retina.
vessels develop a fibrous tissue covering and Laser photocoagulation can be used to destroy
expanding fibrous tissue tends to contract, caus- specific targets (e.g. peripheral new vessels) or to
ing retinal traction and detachment. The result is perform panretinal photocoagulation.
sudden and unexpected visual loss. The retinop-
athy shown here is untreatable.
panretinal approach is to reduce retinal ischaemia
overall, thereby reducing the stimulus to new
vessel formation (Figure 8.16). Photocoagulation
may also be used for the treatment of diabetic
macular oedema, with focal treatment given for
discrete lesions and diffuse treatment for wide-
spread capillary leakage and non-perfusion.
Intravitreal injection of vascular endothelial
growth factor (VEGF) inhibitors such as bevaci-
zumab, ranibizumab, brolucizumab, faricimab
and aflibercept is now the preferred treatment
for central-involved macular oedema, with most
patients requiring near-monthly intravitreal ther-
apy in the first year. VEGF inhibitor therapy is also
Figure 8.14 In profoundly ischaemic diabetic an effective treatment of proliferative diabetic ret-
eyes, thromboneovascular glaucoma may occur inopathy. Intravitreal triamcinolone (or an intra-
with new vessel and fibrous tissue proliferation in vitreal dexamethasone implant—Ozurdex) may
the angle of the anterior chamber, which inter- be employed in the treatment of diabetic macular
feres with normal aqueous drainage. The condi- oedema, proliferative diabetic retinopathy and
tion is associated with rubeosis iridis (shown here) neovascular glaucoma as a consequence of pro-
wherein new vessel growth occurs on the iris.
liferative retinopathy and has been found to be
effective in reducing central macular thickness
Laser photocoagulation (Figures 8.15) can be and improving visual acuity (Figures 8.17–8.19).
used to destroy isolated new vessels or to under- It may also have an antiangiogenic effect. In
take panretinal photocoagulation in cases of more advanced cases, vitreoretinal surgery, including
severe proliferative retinopathy. The aim of the vitrectomy, may need to be performed to treat
68 Chronic complications of diabetes

Figure 8.16 Panretinal laser photocoagulation.

The entire retina is treated except for the macula Figure 8.18 The same retina as in Figure 8.17
and papillomacular bundle, which are essential at 3 months postintravitreal triamcinolone
for central vision. The rationale for using photo- therapy. The changes are not dramatic, but
coagulation in proliferative retinopathy is that it there is an improvement with partial resolution
destroys the ischaemic areas of the retina which of hard exudates around the macula. The role
produce vasoproliferative factors that stimulate of intravitreal triamcinolone therapy has not
new vessel growth. Panretinal photocoagulation been fully established; however, some retina
may require 1500–2000 burns. The treatment is specialists use it to treat diabetic macular
well tolerated and divided into several sessions, oedema which persists despite laser therapy.
and regression of new vessels is usually seen It is not a substitute for laser therapy and one
within 3–4 weeks. Once the treatment is effec- recent study showed it had only a marginal
tive, the results are long-lasting. In maculopathy, benefit over the long term, while increasing the
laser treatment is either focused on discrete incidence of cataract and glaucoma.
lesions or uses a diffuse ‘grid’ treatment in cases
of widespread capillary leakage and non-perfu-
sion. However, treatment is less effective and the
long-term outlook is not as good.

Figure 8.19 This is the retinal photograph of a

77-year-old pseudophakic diabetic female with
severe bilateral diabetic macular oedema refrac-
Figure 8.17 Triamcinolone has been inserted tory to anti-vascular endothelial growth factor
into the vitreous under topical anaesthesia in a (anti-VEGF) with an Ozurdex implant in situ,
patient with diabetic maculopathy. resulting in improved visual acuity.
 Diabetic nephropathy 69

severe vitreous haemorrhage and retinal detach-

ment (Figures 8.20–8.22).
Detection of diabetic retinopathy at an early
stage is essential. All diabetic patients should have
a regular ophthalmic examination, with patients

Figure 8.22 Severe vitreous haemorrhage may

lead to secondary retinal detachment. Although
vitrectomy may be performed electively for
severe vitreous haemorrhage alone, urgent sur-
gery is required for operable retinal detachment.
Vitreoretinal microsurgery requires a closed
intraocular approach (shown here). An operating
microscope allows precise intraocular manipula-
tion to remove the vitreous and its contained
haemorrhage, which is replaced with saline and
followed by endolaser photocoagulation to pre-
vent both further detachment and subsequent
neovascularisation.

with T1DM having a comprehensive eye exami-

Figure 8.20 Vitreous haemorrhage has occurred nation within 5 years of diagnosis and patients
despite extensive laser photocoagulation. The with T2DM having an examination at the time of
haemorrhage may clear but, if it fails to do so or diagnosis. Screening programmes for retinopathy
recurrent haemorrhage ensues, visual loss is inevi- should be designed to include all patients with
table and vitreoretinal surgery may be indicated. diabetes in an attempt to avoid visual loss. The
combination of direct ophthalmoscopy and digital
retinal photography with measurement of visual
acuity is often used. Suitably qualified optome-
trists have also been employed in some screening
programmes (Figure 8.23).

DIABETIC NEPHROPATHY
Diabetic nephropathy, one of the most serious
complications of diabetes, is characterised by pro-
teinuria, decreasing glomerular filtration rate and
increasing blood pressure. In the absence of urinary
infection or other renal disease, diabetic nephrop-
athy is defined by the detection of albuminuria of
300 mg/day or greater (200 micrograms/minute)
Figure 8.21 The same patient as in Figure 8.20 or an albumin-to-creatinine ratio (ACR) greater
postvitrectomy with resultant clearing of the than 300 mg/g (30 mg/mmol) on two occasions
vitreous haemorrhage. 3–6 months apart. In patients with T1DM, when
70 Chronic complications of diabetes

Figure 8.23 Once diabetic retinopathy has been identified, referral to an ophthalmologist may be
indicated. This chart shows the types of diabetic eye disease requiring such referral and the urgency
with which it should be undertaken.

this degree of proteinuria is associated with the deposits and glomerular sclerosis due to mesangial
presence of established diabetic retinopathy, the expansion and/or ischaemia. Other histological
histology of the underlying kidneys will inevita- features may be present such as interstitial fibrosis
bly be that of diabetic glomerulopathy, although, and tubular atrophy (Figure 8.24).
in T2DM, nephropathy can exist without con- Approximately 20–50% of patients with diabe-
comitant retinopathy. This degree of proteinuria tes will develop nephropathy. Those who develop
is detectable by dipstick urine testing. However, it diabetes before the age of 15 years are at higher
is recognised that this stage is preceded by a long risk. About 35% of T1DM patients will develop
phase of incipient nephropathy associated with nephropathy, although there is evidence of a
microalbuminuria (30–300 mg/day; 30–299 mg/g declining incidence. After about 20 years of dia-
creatinine) that is not detectable on dipstick testing. betes duration in T1DM, the incidence of diabetic
As microalbuminuria presages diabetic nephropa- nephropathy falls off. The risk of developing dia-
thy, most national guidelines recommend screen- betic nephropathy varies between individuals and
ing for the presence of microalbuminuria annually is influenced not only by duration of diabetes but
by measurement of the ACR, allowing the institu- by other factors such as blood pressure, glycaemic
tion of interventional treatment to slow the rate control and genetic susceptibility. Nevertheless,
of progression of nephropathy. Histologically, the diabetic nephropathy is the leading cause of
diabetic kidney is characterised by increased glo- chronic kidney disease (CKD) in the US and other
merular volume secondary to basement membrane Western societies and is responsible for 30–40% of
thickening and mesangial enlargement, hyaline all end-stage renal disease (ESRD) cases in the US.
 Diabetic nephropathy 71

The hypertension of diabetic nephropathy

appears to be of renal origin and to occur after the
onset of microalbuminuria. As proteinuria also
reflects widespread vascular damage affecting both
small and large vessels, the condition is associ-
ated with a poor prognosis unless special strategies
are adopted. The causes of death include not only
end-stage renal failure, but also myocardial infarc-
tion, cardiac failure and cerebrovascular accidents.
T2DM patients with nephropathy are more likely to
die because of major vascular disease than uraemia.
Peripheral vascular disease, neuropathy and ret-
inopathy are common accompaniments of diabetic
nephropathy to the extent that if neuropathy and
retinopathy are not present, an alternative cause of
the proteinuria should be sought. The sudden devel-
opment of nephrotic syndrome, a rapid decline in
renal function, haematuria and a short duration of
T1DM also indicate the need to seek an alternative
cause, with the use of renal biopsy, if necessary.
If there is a marked discrepancy in size between
the kidneys on ultrasound scanning, investiga-
tions should be conducted to exclude renal artery
stenosis, which is common in diabetes, especially
in T2DM with other evidence of vascular disease.
Figure 8.24 Hyalin deposition in the glomerular Angiotensin-converting enzyme (ACE) inhibitors
tuft in a patient with diabetic glomerulopathy. should be avoided in this situation. Regular moni-
Other characteristic histopathological changes of
toring of eGFR and plotting the inverse of serum
diabetic nephropathy are an increase in glomeru-
lar volume, basement membrane thickening and creatinine against time will give an indication of
diffuse mesangial enlargement (often with nodu- the rate of progression of nephropathy; however,
lar periodic acid-Schiff-positive lesions). Diabetic this may be slowed by vigorous treatment of the
nephropathy develops in around 35% of type 1 associated hypertension, preferably with ACE
diabetes mellitus cases and in less than 20% of type inhibitors, which have the additional benefit of
2 diabetes mellitus cases. It is defined as persistent reducing intraglomerular pressure. Inhibition of
proteinuria (albumin excretion rate >300 mg/day) the renal-angiotensin-aldosterone system (RAAS)
associated with hypertension and a falling glo- is the key intervention in diabetic nephropathy
merular filtration rate. Established nephropathy is
with landmark trials demonstrating a reduction in
preceded by years of microalbuminuria (albumin
excretion rate 30–300 mg/day), which is negative the progression of albuminuria in T1DM patients
on reagent-strip testing for albumin. Vigorous con- treated with ACE inhibitors. In T2DM, strong trial
trol of blood pressure and the use of angiotensin- evidence showed a highly significant benefit from
converting enzyme inhibitors have been shown to the blockage of the RAAS with angiotensin recep-
delay the rate of progression of diabetic nephropa- tor blockers (ARBs) including a 20% reduction in
thy. Periodic acid-Schiff stain was used. the composite endpoint of doubling of the serum
creatinine, ESRD or death with the use of irbesar-
The severity and incidence of diabetic nephropathy tan versus placebo in diabetic nephropathy (with
is greater in the Black population and in other eth- similar results with losartan). Dual treatment with
nic groups. Patients with T1DM and established an ACE inhibitor and an ARB is contraindicated
proteinuria have a greatly increased mortality rate. because of adverse effects. Treatment of hyperten-
Because T2DM is much more common globally, sion is fundamental to the management of diabetic
the majority of diabetic patients proceeding to nephropathy to reduce the associated cardiovas-
end-stage renal failure has this form of diabetes. cular risk and the risk of progression to advanced
72 Chronic complications of diabetes

Figure 8.25 Once renal failure has become established in diabetes, there is an inexorable decline
in renal function which, if untreated, leads to end-stage renal failure. The decline in renal function
is linear when plotted as the inverse of serum creatinine over time. Modern treatment strategies
attempt to slow the deterioration of renal function by vigorous antihypertensive regimens.
Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers may be especially
effective because they reduce intraglomerular pressure and, unless renal failure is advanced,
it is still worthwhile to attempt to achieve improved glycaemic control.

renal disease. Guidelines recommend a lowering T2DM patients with diabetic renal disease who
of blood pressure to less than 130/80 in those with need a drug additional to metformin to attain tar-
diabetes and albuminuria to achieve optimal renal get glycaemic control. In 2021, the US Food and
and cardiovascular protection. Smoking cessation Drug Administration (FDA) approved finerenone
and lipid-lowering therapy are also paramount in (Kerendia), a selective mineralocorticoid receptor
this context (Figure 8.25). antagonist, for the treatment of CKD in patients
There is evidence that establishing strict gly- with diabetes mellitus (DM) based on the findings
caemic control retards the progression of estab- of the Finerenone in Reducing Kidney Failure and
lished nephropathy. The DCCT study in patients Disease Progression in Diabetic Kidney Disease
with T1DM revealed a significant reduction in the (FIDELIO-DKD) trial, but treatment with an ACE
development of moderate and severe albuminuria inhibitor or an ARB take precedence in its man-
in the intensively treated arm of the trial. Similar agement. With declining renal function, insulin
results for an improvement in glycaemic control requirements fall and, as most sulphonylureas and
were also seen in T2DM studies (Action in Diabetes metformin undergo renal excretion or metabolism,
and Vascular Disease: Preterax and Diamicron these compounds should not be used in patients
Modified Release Controlled Evaluation with renal failure; in such cases, insulin treatment
[ADVANCE], VETERANS AFFAIRS DIABETES is preferable, although some agents, such as glicla-
TRIAL). Importantly, sodium-glucose co-trans- zide which are cleared predominantly through the
porter-2 (SGLT2) inhibitors have a significant liver, may be relatively safe.
reno-protective effect in patients with T2DM With aggressive treatment of hypertension and
and are recommended in the American Diabetes hyperlipidaemia and improvement of glycaemic
Association (ADA) and European Association control, the need for renal replacement therapy
for the Study of Diabetes (EASD) guidelines for may be delayed for several years. However, late
 Diabetic neuropathy 73

referral of diabetic patients with advanced diabetic DIABETIC NEUROPATHY

nephropathy to a nephrologist should be avoided:
referral should be instigated when serum creati- Diabetic neuropathy, a common complication of
nine levels start to rise, and certainly before they diabetes, is a heterogeneous disorder that encom-
reach 300 µmol/l. Renal physicians prefer to see passes a wide range of abnormalities affecting
such patients earlier rather than later. Although proximal and distal peripheral sensory and motor
renal transplantation offers the best method of nerves as well as the autonomic nervous system
treatment in suitable patients, haemodialysis is (Figure 8.26).
indicated in patients unsuitable for transplanta-
tion, while awaiting transplantation or follow-
ing graft failure. Dialysis may need to be started
at lower creatinine levels than in non-diabetic
patients because of the tendency to increased fluid
retention and volume-dependent hypertension.
Vascular access and arterio-venous fistulae failures
are additional problems for diabetic patients, as is
difficulty achieving blood-glucose control during
haemodialysis. However, the prognosis of diabetic
patients receiving haemodialysis, although poorer
than in non-diabetic subjects, has improved dra-
matically over the past 20 years.
Long-term survival of diabetic patients with
continuous ambulatory peritoneal dialysis (CAPD)
is possible. Survival rates may be lower than in non-
diabetic patients receiving CAPD. Advantages of
CAPD include that vascular access is not required
and that good glycaemic control may be achieved
by the intraperitoneal route of insulin.
Renal transplantation is the treatment of choice
for those <65 years who are free of significant car-
diovascular disease, cerebrovascular disease and
significant sepsis, and for whom a suitable donor
may be found. Survival rates for diabetic patients Figure 8.26 Diabetic neuropathy is a common and
who receive grafts from living donors are now often disabling complication of diabetes. Distal
almost the same as for non-diabetic patients, while symmetrical polyneuropathy is the most common
results of cadaver transplantation, although less form of diabetic neuropathy and can be either
favourable, have improved greatly. Histological sensory or motor and involve small fibres, large
fibres or both. Large-fibre neuropathies can involve
changes compatible with diabetic nephropathy can
sensory or motor nerves or both resulting in abnor-
be detected in most transplanted kidneys. Today, malities of motor function, vibration perception,
many diabetic patients with end-stage renal failure position sense and cold-thermal perception with,
who require a transplant receive both a kidney and commonly, a ‘glove and stocking’ distribution of
a pancreas at the same time. sensory loss. Small-fibre neuropathy is manifested
A major Finnish study of 20,005 patients with by pain and paraesthesiae but may develop into
T1DM showed that during a follow-up of 35 years, a chronic painful neuropathy. Mononeuropathies
the overall incidence of end-stage renal failure was and entrapment syndromes are common. Proximal
only 2.2% at 20 years and 7.8% at 30 years after motor neuropathies (diabetic amyotrophy) have
more complex aetiologies, but are usually associ-
diagnosis. The risk of end-stage renal failure was
ated with great pain and disability. Autonomic
virtually zero for the first 15 years after diagnosis. neuropathy is rare and leads to a wide variety of
These data suggest a greatly improved renal out- symptoms correlating with the affected autonomic
look for patients with T1DM, especially for those nerve damage. After 20 years of diabetes, about
under age 50. Overall survival has also improved. 40% of patients will have diabetic neuropathy.
74 Chronic complications of diabetes

Prevalence
The exact prevalence of diabetic neuropathy is
unknown, partly because of difficulties with defi-
nition, but it is estimated that as many as 50% of
patients with diabetes will have demonstrable
evidence of diabetic nerve damage. It is known,
however, that the risk of developing neuropathy
is directly linked to the duration of diabetes: after
20 years of diabetes, about 40% of patients will have
neuropathy. Other significant risk factors for the
development of diabetic neuropathy are poor gly-
caemic control, heavy alcohol use and tall height.
In patients attending a diabetic clinic, 25% reported
symptoms, 50% were found to have neuropathy
using a simple clinical test and almost 90% tested
positive with more sophisticated tests. Neuropathy
may be present at the time of diagnosis of T2DM,
but neurological complications occur equally in
T1DM and T2DM. Neuropathy may lead to a sig-
nificant reduction in quality of life and is a major
determinant of foot ulceration and amputation.

Pathogenesis
The pathogenesis of diabetic neuropathy is Figure 8.27 Transverse semithin sections of
unknown, but there is no doubt that hyperglycae- resin-embedded sural nerve biopsy speci-
mens stained with thionin and acridine orange.
mia is an important factor. Pathological studies
Appearance of a normal nerve (a). Nerve from
demonstrate axonal degeneration with segmen-
a patient with diabetic neuropathy shows a loss
tal demyelination and remyelination. Narrowing of myelinated nerve fibres and the presence of
of the vasa nervorum may also be contribu- regenerative clusters (b). The walls of the endo-
tory. Neurophysiological studies show reduced neural capillaries are thickened. Diabetic neu-
motor and sensory nerve conduction velocities. ropathy is a common complication that usually
Abnormalities of the polyol pathway have been manifests as a sensory, motor or combined sym-
invoked as a cause of diabetic neuropathy. In ani- metrical polyneuropathy. Acute painful neuropa-
mals, elevated glucose levels in peripheral nerves thy and diabetic amyotrophy both cause acute
pain in the thighs or legs, associated with muscle
lead to increased activity of aldose reductase,
wasting and weight loss. Painful neuropathy may
with consequent increased concentrations of sor-
respond to tricyclic drugs, especially amitriptyline
bitol and fructose, accompanied by a decrease in or anticonvulsants, such as gabapentin.
the polyol myoinositol. This may lead to reduced
membrane sodium–potassium–ATPase activity.
It has been postulated that such changes may be and the production of free radicals may also be
reversed by the use of aldose reductase inhibitors. significant factors in the development of diabetic
Although these agents have been shown clinically neuropathy (Figure 8.27).
to improve neural conduction velocity, their role
in the treatment of diabetic neuropathy remains Chronic insidious sensory neuropathy
to be elucidated. Non-enzymatic glycosylation of
nerve proteins and lipids resulting in advanced Chronic insidious sensory neuropathy is the most
glycation end products (AGEs) that may disrupt frequently encountered neuropathy in diabetes
neuronal integrity and repair mechanisms and with paraesthesiae, discomfort, pain, distal sen-
ischaemia caused by increased oxidative stress sory loss, loss of vibration sense and reduced or
 Diabetic neuropathy 75

absent tendon reflexes. This type of neuropathy is

usually refractory to treatment.

Acute neuropathy
Acute painful neuropathy is relatively uncommon
and usually occurs in the context of poor glycae-
mic control (or a sudden improvement in glycae-
mic control). Lower limb pain may be particularly
severe and accompanied by muscle weakness and
wasting. Recovery usually occurs within a year
with good control of the diabetes.
Figure 8.29 Diabetic right-third cranial nerve
palsy. The right eye is deviated outwards and
Diabetic mononeuropathy downwards, and there is associated ptosis.
Pupillary sparing is often encountered. Third-
Diabetic mononeuropathies, affecting single nerve palsy is the most commonly seen cra-
nerves or their roots, also occur (Figure 8.28). nial neuropathy of diabetes, although fourth-,
They are usually of rapid onset and severe in sixth- and seventh-nerve lesions have also been
nature, although eventual recovery is the rule in reported as well as intercostal and phrenic nerve
most cases. Such features may point to an acute lesions. These lesions usually improve over time.
vascular event as causation rather than chronic
metabolic disturbance. Such neuropathies occur
mainly in older patients, usually male. When two commonly, although fourth-, sixth- and seventh-
or more nerve palsies occur within a short time- nerve lesions are also described (Figure 8.29).
frame, mononeuritis multiplex must be excluded.
Truncal radiculopathies are also encountered, Proximal motor neuropathy
occurring in a dermatomal distribution over the
thorax or abdomen (with possible local bulging Proximal motor neuropathy (diabetic radiculo-
of the abdominal wall). The acute asymmetri- plexus neuropathy, femoral neuropathy or dia-
cal pain is described as burning or aching and betic amyotrophy) is a particularly devastating
is frequently intensified at night with sensitiv- neurological complication of diabetes. It can be
ity to touch. Cranial nerve lesions are seen rela- identified clinically by certain common features.
tively frequently. Third-nerve palsies occur most It primarily affects the elderly and is of gradual
or abrupt onset beginning with pain in the thighs
and hips or buttocks. Weakness of the proximal
muscles of the lower limbs follows. The condition
begins unilaterally but often spreads bilaterally
and is associated with weight loss and depression.
Slow, sometimes incomplete, recovery usually
occurs, but may take several months to a year or
more. Electrophysiological evaluation reveals a
lumbosacral plexopathy, and the condition is now
thought to be secondary to a variety of causes
that occur more frequently in diabetes, such as
chronic inflammatory demyelinating polyneurop-
athy, monoclonal gammopathy and inflammatory
Figure 8.28 This diabetic patient has an ulnar
neuropathy. Such entrapment neuropathies are vasculitis. If found to be immune mediated, reso-
commonly seen in diabetic patients, the most lution may be very prompt with immunotherapy.
common being carpal tunnel syndrome. It has Mononeuropathies must be distinguished from
been postulated that diabetic nerves may be entrapment syndromes. Common entrapment
more susceptible to mechanical injury. sites in diabetic patients involve median, ulnar,
76 Chronic complications of diabetes

radial, femoral and lateral cutaneous nerves of the of other systems, such as the gastrointestinal tract
thigh. Carpal tunnel syndrome occurs twice as and micturition, is much more complex.
frequently in diabetic patients compared with the Diabetic autonomic neuropathy produces dys-
normal population. function in the cardiovascular system, the gastro-
intestinal system, the genitourinary system and
Diabetic autonomic neuropathy the sweat glands. This results in a wide spectrum of
autonomic symptoms, including male impotence,
Damage to the autonomic nervous system, or auto- postural hypotension, sinus arrhythmia, nocturnal
nomic neuropathy, is seen in diabetic patients, diarrhoea, faecal incontinence, nausea and vomit-
although the exact prevalence is unknown, ing, gustatory sweating, heavy sweating of the face,
reported prevalence rates in studies vary widely neck and trunk, diminished or absent sweating in
(Figure 8.30). Tests of autonomic nerve function the feet, a feeling of incomplete bladder empty-
often reveal abnormalities in patients with no ing and loss of awareness of acute hypoglycaemia,
symptoms of autonomic dysfunction. These tests plus many other rarer manifestations of autonomic
include the heart-rate response to the Valsalva dysfunction. Gastric atony (diabetic gastroparesis),
manoeuvre, to deep breathing and to moving from especially when associated with vomiting, results
the supine to the erect posture, and the blood pres- in loss of glycaemic control in insulin-treated
sure response to sustained handgrip and stand- subjects (Figure 8.31). Bladder enlargement with
ing up. Cardiovascular tests are relatively simple defective micturition is also reported. Resting
to perform, but evaluating the autonomic control tachycardia is a common sign. Many studies have

Figure 8.30 Clinical features of diabetic autonomic neuropathy. Many diabetic patients have evidence
of autonomic dysfunction, but very few have autonomic symptoms. The most prominent symptom is
postural hypotension. Erectile dysfunction, common in diabetic men, is not always due to autonomic
neuropathy. Late manifestations other than postural hypotension include gustatory sweating, diabetic
diarrhoea, gastric atony and reduced awareness of hypoglycaemia. Symptomatic autonomic neuropa-
thy may be associated with a poor prognosis.
 Major vascular disease 77

may be necessary, when the drugs mentioned here

fail, to deliver acceptable pain relief (considered in
this context to be a 50% reduction in pain levels)
to exhibit opioid drugs such as tramadol, but cau-
tion must be exercised to avoid the risk of addiction.
Localised transdermal lignocaine (lidocaine) has
also been shown to be effective.
Non-pharmacological therapies include nerve
stimulation therapies and electrical spinal-cord
stimulation. It is, however, recognised that despite
pharmacological treatment, many patients con-
tinue to experience pain or discomfort, and treat-
ment may be considered successful in patients
who experience a moderate decrease in pain or
improved function. Depletion of axonal neu-
ropeptide substance P with capsaicin extracted
from chilli peppers may help in some patients
with C-fibre pain. The combination of erythromy-
cin and metoclopramide is recommended for the
treatment of gastroparesis.

Figure 8.31 Intractable vomiting due to diabetic MAJOR VASCULAR DISEASE

gastroparesis is notoriously difficult to treat.
This patient was successfully treated by the Although microvascular disease is a major con-
surgical implantation of the EnterraTM Gastric cern in diabetic patients, it should be emphasised
Neurostimulator (GES) system (Medtronic that most patients with long-term T1DM and most
Inc, Minneapolis, US). This novel experimen- patients with T2DM will die because of cardio-
tal approach may prove to be an effective vascular disease. Diabetic patients have an excess
treatment strategy in such rare but difficult- mortality, owing to coronary artery disease, com-
to-treat patients.
pared with the non-diabetic control population.
Although death rates from coronary heart disease
suggested that once symptomatic autonomic neu- have fallen in the US, this has not been observed in
ropathy is present, the life prognosis for the patient the diabetic population. Additionally, a three-fold
is significantly diminished. risk of death from cardiovascular disease was seen
in men with diabetes compared to non-diabetic
Treatment of diabetic neuropathy men in the Multiple Risk Factor Intervention Trial
(MRFIT). Excess cardiovascular mortality also
Improving glycaemic control has been shown to occurs in females. There is also an increased mor-
slow the progression of neuropathy. Various agents, tality due to peripheral vascular disease and stroke.
other than simple analgesics and NSAIDs, have been Diabetes is an independent risk factor for stroke,
used to diminish the distressing discomfort associ- especially in a younger population. Mechanisms
ated with painful diabetic neuropathies. Tricyclic for vasculopathy in diabetes include vascular
antidepressants, such as amitriptyline, which have endothelial dysfunction, increased arterial stiff-
a central action that modifies pain perception, and ness and systemic inflammation. Diabetic patients
serotonin-noradrenaline (norepinephrine) reup- account for about 60% of all non-traumatic lower-
take inhibitors, such as duloxetine and venlafaxine, limb amputations in the US. Atheromatous lesions
are recommended first-line agents for the treat- in diabetic patients are histologically identical to
ment of pain when simple agents are ineffective. those in the non-diabetic population, but are more
Anticonvulsants, such as gabapentin, sodium val- severe and widespread. Coronary artery disease
proate and pregabalin, are useful in the treatment of may progress more quickly and, hence, present at a
painful neuropathy as first- or second-line agents. It younger age (Figures 8.32–8.37).
78 Chronic complications of diabetes

Figure 8.34 The same foot as in Figures 8.32

Figure 8.32 Distal gangrene in a diabetic isch- and 8.33 after amputation of the second toe.
aemic foot (dorsal view). A good result has been obtained. However, a
large proportion of diabetic patients with criti-
cal ischaemia or gangrene of the lower limbs
undergo major amputation. Thus, the impor-
tance of adequate screening and preventive
measures to avoid these operations cannot be
overemphasised.

Figure 8.33 Plantar view of the same foot as in

Figure 8.32 shows the common diabetic com-
plications of ischaemia and neuropathy, both
of which may lead to ulceration. The ischaemic
foot is cold, pulseless and subject to rest pain, Figure 8.35 Digital arterial calcification in a
ulceration and gangrene (shown here). Ischaemic diabetic foot. Peripheral vascular disease is a
ulceration usually affects the margins of the foot particularly common vascular complication of
and may be amenable to angioplasty or recon- diabetes and about half of all lower limb amputa-
structive arterial surgery. tions involve diabetic patients.
 Hypertension 79

Hyperglycaemia during acute coronary syn-

drome is associated with a worse outcome. The
Diabetes Mellitus Insulin Glucose infusion in
Acute Myocardial Infarction (DIGAMI) study
demonstrated a 11% reduction in mortality at
1 year in patients treated intensively with insu-
lin at the time of a myocardial infarction and
for a minimum of 3 months thereafter. Diabetic
patients with an acute STEMI should be treated
promptly with revascularisation with fibrinolysis
and primary percutaneous coronary interven-
tion (PCI). Nevertheless, even if reperfusion is
achieved, diabetic patients have a higher mortal-
ity than non-diabetic subjects, particularly those
Figure 8.36 Angiogram showing occlusion of with a recurrent myocardial infarction. Diabetes
the right popliteal artery at the adductor canal may also cause a specific cardiomyopathy in the
in a diabetic patient with peripheral vascular
absence of coronary artery disease.
disease (left). There are many collateral vessels
and the artery reconstitutes distally below the Although risk factors for macrovascular dis-
knee. The opposite side (right), which is normal, ease that pertain to the general population are
is shown for comparison. also relevant to diabetic patients, haemostatic
abnormalities (for example, decreased fibrinolysis
or increased fibrinogen levels), hypertension and
hyperlipidaemia are particularly important in the
latter. Hyperinsulinaemia and insulin resistance
are considered to be significant risk factors for the
development of atherosclerosis.

HYPERTENSION
Hypertension is a major risk factor in the devel-
opment of diabetic complications, both macrovas-
cular and microvascular. Therefore, its detection
and treatment are of vital importance in overall
diabetic management. Hypertension is common in
diabetes: study prevalence rates vary, but it affects
more than 50% of patients with T2DM. The preva-
lence rate is less in patients with T1DM, where it
is particularly associated with incipient and estab-
lished nephropathy. It is a major risk factor for
stroke and coronary artery disease, but also aggra-
vates nephropathy and retinopathy. Blood pressure
starts to rise when microalbuminuria develops,
and the close link between hypertension and
nephropathy may be explained by genetic factors
Figure 8.37 Calcification accompanying medial leading to an increased susceptibility to develop,
sclerosis of the distal lower limb arteries. In diabe- both associated with increased sodium–lithium
tes, the distal blood vessels are often affected by
counter-transport activity in red blood cells. It is
both atheroma and medial sclerosis with calcifica-
tion. This must be borne in mind if reconstructive
now thought that the common link between obe-
vascular surgery or percutaneous transluminal bal- sity, diabetes, hyperlipidaemia and hypertension in
loon angioplasty is contemplated for symptomatic T2DM is insulin resistance and associated hyper-
peripheral vascular disease. The initial success rate insulinaemia, either inherited or perhaps acquired
with angioplasty is reduced in diabetic patients. through malnutrition in early life. Occasionally,
80 Chronic complications of diabetes

hypertension is associated with renal artery ste- THE DIABETIC FOOT

nosis, and this should be investigated, and ACE
inhibitors and ARBs avoided, when this clinical Foot ulceration represents a common, but poten-
suspicion arises. tially serious, complication of diabetes. The esti-
The ADA guidelines for the treatment of hyper- mated prevalence of diabetic foot ulcers is 13% in
tension in diabetes patients recommend initiation North America and 6.4% globally. There is a 2–5%
of therapy if blood pressure is 140/90 or greater with annual incidence of foot ulceration or necrosis and
a target blood pressure of less than 140/90 (lower in 1% may end up with an amputation. Diabetic foot
high-risk patients). Other guidelines recommend a lesions are responsible for more hospital admis-
lower target blood pressure e.g. less than 130/80. It sions than any other complication of diabetes.
has been suggested that targets for blood pressure Diabetic patients with foot ulceration are at a
lowering should be lower than for the non-diabetic higher risk of death than those without foot ulcers.
population because of the major adverse effect of The associated healthcare costs are enormous. In
hypertension in this group. However, caution is 2014, it was estimated that diabetic foot ulceration
advised as the Action to Control Cardiovascular in the US cost $9–13 billion USD in excess of costs
Risk in Diabetes (ACCORD) blood pressure trial of related to diabetes generally. In 2018, a UK study
lowering systolic blood pressure (SBP) to a target of showed that diabetic foot ulceration cost £7800
120 mm Hg versus 140 mm Hg showed no differ- per healed ulcer and £16,900 per amputation. The
ence in primary cardiovascular outcomes between tragedy of this, from both a patient and economic
groups, but an increased incidence of adverse perspective, is that such morbidity and costs result
events in the lower SBP group. The Blood Pressure from lesions that are potentially preventable by the
Control Study incorporated into the UKPDS dem- institution of, and compliance with, diabetic foot
onstrated that a tight blood pressure control policy care policies.
achieving a mean blood pressure of 144/82 gave The main antecedents of diabetic foot ulcer-
a reduced risk for any diabetes-related endpoint, ation are poor glycaemic control, callus formation,
diabetes-related death, stroke, microvascular dis- neuropathy, medium- and small-vessel peripheral
ease, heart failure and progression of retinopathy. vascular disease, improper foot care, ill-fitting
It also demonstrated that in many patients, combi- footwear, dry skin and abnormal foot biome-
nation therapy was necessary to achieve this level chanics (Figure 8.38). These factors are frequently
of blood pressure control. However, effective blood compounded by bacterial infection. The range of
pressure reduction is likely to be more achievable organisms associated with diabetic foot ulceration
than effective blood glucose control. is diverse but Staphylococcus aureus, Pseudomonas
ACE inhibitors (captopril, enalapril, lisinopril,
fosinopril, ramipril, etc.) and ARBs (candesartan,
irbesartan, olmesartan, azilsartan, losartan, etc.)
are the first-line choice to treat diabetic hyperten-
sion, as not only are they effective, but they also
delay the progression of diabetic retinopathy and
diabetic nephropathy (perhaps in the latter by
reducing intraglomerular pressure). The effect of
ramipril in reducing the rates of death, myocardial
infarction and stroke in a broad range of high-risk
patients, about 40% of whom had diabetes, was
demonstrated in the Heart Outcomes Prevention
Evaluation (HOPE) study. Second-line agents rec-
ommended for the treatment of diabetic hyperten-
sion (or first-line when ACE inhibitors and ARBs
cannot be tolerated or are contraindicated) include
thiazide-like diuretics (indapamide, chlorthali-
done) and calcium channel blockers (amlodipine, Figure 8.38 Risk factors for diabetic foot
felodipine, isradipine). ulceration.
 The diabetic foot 81

Figure 8.39 This diabetic patient had known

diabetic neuropathy and had been repeatedly
given foot care advice in his diabetes centre.
Despite this, he walked over a hot surface in a
Mediterranean country in a summer month. By
the time he realised that there was a problem,
he had sustained extensive burn injuries to both
feet, requiring urgent medical attention.

and Escherichia coli species predominate fol-

lowed by Proteus, Klebsiella and Enterococcus.
Bacteroides species occur rarely. Neuropathy is
thought to be the main causative factor in the
development of ulcers with trauma occurring as a
result of loss of pain sensation. Minimal trauma,
such as a foreign body in the shoes, ill-fitting
shoes or walking barefoot on a hot surface, may
lead to devastating effects (see Figures 8.39 and
8.40). Non-enzymatic glycosylation of skin and Figure 8.40 In spite of his diabetes and neu-
connective tissue, together with reduced collagen ropathy, and with good care from the podiatrist,
production, may result in altered biomechanics in this patient’s burns healed remarkably quickly,
fortunately with no adverse sequelae.
the diabetic foot. Excessive pressure loading on the
sole, especially over the metatarsal heads and heels,
predisposes to the formation of calluses, which joint mobility and local deformities including
can break down and lead to ulceration. Indeed, Charcot arthropathy (Figure 8.41). Autonomic
the callus is an important predictor of ulceration. nerve damage leads to reduced sweating and a dry
Such excess pressure is generated by motor-nerve skin which may crack or split more easily, allowing
damage, altering the posture of the foot, limited the ingress of infection. Atherosclerotic disease of
82 Chronic complications of diabetes

Figure 8.42 This neuropathic ulcer on the medial

aspect of the foot in a diabetic patient shows
the characteristic punched-out appearance on
heavily calloused skin. The neuropathic foot
Figure 8.41 Magnetic resonance image of a is numb, warm and dry with palpable pulses.
diabetic foot showing disorganisation of the Charcot arthropathy complicates the neuropathic
talocalcaneonavicular joint with erosions of the foot and presents with warmth, swelling and
articular surface. Such appearances in a diabetic redness (shown here). Ulceration occurs at areas
patient are typical of a Charcot joint. of high pressure in the deformed foot, especially
over the metatarsal heads. Minor trauma, such
as ill-fitting or new shoes, or the presence of a
the peripheral vessels, especially the small vessels,
small undetected object in the shoe can result in
is common in diabetic patients and is an important
serious foot ulceration. Treatment is by bedrest,
predisposing factor in most cases of diabetic foot debridement and appropriate antibiotics to treat
ulceration. Ulcers attributable purely to ischaemia secondary infection. Special shoes and plaster
are relatively rare and, as neuropathy usually co- casts (to allow mobility while taking pressure off
exists, such ulcers are described as neuroischaemic the ulcer) are also useful.
as opposed to the more common neuropathic
ulcers where neuropathy is the critical antecedent
factor. When ulcers are infected, they exhibit local
signs of inflammation such as erythema, warmth
and tenderness, although such signs might be
unimpressive despite definite infection. Deep-
seated infection and osteomyelitis are important
to diagnose. If bone can be felt when probing an
ulcer, osteomyelitis can be assumed. Deep infec-
tion is suggested by the presence of deep sinuses,
a foul discharge and crepitus on palpating the foot
(Figures 8.38–8.40, 8.42–49).
It follows from the previous discussion that risk
factors for the development of diabetic foot ulcers
include the presence of neuropathy (and other Figure 8.43 A deeply penetrating diabetic neuro-
microvascular complications), peripheral vascular pathic ulcer over the metatarsal head caused by a
disease, previous amputation and foot deformity, foreign body. Foot education, especially in those
together with previous foot ulceration, poor foot patients with documented neuropathy, is essential
care advice and advanced age. for preventing such lesions and should be under-
taken by chiropodists, diabetic specialist nurses
The management of diabetic foot ulceration
and diabetic physicians. Diabetic patients should
is complicated and requires great exper- not put their feet in front of fires or on radiators.
tise and experience, particularly because Their feet should also be regularly inspected for
many approaches to treatment are not evi- early ulceration and their shoes carefully checked
dence based. A multidisciplinary approach is for foreign objects before being worn.
 The diabetic foot 83

Figure 8.44 Three radiographs of the same neuropathic foot taken 1 month apart. Progressive damage
to the foot has led to complete disorganisation of the midtarsal joints without osteoporosis. These are
typical appearances of a Charcot joint.

Figure 8.45 Radiographs of the feet of a diabetic

patient showing a neuropathic ulcer over the meta-
tarsal heads of the left foot. Destruction of the left
second metatarsal head and associated soft-tissue Figure 8.46 Osteomyelitis in the diabetic foot
swelling are secondary to osteomyelitis, complicat- with destruction of the base of the third metatar-
ing the ulcer. A fracture on the base of the fifth sal (right) and a periosteal reaction in the shafts
metatarsal is also present. The right foot shows of the adjacent metatarsals accompanied by
Charcot disorganisation of the midtarsal joints. osteoporosis.
84 Chronic complications of diabetes

Figure 8.47 Sagittal magnetic resonance image

of the hind foot of a diabetic patient showing
marrow oedema of the calcaneus consistent with
acute osteomyelitis. There is also fluid deep to
the plantar fascia, consistent with cellulitis. An Figure 8.49 Bone scan showing osteoporotic
ankle effusion is also present. vertebral collapse in a patient with type 1 diabetes
mellitus, which has been associated with a gener-
alised reduction in bone density (diabetic osteopae-
nia). It is probably more common in those patients
exhibiting poor metabolic control and is due to
reduced bone formation rather than increased
resorption. A slightly increased risk of susceptibility
to fracture results from this abnormality.

warranted involving, as necessary, diabetologists,

podiatrists, orthopaedic surgeons, vascular sur-
geons, microbiologists, primary-care physicians,
nurses and orthotists. Debridement and removal
of slough and necrotic eschar is vital to promote
healing. Surgical debridement may occasionally be
necessary for an extensive lesion; however, aggres-
sive debridement should be postponed where
severe ischaemia is present or suspected until
vascular assessment has been undertaken. For
plantar ulcers, off-loading is an important part of
treatment (Figure 8.50). Relief of pressure is a basic
principle of management of all neuropathic ulcers.
The most effective method of off-loading is the use
of a non-removable total-contact cast (TCC) made
of plastic or fibreglass materials (Figure 8.51). For
those who cannot tolerate TCCs, removable casts
may also be used. Therapeutic shoes, customised
insoles and the use of felted foam are alternatives.
Ulcers heal more quickly in a moist environment.
Figure 8.48 Bone scan of the spine (posterior Dressings should be absorbent enough to remove
view) in a poorly controlled type 2 diabetes excess wound exudation, should maintain a moist
mellitus patient shows the florid increase in activity environment and be impermeable to microor-
in adjacent vertebrae typical of osteomyelitis. ganisms. Infection must be treated when present,
 The diabetic foot 85

Figure 8.50 The reduction of weight-bearing Figure 8.51 Off-loading pressure from diabetic
forces is an essential part of the treatment of foot ulcers is essential to allow healing. Total
significant neuropathic ulceration and can be contact plaster casts may be used, but are not
achieved, on a short-term basis, by the use of a free from problems. A more recent alternative
total-contact lightweight plaster cast designed is the Aircast Pneumatic Walker with a Diabetic
to unload pressure from the ulcer and other Conversion Kit. It is a lightweight removable
vulnerable areas while allowing continued plastic brace lined with inflatable chambers to
mobility. For the long term, however, equal promote off-loading. Experience to-date has
redistribution of weight-bearing forces over the shown that such a boot greatly increases the
sole of the foot is achieved by the use of special immediate off-loading capacity of the diabetic
footwear and insoles. foot clinic.

but may be difficult to determine as may be the antibiotic treatment is necessary, usually of at least
causative organism. There is little consensus as to 6 weeks. It should be emphasised, however, that
which antibiotic regimens to use. For mild infec- the duration of treatment has to be individualised.
tions, antibiotics such as cephalexin, amoxicillin- Routine radiography has a role to play in reveal-
clavulanate and clindamycin are indicated. If ing the presence of gas or evidence of osteomyeli-
MRSA is suspected, clindamycin, trimethoprim- tis. It often reveals calcification of the small vessels
sulphamethoxazole, minocycline or linezolid may of the foot. Osteomyelitis can be confirmed by
be used. When anaerobes are implicated, combi- alternative imaging techniques such as magnetic
nation therapy is recommended (e.g. trimethoprim resonance imaging (MRI) or white-cell scanning
with amoxicillin-clavulanate; clindamycin with (Figures 8.46–8.48). In all cases, a vascular assess-
levofloxacin). Patients with moderate to severe ment should be made and amputation may be nec-
infection will require admission to the hospital essary if there is extensive gangrene or spreading
for parenteral antibiotic treatment with agents necrosis in a toxic patient. Revascularisation may
such as vancomycin, meropenem or levofloxacin, be possible for neuroischaemic ulcers.
according to the organism isolated and microbio- Bioengineered skin substitutes, either cell-
logical advice. Mild infections require 7–14 days of containing (Apligraf, Dermagraft, Hyalograft,
antibiotic treatment. Parenteral treatment should Trancell) or acellular (OASIS, GRAFTJACKET),
normally be for 2–4 weeks, but when osteomyelitis show promise as an adjunct therapy for non-
is suspected or present, a much longer duration of infected diabetic foot ulcers and have been shown
86 Chronic complications of diabetes

an orthotist, may be all that is necessary to prevent

one of the most devastating and feared complica-
tions of diabetes: amputation.

ERECTILE DYSFUNCTION
IN DIABETES
Erectile dysfunction (ED) is common in diabetes.
The reported prevalence in one study was 37.5% in
T1DM, 66.3% in T2DM and 57.7% overall, mak-
ing it one of the most common complications of
Figure 8.52 A topical preparation of becapler- diabetes (although figures vary). It is now recog-
min (Regranex♦) has been recently introduced nised that ED represents a vascular complication
as an adjunct in the treatment of full-thickness, of diabetes. Cardiovascular disease increases the
neuropathic, diabetic foot ulcers. Becaplermin risk of ED, but ED itself is probably a risk factor
is a recombinant human platelet-derived growth
for cardiovascular disease. Certainly, studies have
factor. Experience to-date with this product is
limited and it is very expensive. Accurate cost–
shown an association between ED and most of the
benefit analyses are awaited. cardiovascular risk factors, including smoking,
hypertension, hyperlipidaemia, metabolic syn-
drome and depression. ED in diabetes is most
to shorten healing time and to produce a sig- likely a result of a defect in nitric oxide-mediated
nificantly greater proportion of healed ulcers. cavernosal smooth muscle relaxation as a conse-
The platelet-derived growth factor (PDGF-beta), quence of autonomic nerve damage and endothe-
becaplermin (Regranex), a topical agent used as lial dysfunction. Large vessel disease, advanced
a once-daily gel in conjunction with debride- age, hypertension, concomitant drug therapy, long
ment, has been shown to improve healing of duration of diabetes and psychological factors may
small low-grade ulcers, but the FDA has issued also contribute. Furthermore, men with diabetes
a warning of an increased risk of cancer with may be at increased risk of having low serum tes-
excessive use (Figure 8.52). Hyperbaric oxygen tosterone levels which, together with other factors,
has been shown to accelerate the rate of healing may decrease sexual drive. It is important to recog-
and increase the number of wounds completely nise that diabetic women also are at risk of sexual
healed. Studies have attested to the potential ben- dysfunction (problems with desire, arousal, lubri-
efit of negative-pressure wound therapy in the cation, dyspareunia and orgasm).
treatment of diabetic foot ulcers. Debridement Today, male diabetic patients with ED are much
with maggots is simple and effective for cleaning more likely to seek advice and treatment. Every
chronic wounds and initiating granulation. None opportunity for them to so do should be made
of these techniques has become an accepted stan- available and routine enquiry into sexual function,
dard therapy for the treatment of diabetic foot especially in older patients, may well be appro-
ulcers, and further assessments of efficacy and priate. Few investigations are needed. Measuring
cost-effectiveness are required. serum testosterone is indicated if sex drive is
The assessment of foot ulcer risk, the dissemina- reduced. Other endocrine testing should only be
tion of good foot care advice and early and urgent undertaken in the rare situation when a clinical
treatment of established ulceration are the main- suspicion of hypogonadism exists. A detailed his-
stays of the prevention of amputation secondary to tory should be taken to define the precise problem
diabetic foot ulcers. Comprehensive screening and with sexual function.
treatment programmes have been shown to reduce If a diabetic male with ED wishes treatment for
the risk of amputation. Preventative podiatric care the condition, he should be offered an oral agent
should be given to all patients at risk. Simple mea- as a first-line therapy, assuming there is no con-
sures, such as the debridement of callus and the traindication. It is fruitless to try and determine
fitting of appropriate shoes, often with the help of whether the ED has a psychogenic component.
 Erectile dysfunction in diabetes 87

Figure 8.53 Oral treatment of erectile dysfunction with sildenafil is effective in about 60% of patients
with diabetes. Sildenafil selectively inhibits phosphodiesterase type 5 (PDE 5), thereby increasing
levels of cyclic GMP within the corpora cavernosa. This enhances the natural erectile response to
sexual stimulation.

Phosphodiesterase inhibitors (PDE5 inhibitors), with nitrates is an absolute contraindication to the

such as sildenafil (Viagra®), vardenafil (Levitra/ use of PDE5 inhibitors, as the combination may
Staxyn), tadalafil (Cialis) and avanafil (Stendra), produce profound hypotension. Temporary visual
are the agents of choice (Figure 8.53). Inhibition changes have been reported. The success rate for
of this enzyme diminishes the breakdown of PDE5 inhibitors for the treatment of ED in diabetic
nitric oxide via the second messenger cGMP. men is of the order of 50–60%. If one agent is inef-
PDE5 inhibitors only work in the presence of fective, a trial of an alternative PDE5 inhibitor is
sexual stimulation and have no effect on libido. warranted. Once-daily administration of low-dose
Recommended doses should be taken 30 minutes tadalafil has been licensed by the FDA. With some
to 4 hours before planned sexual activity, depend- agents, efficacy may persist for up to 36 hours after
ing on the agent used. The most common side administration. Apomorphine, a centrally act-
effects are headaches, dyspepsia, flushing, nasal ing inducer of erections, has been suggested as an
congestion and nasopharyngitis. Priapism is a alternative to phosphodiesterase inhibitors, but
rare complication and calls for immediate medi- current opinion is that it is of limited benefit.
cal attention to avoid permanent damage to the In those failing to respond to oral agents, erec-
penis. PDE5 inhibitors are not associated with an tion may be induced by the intracavernosal injec-
increased risk of cardiovascular events, although tion of alprostadil (prostaglandin E1), papaverine
the resultant sexual activity may be. Treatment and phentolamine, either alone or in combination.
88 Chronic complications of diabetes

Figure 8.54 Erectile dysfunction in diabetes may be treated by self-injection of the vasoactive drug
alprostadil (Caverject, Pharmacia, Peapack, NJ, US) prostaglandin E1 into the corpus cavernosum of
the penis. The resultant smooth muscle relaxation allows increased blood flow into the penis, and
penile erection will occur whether or not sexual stimulation is present.

However, long-term discontinuation rates are high, Devices which produce a passive penile tumes-
penile pain is a relatively common side effect of cence by applying a vacuum via a hand or battery
such therapy and patients must be warned of the operated pump are available (Figure 8.56). Penile
much more serious complication of priapism. An engorgement is maintained using a rubber con-
alternative mode of delivery of alprostadil is by the striction ring at the base of the penis. Although
transurethral routine using a slender applicator to rigidity sufficient for vaginal penetration may be
deposit a pellet containing alprostadil in polyeth- induced in most patients, the quality of erection
ylene glycol. Such therapy, marketed as Medicated may not be as good as that achieved by pharma-
Urethral System for Erection (MUSE), has been cological methods and many couples may not
successful in about 65% of diabetic men, although find such a technique acceptable for a variety of
often associated with penile pain. Long-term usage reasons. For those who have failed to respond to
rates are not high and some men may actually pre- the approaches mentioned here, and with careful
fer to inject intracavernosally. Patients with low selection and counselling, the surgical implanta-
serum testosterone levels may benefit from replace- tion of a penile prosthesis can be a successful treat-
ment therapy (Figures 8.54, 8.55). ment for erectile failure
 Erectile dysfunction in diabetes 89

Figure 8.55 An alternative method of administering alprostadil is by transurethral application of a

narrow (1.4 mm) pellet of synthetic prostaglandin E1 directly into the male urethra. Although this
removes the need to inject alprostadil, there is still an incidence of penile pain, and controversy exists
as to the efficacy of this procedure.

Figure 8.56 A vacuum system for management of diabetic impotence. Placing the cylinder over the
penis and creating a vacuum with the pump produces an erection which can be maintained by plac-
ing constrictor rings over the base of the penis. Studies have shown that many patients prefer this
non-invasive technique to other, more invasive, methods.
90 Chronic complications of diabetes

NON-ALCOHOLIC or discomfort in the right hypochondrium are

STEATOHEPATOSIS recognised symptoms when symptoms exist, and
hepatomegaly is the only consistent physical sign.
Non-alcoholic fatty liver disease (NAFLD) is a com- Mild to moderate elevation of liver enzymes is often
mon finding in T2DM (with an estimated preva- the only laboratory abnormality. The evaluation of
lence of 70% in obese diabetic adults) and is related patients includes ultrasonography to detect NASH
to obesity and insulin resistance. It less frequently and fibrosis. The ADA guidelines for risk stratifi-
occurs in T1DM. NAFLD is an overarching term cation recommend the use of vibration controlled
which includes simple hepatic steatosis (excess fat in transient elastography (VCTE, Fibroscan) and non-
the form of triglycerides in liver cells, NAFL) and invasive biomarkers. NAFLD is defined by the pres-
non-alcoholic steatohepatitis (NASH). The main ence of 5% or greater of hepatic steatosis by imaging
histological finding in NAFL is, thus, excess triglyc- or histology in the absence of other causes of liver
erides in hepatic cells, while NASH is characterised injury. Various scoring systems are in use to assess
histologically by steatosis, hepatic cell injury in the severity of NAFLD (e.g. NFS, BARD). Liver
the form of ballooning and lobular inflammation. biopsy and histology are the ultimate techniques to
Patients with NASH may progress to hepatic fibrosis quantify steatosis, inflammation and fibrosis.
(cirrhosis), end-stage liver disease and hepatic car- No entirely satisfactory treatment for NAFLD
cinoma. In one study, 35% of cases of NASH pro- has been found. Lifestyle intervention to promote
gressed to liver fibrosis. However, the cause of death weight loss has been shown to be effective in reduc-
in patients with NAFLD is more likely to be cardio- ing steatosis and inflammation. Fibrosis regression
vascular than hepatic, and some authorities consider is more difficult to achieve. Bariatric surgery and
NAFLD to be an independent risk factor for cardio- endoscopic bariatric techniques may also be con-
vascular disease. NAFLD is the most common cause sidered. Therapeutic agents that have been shown to
of abnormal liver blood results among adults in the be beneficial include metformin, SGLT2 inhibitors
US. It is particularly common in those with com- and the thiazolidinedione pioglitazone. Glucagon-
bined diabetes and obesity: in a group of severely like peptide-1 (GLP-1) and gastric inhibitory poly-
obese patients with diabetes, 100% were found to peptide (GIP) receptor agonists have been studied
have mild steatosis, 50% had NASH and 19% had in NAFLD and the dual GLP-1 and GIP agonist
cirrhosis. The pathogenesis of NAFLD in diabetes tirzepatide shows promise in this area.
is complex. Insulin resistance seems to be the most
reproducible causative factor in the development of THE SKIN IN DIABETES
NAFLD and this condition is increasingly viewed as
part of the spectrum of the metabolic syndrome. A variety of disorders of the skin occur in patients
The pathogenesis of NAFLD is complex and not with DM. Some of these conditions are associated
yet fully understood. An incestuous relationship with endocrine or metabolic disorders that may
exists between NAFLD and T2DM. The accumula- themselves cause diabetes (Figure 8.57).
tion of hepatic fat may occur as a consequence of
dietary fat intake, obesity and insulin resistance, Acanthosis nigricans
with insulin resistance playing a key role. Deposition
of lipid in hepatocytes comes from triacylglycerols This skin manifestation is often missed on exami-
derived from free fatty acids (FFAs), de novo lipo- nation, but is nevertheless fairly frequently encoun-
genesis and diet. Diabetes-related hyperinsulinae- tered in patients with DM, especially in those
mia stimulates lipogenesis with a resultant increase with genetic syndromes of insulin resistance and
in delivery of FFAs to the liver. Excess stored fat metabolic syndrome. It is characterised by a velvety,
leads to abnormal lipid peroxidation and release papillomatous, usually pigmented, overgrowth of
of pro-inflammatory cytokines and other factors, the epidermis and occurs particularly in the axillae,
which results in liver damage. Other proposed neck, groin and inframammary areas (Figure 8.58).
aetiological factors include hyperglycaemia-related It may be caused by hyperinsulinaemia-induced
glucotoxicity, glucagon resistance, environmental stimulation of insulin-like growth factor (IGF)-1
and genetic factors and dysregulation of the gut receptors, leading to keratinocyte and dermal
microbiome. Malaise and a sensation of fullness fibroblast proliferation.
 The skin in diabetes 91

Necrobiosis lipoidica diabeticorum

Necrobiosis occurs in 0.3% of diabetic patients
with 50% having T1DM. Although traditionally
thought of as a classical diabetic skin manifesta-
tion, it can also occur in patients without diabe-
tes. Necrobiosis usually develops in young adults
or in early middle life and is much more common
in women than in men. The skin is the most com-
monly affected site and the appearance ranges
from early dull red papules or plaques to indurated
plaques with skin atrophy, often with telangiectatic
vessels on a waxy yellowish background to actual
skin ulceration (Figures 8.59 and 8.60). Treatment

Figure 8.57 Many abnormalities of the skin are

found in diabetic patients. Some may not be
specific to diabetes. Acanthosis nigricans is a skin
manifestation of insulin-resistant states, while
vitiligo is a cutaneous marker of autoimmunity.
Eruptive xanthomata are associated with signifi-
cant hypertriglyceridaemia. Necrolytic migratory
erythema occurs in patients with a glucagonoma
and associated diabetes and is very rare. The
rashes of insulin allergy, lipoatrophy and lipo-
hypertrophy are all associated with exogenous Figure 8.59 A typical lesion of necrobiosis lipoidica
insulin administration. diabeticorum on the shin. These lesions are usually
non-scaling plaques with yellow atrophic centres
and an erythematous edge, and predominantly
affect diabetic women. They vary consider-
ably in size, and are often multiple and bilateral.
Necrobiosis may occur in non-diabetic subjects.

Figure 8.58 Acanthosis nigricans is uncommon.

These brown hyperkeratotic plaques with a
velvety surface occur most frequently in the Figure 8.60 Necrobiosis may become severe
axillae and flexures, and on the neck. Acanthosis and ulcerative, causing great distress in affected
is associated with insulin resistance caused by patients. Spontaneous regression may occur and
genetic defects in the insulin receptor or postre- treatment tends to be unsatisfactory. Skin grafts
ceptor function or the presence of antibodies to may become complicated by recurrence within
the insulin receptor. the graft or at an adjacent site.
92 Chronic complications of diabetes

is controversial, largely unproven and usually inef-

fective. Intralesional or topical corticosteroids,
photochemotherapy or excision and skin grafting
may have limited roles.

Diabetic dermopathy
These well-circumscribed, atrophic, brownish scars
commonly seen on the shin (‘shin spots’) occur
in up to 50% of diabetic patients (Figure 8.61)
and are also seen much less frequently in non-
diabetic subjects. Although there is no effective
treatment, they tend to regress over time.

Diabetic bullae
Tense blisters, more common in men than women,
occurring most frequently on the lower legs and
feet, occur rarely in diabetic patients (Figure 8.62).
They appear rapidly and heal after a few weeks.

Other
Other skin conditions encountered in diabetic
patients are diabetic erythema, periungual tel-
angiectasia, diabetic thick skin (linked with the Figure 8.62 Bullous lesions rarely occur in dia-
formation of advanced glycation end-products), betes, and can only be diagnosed when other
vitiligo (autoimmune destruction of melanocytes, bullous disorders have been excluded. They
usually occur suddenly with no obvious history
Figure 8.63), eruptive xanthomata (caused by
of trauma and may take a long time to heal. The
hypertriglyceridaemia in diabetic dyslipidaemia, lower legs and feet are usually affected, and
there is a male preponderance.

Figure 8.61 Diabetic dermopathy. These

pigmented pretibial patches are often seen in
diabetic patients, but are not pathognomonic of Figure 8.63 Vitiligo, autoimmune destruction
the disease. There is a male preponderance and of melanocytes, is commonly seen in patients
the lesions are discrete, atrophic, scaly or hyper- with type 1 diabetes mellitus, itself an autoim-
pigmented. The underlying cause is not known. mune condition.
 The skin in diabetes 93

Figures 8.64 and 8.65), migratory necrolytic ery-

thema (associated with glucagonoma syndrome,
Figure 8.66) and urticarial reactions to insulin
allergy. Granuloma annulare (Figure 8.67) has
been linked with diabetes but evidence is lacking
to prove a true association.

Figure 8.66 Migratory necrolytic erythema.

This rash is associated with glucagon-secret-
ing pancreatic tumours (or occasionally zinc
deficiency). Such rashes tend to wax and wane
in cycles of 1–2 weeks. Diabetes is presumed
to be due to increased glucagon-stimulated
hepatic gluconeogenesis. Weight loss, diar-
rhoea and mood changes are frequent fea-
Figure 8.64 Eruptive xanthomata. Type V hyper- tures, but death is usually due to massive
lipoproteinaemia with an increase in very-low- venous thrombosis. Treatment is by zinc
density lipoproteins and chylomicrons is often supplementation, or somatostatin or a soma-
associated with glucose intolerance. This lipo- tostatin analogue.
protein abnormality is accentuated by obesity
and alcohol consumption, and may lead to acute
pancreatitis and peripheral neuropathy.

Figure 8.67 Granuloma annulare. Although

this skin condition is occasionally seen in
diabetic patients, several large studies failed
to reveal a significant association between
Figure 8.65 Massive eruptive xanthomata in a the two disorders, both of which are relatively
young man with type 2 diabetes mellitus. common.
94 Chronic complications of diabetes

RARER MANIFESTATIONS Although seen in both adult-onset T1DM and

OF DIABETES MELLITUS T2DM, it is most commonly encountered in chil-
dren and young adults with T1DM, often related
Diabetic cheiroarthropathy to poor glycaemic control and associated with
other more specific diabetic complications, such
This rheumatic complication of diabetes manifests as retinopathy.
itself as limited joint mobility associated with
thickening and tightening of the skin, especially
Dupuytren’s contracture
noticed on the dorsal surfaces of the hands.
Resultant contraction prevents the affected patient Dupuytren’s contracture (Figure 8.69) has a
from placing their hand flat on to a surface and quoted prevalence varying between 20% and 63%
from approximating the palmar surfaces of in DM. Furthermore, in patients presenting with
the hand—the ‘prayer’ hand sign (Figure 8.68). Dupuytren’s contracture, a high prevalence of
diabetes is found. It is more commonly found in
elderly patients with a long duration of diabetes
and may have an association with carpal tunnel
syndrome.

Adhesive capsulitis of the shoulder

There are numerous reports of an association
between periarthritis of the shoulder—‘frozen
shoulder’—and DM, and such patients are encoun-
tered frequently in routine diabetic follow-up clin-
ics. This condition is characterised by pain and the
limitation of movement of the shoulder joint, both
active and passive. Referral to a rheumatologist is
appropriate (Figures 8.70–8.73).

Figure 8.68 Diabetic cheiroarthropathy or lim-

ited joint mobility is characterised by an inability
to extend fully the metacarpophalangeal and
proximal interphalangeal joints when the tips of
the fingers and palms of the hands are opposed
in the so-called prayer sign. Although it may be
seen in adult-onset type 1 and 2 diabetes mel- Figure 8.69 Dupuytren’s contracture is common
litus, it is most commonly seen in children and in patients with diabetes mellitus. Conversely,
young adults with type 1 diabetes mellitus. The in patients presenting with Dupuytren’s contrac-
development of this abnormality is linked to the ture, a high prevalence of diabetes is found. The
duration of diabetes. When present, other dia- exact nature of the link between the two condi-
betic complications are likely to coexist. tions remains unclear.
 Rarer manifestations of diabetes mellitus 95

Figure 8.70 Candidiasis is a common fungal Figure 8.72 Severe bacterial infection in a poorly
infection in diabetic patients. Although particularly controlled diabetic patient. Although it is widely
common in the vagina or perineum (pruritus vulvae), believed that diabetic patients are more prone to
under the breasts (intertrigo) and on the tip of the infection than non-diabetic subjects, it is unclear
penis (balanitis), it may occur elsewhere. The yeasts whether diabetic patients have an increase in the
thrive in glucose-containing media and, hence, rate of infection in general. Diabetic patients are
control of blood-glucose levels helps to eradicate susceptible to certain infections, including tuber-
this troublesome infection. Antifungal creams may culosis, urinary tract infections and infections due
be necessary until glucose levels are controlled, but to unusual micro-organisms, such as osteomyeli-
oral antifungal agents are rarely required. tis, mucormycosis and enterococcal meningitis.
Diabetes is thought to impair several aspects of
cellular function necessary to combat infection.

Figure 8.73 Malignant otitis externa. This infec-

tion, which can be extremely serious, is almost
always due to the Pseudomonas species, as was
the case here. Affected patients usually have
Figure 8.71 Balanitis secondary to diabetes mel- poorly controlled diabetes. This elderly diabetic
litus is a candidal infection of the distal end of patient has a seventh cranial nerve palsy as a
the penis and is common at the time of presenta- complication. Antipseudomonal antibiotics and
tion of diabetes in men. an early surgical opinion are advised.
96 Chronic complications of diabetes

BIBLIOGRAPHY Finne P, Reunanen A, Stenman S, et al.

Incidence of endstage renal disease in
Aiello LP, Gardner TW, King GL, et al. Diabetic patients with Type 1 diabetes. JAMA.
retinopathy. Diabetes Care. 1998; 21: 143–56 2005; 294: 1782–7
Alexiadou K, Doupis J. Management of diabetic Gross JL, et al. Diabetic nephropathy: Diagnosis,
foot ulcers. Diabetes Ther. 2012 Dec: 3(1): 4. prevention, and treatment. Diabetes Care.
Doi: 10.1007/s13300-012-0004-9 2005 Jan; 28(1): 164–76. Doi: 10.2337/
Angulo P. Nonalcoholic fatty liver disease. N Engl diacare.28.1.164
J Med. 2002; 346: 1221–31 Ho T, Smiddy WE, Flynn HW Jr. Vitrectomy in the
Archer AG, Watkins PJ, Thomas PK, Sharma AK, management of diabetic eye disease. Surv
Payan J. The natural history of acute pain- Ophthalmol. 1993; 37: 190–202
ful diabetic neuropathy. J Neurol Neurosurg Javed S, et al. Treatment of painful diabetic neu-
Psychiatr. 1983; 46: 491–9 ropathy. Ther Adv Chronic |Dis. 2015 Jan 6(1):
Arkkila PE, Kantola IM, Viikari JS, et al. 15–28. Doi: 10.1177/2040622314552071
Dupuytren’s disease in type 1 diabetic Jelinek JE. The skin in diabetes. Diabetic Med.
patients: A five-year prospective study. 1993; 10: 210–13
Clin Exp Rheumatol. 1996; 14: 59–65 Jonas JB. Intravitreal triamcinolone acetonide for
Barnett AH, Dodson PM. Hypertension and diabetic retinopathy. Dev Ophthalm. 2007; 39:
Diabetes. London: Science Press Ltd, 1990 96–110. Doi: 10.1159/000098502
Bell DS. Diabetic cardiomyopathy. A unique Lewis EJ, Hunsicker LG, Pain RP, Rohde RD. The
entity or complication of coronary artery dis- effect of angiotensin-converting enzyme
ease? Diabetes Care. 1995; 18: 708–14 inhibition on diabetic nephropathy. N Engl J
British Multicentre Study Group. Photocoagulation Med. 1993; 329: 1456–65
for - proliferative diabetic retinopathy: A Maiorino MI, et al. Diabetes and sexual dysfunc-
randomised controlled clinical trial using the tion: Current perspectives. Diabetes Metab
zenon arc. Diabetologia. 1984; 26: 109–15 Syndr Obes. 2014; 7: 95–105. Doi: 10.2147/
Chauhan A, Foote J, Petch MC, Schofield PM. DMSO.S36455
Hyperinsulinemia, coronary artery disease Malmberg K. Prospective randomised study
and syndrome X. J Am Coll Cardiol. 1994; of intensive insulin treatment on long term
23: 364–8 survival after acute myocardial infarction
Dyck PJ, Thomas PK, Asbury AK, et al. Diabetic in patients with diabetes mellitus. GIGAMI
Neuropathy. Philadelphia: WB Saunders, 1987 (Diabetes Mellitus, Insulin Glucose Infusion
Early Treatment of Diabetic Retinopathy Study in Acute Myocardial Infarction) Study Group.
Research Group. Photocoagulation for Br Med J. 1997; 314: 1512–15
diabetic macular oedema. Arch Ophthalmol. McCulloch DK, Young RJ, Prescott RJ, Clarke BF.
1985; 103: 1796–806 The natural history of impotence in diabetic
Edmonds ME. The diabetic foot: Pathophysiology men. Diabetologia. 1984; 26: 437–40
and treatment. Clin Endocrinol Metab. 1993; Mogensen CE. Microalbuminuria predicts clinical
15: 889–916 proteinuria and early mortality in maturity-
Estacio RO, Schrier RW. Diabetic nephropathy: onset diabetes. N Engl J Med. 1984; 310:
Pathogenesis, diagnosis, and prevention 356–60
of progression. Adv Intern Med. 2001; 46: Mogensen CE, Cooper ME. Diabetic renal dis-
359–408 ease: From recent studies to improved clinical
Everett E, Mathioudakis N. Update on manage- practice. Diabet Med. 2004; 21: 4–17
ment of diabetic foot ulcers. Ann NY Acad Passadakis P, Oreopoulos D. Peritoneal dialysis
Sci. 2018 Jan; 1411(1): 153–65. Doi: 10.1111/ in diabetic patients. Adv Ren Replace Ther.
nyas.13569 2001; 8: 22–41
Ewing DJ, Campbell IW, Clarke BF. The natural Passarella P, et al. Hypertension management in
history of diabetic autonomic neuropathy. Q J diabetes. Diabetes Spectr. 2018 Aug; 31(3):
Med. 1980; 193: 95–108 218–24. Doi: 10.2337/ds17-0085
 Rarer manifestations of diabetes mellitus 97

Perez MI, Kohn SR. Cutaneous manifestations of Tomah S, et al. Nonalcoholic fatty liver disease
diabetes mellitus. J Am Acad Dermatol. 1994; and type 2 diabetes: Where do diabetologists
30: 519–31 stand. Clin Diabetes Endocrinol 6, 9 (2020).
Reaven GM. Role of insulin resistance in human Doi: 10.1186/s40842-020-00097-1
disease. Diabetes. 1988; 37: 1595–607 UK Prospective Diabetes Study Group. Efficacy
Scobie IN, MacCuish AC, Barrie T, et al. Serious of atenolol and captopril in reducing risk of
retinopathy in a diabetic clinic: Prevalence and macrovascular and microvascular complica-
therapeutic implications. Lancet. 1981; 2: 520–1 tions in type 2 diabetes; UKPDS 39. Br Med J.
Selby NM, Taal MW. An updated overview of 1998; 317: 713–20
diabetic nephropathy: Diagnosis, progno- UK Prospective Diabetes Study Group. Tight
sis, treatment goals and latest guidelines. blood pressure control and risk of macrovas-
Diabetes Obes Metab. 2020, April; 22(Suppl cular and microvascular complications in type
1): 3–15. Doi: 10.1111/dom.14007 2 diabetes: UKPDS 38. Br Med J. 1998; 317:
Shapiro LM. A prospective study of heart disease 703–13
in diabetes mellitus. Q J Med. 1984; 209: Vinik A, Park TS, Stansberry KB, Pittenger GL.
55–68 Diabetic neuropathies. Diabetologia. 2000;
Solomon SD, Chew E, Duh EJ, Sobrin L, Sun JK, 43: 957–73
VanderBeek BL, Wykoff CC, Gardner TW. Watkins PJ. The diabetic foot. Br Med J. 2003;
Diabetic retinopathy: A position statement by 326: 977–9
the American diabetes association. Diabetes Young MJ, Boulton AJM, MacLeod AF, et al.
Care. 2017; 40(3): 412–18. Doi: 10.2337/ A multicentre study of the prevalence of
dc16-2641 diabetic peripheral neuropathy in the
Spruce MC, Potter J, Coppini DV. The pathogen- United Kingdom hospital clinic population.
esis of painful diabetic neuropathy: A review. Diabetologia. 1993; 35: 150–4
Diabet Med. 2003; 20: 88–98 Yusuf S, Sleight P, Pogue J, et al. Effects of an
Stern M. Natural history of macrovascular disease angiotensinconverting-enzyme inhibitor,
in type 2 diabetes. Role of insulin resistance. ramipril, on cardiovascular events in high-risk
Diabetes Care. 1999; 22(Suppl 3): c2–5 patients. The heart outcomes prevention
Taylor KG, ed. Diabetes and the Heart. Tunbridge evaluation study investigators. N Engl J Med.
Wells: Castle House Publications, 1987 2000; 342: 145–53
 9
Diabetic dyslipidaemia

Lipid disorders assume a position of utmost impor- from lipid-lowering therapy with statins (hydroxy-
tance in patients with diabetes because of the high methylglutaryl-coenzyme A [HMG-CoA] reduc-
risk of macrovascular disease in this condition tase inhibitors). Such agents include simvastatin
which accounts for 50–70% of deaths. Patients with (Zocor, FloLipid), atorvastatin (Lipitor), pravas-
well-controlled type 1 diabetes mellitus (T1DM) tatin (Pravachol), pitavastatin (Livalo) and rosu-
have lipoprotein concentrations similar to the back- vastatin (Crestor, Ezallor). Simvastatin-treated
ground non-diabetic population. With poor con- patients with diabetes in the Scandinavian
trol, increased concentrations of triglyceride-rich Simvastatin Survival Study (4S Trial) exhibited
lipoproteins are seen, giving rise to hypertriglyc- reductions in major coronary events and revascu-
eridaemia. However, it is estimated that 30–60% larisation procedures of 42% and 48%, respectively.
of patients with type 2 diabetes mellitus (T2DM) The Collaborative Atorvastatin Diabetes Study
have hyperlipidaemia. The most common lipopro- (CARDS) included 2838 patients with T2DM and
tein abnormalities in T2DM are increased levels of no documented previous history of CVD with at
triglycerides, very-low-density lipoprotein (VLDL) least one of the following features: retinopathy,
and intermediate-density lipoprotein (IDL) caused albuminuria, current smoking or hypertension.
by an overproduction of VLDL triglyceride. Low- Patients had an LDL cholesterol concentration of
density lipoprotein (LDL) levels are no different 4.14 mmol/l (160 mg/dl) or lower. As compared to
from normal subjects, but a number of poten- a placebo, the addition of atorvastatin 10 mg daily
tially atherogenic changes in LDL composition led to a 37% reduction in major cardiovascular
have been observed, particularly a predominance events and reduced the risk of stroke by 48% with,
of small dense LDL particles which are known to overall, a highly statistically significant reduc-
be particularly atherogenic. The increase in LDL tion in the composite primary endpoint of acute
particles, together with the increased VLDL and coronary events, coronary revascularisation and
IDL, leads to an increase in apolipoprotein B levels. stroke. A 27% decrease in all-cause mortality was
The finding of decreased high-density lipoprotein also observed, however, this just failed to reach
(HDL) concentrations is very prevalent in T2DM, statistical significance. The Cholesterol Treatment
contributing to the atherogenic lipid profile of this Trialists analysed data from 18,686 subjects with
disorder. Elevation of postprandial lipids including diabetes (mostly T2DM) from 14 randomised
triglycerides further increases the risk of cardiovas- trials and observed a 9% decrease in all-cause
cular disease (CVD). The lipid changes of T2DM mortality, a 13% decrease in vascular mortality
described previously mimic the lipid changes in and a 21% decrease in major vascular events per
obesity and the metabolic syndrome, features fre- 39 mg/dl (1.01 mmol/l) in LDL cholesterol in the
quently seen in patients with T2DM. No consistent statin-treated group. Similar results were seen in
change in lipoprotein A (Lp(a)) concentrations has the Heart Protection Study (HPS) in the subgroup
been found in T2DM. with T2DM, with the suggestion that patients with
Studies have shown that patients with T2DM T1DM in the study benefited to the same degree
benefit at least as much as non-diabetic subjects as those with T2DM. Secondary prevention trials

98 DOI: 10.1201/9781003342700-9
 Diabetic dyslipidaemia 99

yielded similar results. The results of trials using guidelines with a cut-off of a LDL cholesterol of
fibrates as lipid-lowering monotherapy in diabe- ≥70 mg/dl (1.8 mmol/L), leading to the initiation
tes have not shown results as robust as the statin of statin therapy. A target reduction of LDL choles-
trials. In the Fenofibrate Intervention and Event terol of 30–49% is recommended, while the ADA
Lowering in Diabetes (FIELD) trial of fenofibrate recommends a reduction of LDL of 50% in those
in 9795 patients between the ages of 50 and 75 patients with a 10-year cardiovascular risk >20%.
with T2DM, there was a reduction of 11% in the
primary outcome of coronary events (coronary BIBLIOGRAPHY
heart disease death and non-fatal MI (myocardial
infarction)) that did not reach statistical signifi- Colhoun HM, Betteridge DJ, Durrington PN,
cance, although there was a statistically significant et al. Primary prevention of cardiovascular
decrease in non-fatal MI and total cardiovascu- disease with Atorvastatin in Type 2 Diabetes
lar events. A greater reduction in cardiovascular in the Collaborative Atorvastatin Diabetes
events in patients with high triglyceride levels was Study (CARDS): Multicentre randomised
noted in the fibrate trials. No useful recent trials of placebo-controlled trial. Lancet. 2004; 36:
niacin, ezetimibe and PCSK9 inhibitors in diabetic 685–96
subjects have been reported. No useful benefit of Durrington P. Statins and fibrates in the manage-
a statin-fibrate combination was demonstrated ment of diabetic dyslipidemia. Diabet Med.
beyond statin therapy alone. As patients with 1997; 14: 513–16
T2DM are known to be at the same risk of a CVD Goldberg RB, Mellies MJ, Sacks FM, et al.
event as non-diabetic patients with existing CVD, Cardiovascular events and their reduction
and given the evidence stated here, lipid-lowering with pravastatin in diabetic and glucose-
therapy is likely to be as clinically effective and intolerant myocardial infarction survivors with
cost-effective in patients with T2DM who have not average cholesterol levels. Circulation. 1998;
yet sustained a cardiovascular event as in non-dia- 98: 2513–19
betic subjects with documented CVD. Haffner SM, Alexander CM, Cook TJ, et al.
The American Diabetes Association (ADA) Reduced coronary events in simvastatin-
recommends that all adult patients with diabetes treated patients with coronary heart dis-
should have a fasting lipid profile at diagnosis to ease and diabetes or impaired fasting
assess their lipid status, repeated every 5 years or glucose levels: Sub-group analyses in the
sooner as clinically indicated. If statin therapy Scandinavian Simvastatin Survival Study.
is instituted, a further profile should be carried Arch Intern Med. 1999; 159: 2661–7
out 4–12 weeks after the initiation of treatment. Jialal I, Singh G. Management of diabetic
Lifestyle modification focusing on the reduction dyslipidemia: An update. World J Diabetes.
of saturated fat and cholesterol intake, weight loss 2019 May 15; 10(5): 280–90. Doi: 10.4239/
(where indicated) and increased physical activity is wjd.v10.i5.280
recommended for diabetic patients with hyperlipi- Rubins HB, Robins SJ, Collins D, Veterans
daemia and has been shown to improve the lipid Affairs High-Density Lipoprotein Cholesterol
profile. Patients under 40 years of age with cardio- Intervention Trial Study Group, et al.
vascular risk factors and almost all patients over 40 Gemfibrozil for the secondary prevention of
will end up on statin therapy to prevent CVD. The coronary heart disease in men with low levels
addition of ezetimibe or a PCSK9 inhibitor should of high-density lipoprotein cholesterol.
be considered in patients with high cardiovascu- N Engl J Med. 1999; 341: 410–18
lar risk or very high LDL levels. The American Steiner G. Lipid intervention trials in diabetes.
College of Cardiology and The American Heart Diabetes Care. 2000; 23(Suppl 2): B49–53
Association guidelines are similar to the ADA
 10
Diabetes and pregnancy

Over the past two decades, there has been a pro- times that in the background population in various
gressive increase in the incidence of both estab- studies. Given that these abnormalities reflect very
lished and gestational diabetes such that almost 1 early fetal development, optimising blood glucose
in 10 pregnancies over the age of 30 are affected and diabetes control prior to pregnancy is essential
by diabetes. The most striking change has been the and, similarly, in the preconception period, it is
emergence of type 2 diabetes mellitus (T2DM) in important to consider other risk factors related to
pregnancy as a major clinical issue, reflecting the pregnancy, including the use of antihypertensive
earlier age of onset of T2DM across the Western and lipid-lowering medications, which should be
world. Of note, in data from the UK National stopped prior to conception. There is strong evi-
Pregnancy in Diabetes Audit, the median age of dence that supplementation with folic acid reduces
women with T2DM in pregnancy was only 34 years, the risk of neural tube defects and initiation of this
and this group included a higher-than-expected prior to conception is now standard practice with
proportion of women from socially deprived back- the higher dose of 5 mg being recommended.
grounds, reflecting the impact of socioeconomic A specific complication of diabetic pregnancy is
factors on the development of early type 2 diabetes. the development of macrosomia, defined as a birth
Poor glycaemic control can have an impact weight greater than the 90th percentile of the back-
on fetal development from the time of concep- ground population. This can occur in both gesta-
tion onwards. The exact mechanisms by which tional diabetes and in the context of pregnancy in
hyperglycaemia impacts fetal development remain women with established type 1 and type 2 diabetes
poorly understood and may vary across the course present prior to conception. Infants with macro-
of the pregnancy. Thus, in the early weeks after somia are more likely to have perinatal problems,
conception, the primary impact may relate direct particularly hypoglycaemia, but also respiratory
osmotic effects of glucose and osmotic and oxida- distress, hyperbilirubinaemia and birth injuries,
tive stress associated with hyperglycaemia. Later in particularly shoulder dystocia related to increased
pregnancy, following the development of the fetal size at birth. Despite improvements in medical
islets, hyperinsulinaemia may be an important care, macrosomia rates remain very high, with 57%
contributor to abnormal fetal growth. of type 1 and 24% of type 2 pregnancies resulting
Despite increased understanding of the impact in a baby who was large for gestational age in a
of diabetes on pregnancy, there remains a signifi- 2020 UK national audit.
cantly higher rate of congenital malformations There is an increased incidence of early preg-
complicating pregnancies, including pre-existing nancy loss in diabetes and of preterm labour. At
diabetes. The most common anomalies are those term, there are increased rates of fetal distress with
affecting the cardiovascular system and central characteristic patterns of recurrent heart decel-
nervous system including ventricular septal defect, erations on intrapartum fetal cardiac monitoring,
patent ductus arteriosus and transposition of the indicating hypoxia. This may reflect a decline in
great arteries. Anencephaly and spina bifida are placental function and is particularly seen in the
common, with rates reported at greater than 10 presence of macrosomia. A specific early warning

100 DOI: 10.1201/9781003342700-10

 Management of diabetes in pregnancy 101

Figure 10.1 A macrosomic baby born to a diabetic mother. Macrosomia reflects suboptimal diabetes
control, particularly in late pregnancy, and increased fetal insulin secretion in relation to an increased
substrate load. Macrosomia can occur in all types of diabetic pregnancy. Despite advances in diabetes
care, it remains common, with some 57% of pregnancies in type 1 mothers resulting in babies who
were large for gestational age.

sign of poor placental function in late diabetic preg- hypoglycaemia can be challenging and is depen-
nancy is a drop in insulin requirements or increased dent on frequent monitoring. In view of this, the
frequency of hypoglycaemia and both should war- use of continuous glucose-monitoring (CGM) sys-
rant further assessment of fetal health by cardioto- tems has become widespread and, in the UK, is now
cography accompanied by placental ultrasound recommended for the management of women with
imaging, where appropriate (Figure 10.1). type 1 diabetes mellitus (T1DM) during pregnancy.
This recommendation was based on strong evi-
MANAGEMENT OF DIABETES dence from a UK randomised controlled trial and
IN PREGNANCY a Swedish observational study that showed that the
use of CGM was associated with greater achieve-
The management of diabetes in pregnancy is ment of glycaemic targets, but also fewer Caesarean
aimed at achieving very tight blood-glucose con- sections and neonatal intensive care admissions.
trol throughout with target glucose levels of For women using CGM, an additional target of
<5.3 mmol/l fasting, <7.8 mmol/l at 1-hour post- achieving more than 70% of time in a target range
meal and <6.4 mmol/l at 2 hours postmeal. These of 3.5–7.8 mmol/l is also widely advocated.
targets are consistent regardless of the type of dia- Diabetes management is based primarily on the
betes. Achieving these targets without problematic use of basal bolus insulin regimes with adjustment of
102 Diabetes and pregnancy

mealtime insulin for carbohydrate. Insulin require- and a history of macrosomia following a previous
ments increase progressively through pregnancy and pregnancy) at 24–26 weeks’ gestation.
moderating mealtime carbohydrate portions may be Following diagnosis, treatment is based on
necessary to enable adequate postprandial glucose achieving and sustaining the same glucose controls
control. The use of insulin pump and automated as used for established diabetes. For many women,
insulin-delivery systems in pregnancy is growing this can be achieved with dietary management and
and is widely advocated for the management of type the use of metformin which is now accepted as
1 patients with problematic hypoglycaemia, which being safe during pregnancy and is widely used. A
can be a major issue with rapid tightening of blood minority of women (15–30%) require insulin treat-
glucose control. At present, there is limited specific ment, particularly to optimise postprandial insu-
evidence on the role of insulin pump and automated lin levels and, in some cases, insulin requirements
insulin delivery compared to basal bolus insulin can be very high, reflecting the underlying insu-
regimes on pregnancy outcomes, but several ran- lin resistance that underlies gestational diabetes.
domised clinical trials of closed-loop technology in Without adequate treatment, gestational diabetes
pregnancy are in progress. carries a similar risk of late pregnancy complica-
tions to that seen in established diabetes, with sig-
GESTATIONAL DIABETES nificant rates of adverse outcomes being seen in a
meta-analysis of published studies.
Gestational diabetes mellitus (GDM) is defined as
glucose intolerance first appearing in pregnancy BIBLIOGRAPHY
and reflects the increased metabolic demands
placed on the mother. Following delivery, glucose Murphy HR, Howgate C, O’Keefe J et al.
metabolism returns to normal, but affected women Characteristics and outcomes of pregnant
have an increased lifelong risk of subsequent dia- women with type 1 or type 2 diabetes:
betes, with an approximately ten-fold increased A 5-year national population-based
risk of diabetes compared to the general popula- cohort study. Lancet Diabetes Endocrinol.
tion. In some cases, apparent GDM can be the first 2021 Mar; 9(3): 153–64. doi: 10.1016/
presentation of T2DM and even T1DM unmasked S2213-8587(20)30406-X
by the changes occurring in pregnancy. There is NHS Digital 2021. National Pregnancy in
now consensus that the diagnosis of gestational Diabetes (NPID) Audit Report 2020. Published
diabetes should be based on the results of a 75 g Online 14/1021 at https://www.hqip.org.uk/
glucose tolerance test with the diagnostic thresh- wp-content/uploads/2021/10/REF232_NPID-
olds being a fasting glucose of 5.6 mmol/l or a 2020-Report_v20211010_FINAL.pdf
2-hour postglucose result of 7.8 mmol/l. UK NICE Ye W, Luo C, Huang J, et al. Gestational diabetes
guidance recommends screening of any women mellitus and adverse pregnancy outcomes:
with risk factors for gestational diabetes (includ- Systematic review and meta-analysis. BMJ.
ing BMI >30, family history of diabetes, ethnicity 2022; 377. doi: 10.1136/bmj-2021-067946
 11
Living with diabetes

In common with other chronic medical condi- to the non-diabetic population, with many cases
tions, diabetes mellitus impacts on quality of life, going unrecognised. Meta-analyses have sug-
sometimes significantly so. The fear of hypogly- gested that the global prevalence of depression
caemia (for those patients treated with sulpho- in people with T2DM has increased from 20% in
nylureas or insulin) and concern about glycaemic 2007 to 32% in 2018. A recent study showed that
control and diabetic complications are ever pres- people who develop T2DM at an age less than
ent. Advances in therapeutic agents, such as novel 40 years have a greater risk of developing depres-
insulin preparations, have undoubtedly improved sion than those diagnosed at 50 years or greater.
diabetic patients lives, while the advent of insulin Interestingly, depression commonly precedes the
pen devices to administer insulin was a great step diagnosis in T2DM patients, as previously men-
forward for insulin-treated patients followed by tioned. The course of depression in diabetes may
insulin-pump therapy. Perhaps the greatest revolu- be particularly chronic, and severe and depres-
tion in the care of people with diabetes has been sion is associated with adverse glycaemic control
the relatively recent introduction of sturdy and and clinical outcomes. Separate from depression,
reliable systems of relatively non-invasive continu- studies have identified a high prevalence of diabe-
ous glucose monitoring. Complications of diabe- tes distress, defined as patient concerns about dis-
tes such as visual impairment due to retinopathy, ease management, support, emotional burden and
neuropathy, nephropathy and erectile dysfunction access to care, affecting one in four patients with
clearly have a significant effect on the quality of T1DM and one in five with T2DM. Such patients
diabetic patients’ lives. The diagnosis of diabetes may be identified using simple scales in clinical
invokes stress in affected individuals. In one study, practice (Diabetes Distress Scale, Problem Areas
at the time of diagnosis of type 1 diabetes melli- in Diabetes [PAID] Scale). The diagnosis of dia-
tus (T1DM), 36% of children exhibited significant betes affects other aspects of the diabetic patient’s
psychological distress. Remarkably, however, in life. In most developed countries, drivers with
93%, this had completely abated 9 months after diabetes have a statutory requirement to declare
diagnosis. Not surprisingly, the parents of newly their diabetes to the national licensing authority.
diagnosed children also experience psychological Furthermore, failure to do so may invalidate motor
upset of a temporary nature, more prominent in insurance policies. Following declaration of the
mothers. Adults with new-onset T1DM have simi- diagnosis of diabetes, a driving licence is issued
lar temporary psychological responses. The diag- for a maximum of 3 years in the UK, but is renew-
nosis of gestational diabetes mellitus is associated able at no cost following completion of a medical
with increased maternal anxiety and stress. It has questionnaire. In the UK, if an insulin-treated dia-
been suggested that stressful experiences may lead betic patient has one severe hypoglycaemic event,
to an increased risk of developing both T1DM and defined as an event requiring third-party assis-
type 2 diabetes mellitus (T2DM). tance, the patient must stop driving and inform the
The prevalence of depression is two to three licensing authority (DVLA). If there is more than
times higher in people with diabetes compared one severe hypoglycaemic event in any 12-month

DOI: 10.1201/9781003342700-11 103

104 Living with diabetes

period, the licence will be revoked and a medi- hiring practices, leading to loss of self-esteem and
cal opinion sought. For patients who drive large earning ability, impacting the patient’s ability to
vehicles, they must stop driving after one such support a family and their future quality of life.
event and inform the DVLA. For such patients, Insurance may also pose problems for individu-
licences are issued on an annual basis. Most coun- als with diabetes. Diabetic patients may experience
tries impose limitations on the issue of vocational difficulty obtaining life insurance on favourable
licences (heavy goods vehicles, passenger carry- terms. More favourable insurance terms may be
ing vehicles) to insulin-treated diabetic drivers. In provided by approved brokers recommended by
2012, the UK followed Canada in allowing insulin- national diabetes associations. In the UK, most
treated diabetic patients to fly commercial aircraft car insurance companies no longer penalise people
as long as there was a second pilot in the cockpit with diabetes by charging higher premiums.
and subject to strict conditions including frequent There are many other areas in life where hav-
blood glucose monitoring, which was greatly ing diabetes may cause difficulties, including travel
assisted by the introduction of modern continuous overseas, insurance and medical care abroad,
glucose monitoring systems. In the US, the Federal exposure to unusual foods and drinks in different
Aviation Administration followed suit in 2019. In a countries and the effect of intercurrent illness and
similar vein, such patients are now able to become sport on day-to-day blood glucose control.
air traffic controllers. Diabetic patients may expe-
rience difficulties with employment. Statutory or BIBLIOGRAPHY
company policy make employment in certain occu-
pations, such as off-shore work, difficult. However, Dibato J, et al. Temporal trends in the prevalence
progress in this area is being made, particularly in and incidence of depression and the interplay
the UK with the advent of the Equality Act 2010, of comorbidities in patients with young- and
which renders it against the law for an employer to usual-onset type 2 diabetes from the USA
discriminate because of a disability. In many cases, and the UK. Diabetologia. 2022; 65: 2066–77.
people with diabetes will be covered by the cur- Doi: 10.1007/s00125-022-05764-9
rent definition of disability, helping them in poten- Kovacs M, Goldston D, Obrosky DS, Bonar LK.
tial employment scenarios. Nevertheless, some Psychiatric disorders in youths with IDDM:
countries do not allow employment in the armed Rates and risk factors. Diabetes Care. 1997;
forces. In the US armed forces, diabetes remains 20: 36–44
a disqualifying health condition. Furthermore, Russell-Jones DL, et al. Pilots flying with insulin-
even when there is no risk due to possible hypo- treated diabetes. Diabetes Obes Metab. 2021
glycaemia, discrimination by employers may affect Jul; 23(7): 1439–44. Doi: 10.1111/dom.14375
 12
Future developments in diabetes care

TOWARDS A CURE FOR ‘Edmonton protocol’ was widely adopted in trans-

TYPE 1 DIABETES MELLITUS: plant centres across the world with more than 1000
TRANSPLANTATION recipients being included in an international regis-
try of islet transplantation.
Whole-pancreas and islet transplantation are now Islet cells are obtained from a donated human
well established as a management strategy for pancreas by a process of partial pancreatic diges-
type 1 diabetes mellitus (T1DM). Whole-pancreas tion and a differential centrifugation. The isolated
transplantation was first performed in 1964 and and purified islets are then administered into the
since then more than 60,000 transplants have hepatic portal system when grafting takes place.
been performed. The majority of these have been Successful islet transplantation is associated with
performed as a combined procedure in patients insulin independence, but there remain limita-
requiring a renal transplant for end-stage diabetic tions to the technique. To obtain an adequate islet
nephropathy, with a minority being conducted for mass to achieve insulin dependence, most recipi-
diabetes control alone. Recent data on outcomes ents require at least two separate islet donations
are favourable, with 73% insulin independence at and the supply of human islets remains scarce
5 years postprocedure for combined kidney and (Figures 12.1 and 12.2).
pancreas grafts, with a lower graft survival rate and
insulin independence of 53% being reported for
pancreas transplant alone. Given that the proce-
dure has a significant mortality and morbidity, its
use for the primary management of diabetes in the
absence of renal failure has become less widespread
with the establishment of islet transplantation.
After several false starts, the modern era of islet
transplantation began with refinement of islet iso-
lation techniques in the 1990s and the publication
of the first consistently successful series of islet
transplants by a group led by James Shapiro from
Edmonton, Canada, in 2000. In contrast to ear-
lier attempts, the transplantation was based on a
steroid-free immunosuppression regime, resulting
in a lower metabolic demand on the transplanted Figure 12.1 Isolated human islet cells prepared
transplantation. The islets are isolated from a
islets associated with corticosteroid treatment.
donated human pancreas by a process of partial
In the initial publication from this group, seven digestion and ultracentrifugation in a cooled cen-
consecutive transplanted patients achieved insu- trifuge. The retrieval of good-quality islets from a
lin independence after one or two infusions of donor pancrease is critical to the success of islet
donor islets and, following this early success, the cell transplantation.

DOI: 10.1201/9781003342700-12 105

106 Future developments in diabetes care

with T1DM. The need for lifelong immunosuppres-

sion is associated with significant risks including an
increased risk of malignancy, particularly for skin
cancers and lymphoma. Furthermore, the available
supply of human islets remains small and is likely
to remain a limiting factor in the long term.
In view of this, the primary indication for
islet transplantation remains for patients with
intractable, recurrent severe hypoglycaemia that
persists despite optimised medical management
including use of insulin-pump and sensor tech-
nology. A secondary indication is in the manage-
ment of patients with suboptimal glucose control
who have previously received a kidney trans-
plant and are, thus, already on immunosuppres-
sion. Islet after kidney (IAK) transplantation is
increasingly being used to optimise diabetes in
Figure 12.2 A portal venogram showing the such patients and carries a more favourable risk–
hepatic portal vein prior to administration of benefit ratio through not requiring additional
isolated human islets. In the Edmonton protocol,
long-term immunosuppression and through the
an adequate mass of freshly isolated islets is
infused through a catheter placed into the main potential to improve renal graft survival through
portal vein. improved diabetes control.
Presently, the strongest evidence for the ben-
efits of islet transplantation is in the context of the
Since the initial Edmonton protocol, there have management of hypoglycaemia, with long-term
been further refinements in the immunosuppres- freedom from hypoglycaemia seen in recipients.
sion protocols used for islet transplantation, with Ongoing research in this field aims to improve
more intensive T-cell depletion at the induction islet survival and duration of insulin indepen-
of immunosuppression being widely favoured. dence. This is focused on a greater understand-
Overall, results from transplantation are good with ing of the immune response that ultimately leads
about 75% of patients achieving insulin indepen- to islet loss and recurrence of T1DM and also on
dence in recent series, and with about half of recip- understanding the impact of additional cellular
ients achieving long-term insulin independence. factors that help support islet cell survival and
Even among those who do not achieve insulin function.
independence, significant improvements in gly- More widespread use of islet cell therapy will
caemic control were achieved and sustained, with require improvements in immunosuppression,
long-term freedom from severe hypoglycaemia islet graft survival and alternative sources of
being achieved in the majority of patients, regard- islets other than cadaveric human donor tissue.
less of whether insulin independence is achieved. While various studies have explored encapsula-
The overall duration of insulin independence is tion of islets and use of humanised porcine islets,
variable, with median rates of insulin indepen- the greatest interest, at present, is in the potential
dence of between 40% and 60% being reported at for bioengineered human beta cells (β-cells) and
3 to 5 years in different cohorts. In contrast, free- differentiated islets derived from embryonic stem-
dom from hypoglycaemia among recipients who cells. Two companies ViaCell and Vertex have
have had recurrent severe hypoglycaemia prior to recently performed first-in-man studies and, of
transplantation is sustained beyond 5 years in the particular note, Vertex presented data showing a
majority of recipients. therapeutic effect in a single patient with a marked
There remain significant limitations to islet reduction in insulin requirements, though not
transplantation which mean that it has remained complete insulin independence. Based on these
a niche treatment for a small number of people preliminary results, the United States Food and
 Type 2 diabetes mellitus: surgical and endoscopic interventions 107

Drug Administration (FDA) has granted inves- obesity, surgical intervention can be more effec-
tigational status for a novel device comprising tive than pharmacotherapy. These observations
Vertex’ encapsulated embryonic stem-cell-derived were initially made in patients with a BMI >35
islets, which is now entering Phase 1/2 clinical tri- and have now been extended to those with a BMI
als as a potential treatment for T1DM. in the range of 30–35, which, while still within the
diagnostic criteria for obesity, is below the level
T1DM PREVENTION at which surgical intervention would be consid-
ered. Data from observational studies, notably
Greater understanding of the immune processes the Swedish Obesity Study, have shown that sur-
underlying the onset of T1DM has now led to gical treatment, particularly in the early years
the development of the first proven treatment to after diabetes, is associated with improved glucose
attenuate the immune response. The drug tepli- control, reduction in requirement for pharma-
zumab, a humanised anti-CD3 monoclonal anti- cotherapy and, in some cases, reversal of T2DM.
body, delays overt T1DM in at-risk individuals. Furthermore, long-term follow up in the Swedish
It received FDA approval in 2022 after a 10-year cohort has shown that early surgery is associated
development programme and is now starting to with a reduction in microvascular complications
enter clinical practice. In clinical trials, tepli- and cardiovascular morbidity. Of note, improve-
zumab was associated with delay in the pro- ments in blood glucose control and a reduction in
gression of diabetes by more than 2 years, with insulin requirements are observed very early after
preservation of some β-cell function as mea- surgery and before major weight loss has occurred.
sured by C-peptide production. This gives the This has led to interest in the underlying mecha-
potential for using immunotherapy to alter the nisms by which bariatric surgery improves glycae-
natural history of T1DM, as existing evidence mia, and studies in animals and, in some cases in
has shown that preservation of some β-cell func- man, have identified multiple changes that may
tion and C-peptide positivity is associated with influence glucose homeostasis. Given these exten-
reduced risk of complications and better over- sive effects, it has been suggested that the term
all glycaemic stability with less hypoglycaemia. ‘metabolic’ rather than ‘bariatric’ surgery may be
A future challenge in immunotherapy will be more appropriate to describe surgical manage-
to determine screening strategies for the very ment aimed primarily at reversal or management
early detection of T1DM in the population, as of diabetes (Figure 12.3).
such treatment would be most effective when The surgical procedures with the greatest
the earliest changes in glucose metabolism occur impact on metabolic parameters are those that
and while β-cell mass is well preserved. Another involve the duodenum and this has led to par-
challenge will be to bring down the extreme cost ticular interest in the study of the duodenum’s
of immunotherapy, which, at present, would role in glucose metabolism and its identifica-
limit its uptake. tion as a potential target for diabetes interven-
tions. Studies in rodent models showed that a
high fat and sucrose diet leads to a thickening of
TYPE 2 DIABETES MELLITUS: the duodenal mucosa and that this is associated
SURGICAL AND ENDOSCOPIC with the development of insulin resistance and
INTERVENTIONS associated metabolic derangement. Ablation of
the mucosa was shown to reverse these changes
A major area of advancement in type 2 diabetes and, based on these observations, a therapeutic
mellitus (T2DM) has been the recognition of the intervention has been developed. This inter-
importance of the gut and gut hormones in the vention, Revita Duodenal Mucosal Resurfacing
aetiology of insulin resistance and dysglycaemia. (DMR) is an endoscopic technique by which a
Much has been learned from the field of bariatric balloon catheter is placed in the duodenum and
surgery, which has been shown capable of revers- inf lated with heated saline to produce a focal
ing T2DM independent of its effect on weight. thermal injury and ablate the mucosal surface.
Multiple studies have shown that for patients with In initial randomised controlled trials, DMR
108 Future developments in diabetes care

Figure 12.3 Putative actions of bariatric surgery on metabolic regulation: A broad range of changes
have been described following Roux-en-Y gastric bypass, which may explain the impact of surgery to
improve diabetes control.

treatment was associated with improvements in Boston, US), which was developed primarily to
glucose control and insulin resistance. Of par- support weight loss. The EndoBarrier is a 60 cm-
ticular note, DMR was associated with a reduc- long polymer tube that is placed endoscopically
tion in liver fat content and improvements in into the duodenum and anchored at the duo-
liver transaminases in patients with elevated denal bulb, allowing nutrients to pass directly
baseline liver fat content, suggesting a poten- from the stomach into the jejunum. This is left
tial benefit in the management of non-alcoholic in place for up to 1 year and then removed at
fatty liver disease, which is an increasing issue a further endoscopy. The outcomes associated
in T2DM. DMR has now entered clinical prac- with the use of the device were variable, with
tice in some regions. Other techniques involv- a multicentre trial showing no improvement
ing ablation of the duodenal mucosa, including in glycaemic control over standard treatments,
radiofrequency ablation (repurposing a tech- whereas significant improvements in weight
nique developed for treatment of oesophageal and glycemic control were observed and main-
dysplasia), are also in development. Another tained for up to 3 years in a UK clinical practice
approach to manipulation of the duodenum that series of patients with longer-duration diabetes
has entered clinical practice is the EndoBarrier that had proved refractory to standard treat-
duodeno-jejunal bypass liner (GI Dynamics, ment (Figures 12.4 and 12.5).
 Type 2 diabetes mellitus: surgical and endoscopic interventions 109

Figure 12.4 The RevitaTM Duodenal Mucosal resurfacing technique uses a balloon catheter linked to
a computerized operating console (top left) to deliver a thermal injury to the duodenal mucosa. The
catheter is placed endoscopically and under x-ray guidance into the duodenum (top right, 1). The
mucosa is separated from the underlying submucosa by a local injection of saline (2) and the catheter
balloon is inflated with heated saline to produce a focal thermal injury, which leads to atrophy and
regrowth of the mucosa (3). The balloon catheter is then removed and the mucosa inspected before
withdrawal of the endoscope (4). The resultant ‘resurfacing’ of the mucosa is associated with changes
in multiple metabolic parameters including improved glycaemic control and reduced liver fat.
110 Future developments in diabetes care

in Islet Transplant alone recipients with

type 1 diabetes complicated by severe
hypoglycaemia in the Collaborative
Islet Transplant Registry. Diabetologia.
2023 Jan;66(1):163–173. doi: 10.1007/
s00125-022-05804-4
Mingrone G, van Baar AC, Devière J, et al.
Safety and efficacy of hydrothermal duo-
denal mucosal resurfacing in patients with
type 2 diabetes: The randomised, double-
blind, sham-controlled, multicentre REVITA-2
Figure 12.5 The EndoBarrierTM duodeno-jejunal feasibility trial. Gut. 2022 Feb; 71(2): 254–64.
barrier liner is inserted endoscopically into the
doi: 10.1136/gutjnl-2020-323608
duodenum, creating a barrier between nutri-
ents passing from the stomach to duodenum Ruban A, Miras A, Glaysher MA, et al. Duodenal-
which are prevented from reaching the duodenal jejunal bypass liner for the management
mucosa. of type 2 diabetes mellitus and obesity:
A multicenter randomized controlled trial.
Annal Surg. 2022 March; 275(3): 440–47.
doi: 10.1097/SLA.0000000000004980
BIBLIOGRAPHY Ryder REJ, Yadagiri M, Burbridge W,
et al. Duodenal-jejunal bypass liner for the
Bellin MD, Dunn TB. Transplant strategies for
treatment of type 2 diabetes and obesity:
type 1 diabetes: Whole pancreas, islet and
3-year outcomes in the First National Health
porcine beta cell therapies. Diabetologia.
Service (NHS) EndoBarrier Service. Diabet
2020; 63: 2049–56. doi: 10.1007/s00125-
Med. 2022 Jul; 39(7): e14827. doi: 10.1111/
020-05184-7
dme.14827
Butler PC, Gale EA. Reversing type 1 diabetes
Shapiro AMJ, Lakey JRT, Ryan EA, et al. Islet
with stem cell-derived islets: A step closer to
transplantation in seven patients with type
the dream? J Clin Invest. 2022 Feb 1; 132(3):
1 diabetes mellitus using a glucocorticoid-
e158305. doi: 10.1172/JCI158305
free immunosuppressive regimen. N Engl
Carlsson LMS, Sjöholm K, Karlsson C, et al.
J Med. 2000; 343: 230–23. doi: 10.1056/
Long-term incidence of microvascular
NEJM200007273430401
disease after bariatric surgery or usual care
Tatovic D, Dayan CM. Replacing insulin with
in patients with obesity, stratified by base-
immunotherapy: Time for a paradigm change
line glycaemic status: A post-hoc analysis
in type 1 diabetes. Diabet Med. 2021; 38:
of participants from the Swedish Obese
e14696. doi:10.1111/dme.14696
Subjects study. Lancet Diabetes Endocrinol.
van Baar ACG, Meiring S, Holleman F, et al.
2017 Apr; 5(4): 271–9. doi: 10.1016/S2213-
Alternative treatments for type 2 diabetes
8587(17)30061-X
and associated metabolic diseases:
Cummings DE, Rubino F. Metabolic surgery for
Medical therapy or endoscopic duodenal
the treatment of type 2 diabetes in obese
mucosal remodelling? Gut. 2021 Nov;
individuals. Diabetologia. 2018 Feb; 61(2):
70(11): 2196–204. doi: 10.1136/gutjnl-
257–64. doi: 10.1007/s00125-017-4513-y
2020-323931
Hering BJ, Ballou CM, Bellin MD, et al. Factors
associated with favourable 5-year outcomes
Index

A Apomorphine, 87 Blood glucose, 34–35

Arthropathy monitoring systems, 34–35, 39
ABBOS, 8
Charcot’s, 81, 82, 83 plasma profile
Abbott Freestyle Libre, 35
cheiroarthropathy, 94 ‘glucose excursions’, 37, 38
ABCC8-NDM, 16
Assessing the Effectiveness of insulin injections, 32, 34
Acanthosis nigricans, 90, 91
Communication Therapy non-diabetic, 33
Acromegaly, 4, 19
in the North West stable control, 44
Action to Control Cardiovascular
(ACTNOW) study, 26 self-monitoring technique, 35
Risk in Diabetes
Atheromatous lesions, 77 subcutaneous continuous
(ACCORD) blood
Atorvastatin, 98 glucose monitoring
pressure trial, 80
Automated insulin-delivery system, 35
Acute complications of DM, 56–62
systems, 102 subcutaneously implanted
Addison’s disease, 20
Avanafil, 87 continuous monitoring
Adenovirus, 17
Azathioprine, 25 system, 35
Adhesive capsulitis, shoulder, 94
Azilsartan, 80 Blood Pressure Control Study, 80
Aflibercept, 67
B lymphocytes, 9
Albumin-to-creatinine ratio (ACR),
Bovine serum albumin, 8
69 B
Brolucizumab, 67
Alcohol, 57, 61
Background diabetic retinopathy, Bullae, 92
α-glucosidase inhibitors, 44
63 Bullous lesions, 92
Alprostadil (prostaglandin E1),
Bacterial infection, skin, 80, 95
87–88, 89
Bacteroides spp., 81
American Diabetes Association C
Balanitis, 95
(ADA), 35, 72, 99
Banting, Frederick, 1 Calcium channel blockers, 80
diagnostic criteria, 3, 26
Bariatric surgery, 107–108 Calorie restriction, 42
etiologic classification, 5
Basal bolus insulin regimes, 101 Canagliflozin, 46, 61
GDM criteria, 102
Becaplermin, 86 Candesartan, 80
Amitriptyline, 77
Best, Charles H., 1 Candidiasis, 95
Amlodipine, 80
β-cells, pancreatic Captopril, 80
Amoxicillin-clavulanate, 85
autoimmune destruction, 7, 8 Carbohydrates, 33–34, 36, 42, 44
Amputation, lower-limb, 77, 78
dysfunction, 14–15 Cardiovascular disease (CVD), 53,
Amylin, 14
monogenetic defects, 2, 9 63, 73, 98
Anencephaly, 100
stem cell generated, 106 recurrent coronary heart disease
Angiotensin-converting enzyme
viral infection, 8–9 (CHD) events, 77
(ACE) inhibitor, 71–72, 80
Bevacizumab, 67 Carpal tunnel syndrome, 75, 76
Angiotensin receptor blockers
Bicarbonate, 60 CD4 T lymphocyte, 9
(ARBs), 71
Biguanides (metformin), 43 CD8 T lymphocyte, 9, 25
Antibiotics, 85
Bioengineered skin substitutes, Centripetal obesity, 18
Anticonvulsants, 77
85 Cephalexin, 85

111
112 Index

Cerebral oedema, 61 Definition of DM, 3 DIGAMI study, 79

Charcot’s arthropathy, 81, 82, 83 Dehydration, 59 Digital arterial calcification in
Cheiroarthropathy, 94 Depression, 103 diabetic foot, 78
Children and adolescents Dermopathy, 92 Dipeptidyl peptidase-4 (DPP-IV)
childhood obesity, 19 Dextrogel, 57 inhibitor, 44, 45
childhood type 2 diabetes, 4 Diabetes burnout, 37 DIRECT study, 42
emotional problems, 51 Diabetes Control and Distal gangrene, 78
hypoglycaemia, 51 Complications Trial Dose Adjustment for Normal
insulin requirements, 51 (DCCT), USA, 3, 29, 63, Eating (DAFNE)
macrosomic babies, 101 72 program, 34
treatment, 51–52 Diabetes Distress Scale, 103 Down’s syndrome, 4, 17
Chlorthalidone, 80 Diabetes Education and Self- DQB1 gene, 8
Cholesterol, 98–99 Management for DREAM (Diabetes Reduction
Cholesterol Treatment Trialists, 98 Ongoing and Newly Assessment with
Chronic complications of DM, Diagnosed diabetes Ramipril and
63–95 (DESMOND) Rosiglitazone
Chronic kidney disease (CKD), 70 programme, 42 Medication) study, 26
Circinate exudative retinopathy, 65 Diabetes insipidus, diabetes Driver and Vehicle Licencing
Cirrhosis, 90 mellitus, optic Agency (DVLA), 103–104
Classification of DM, 3–6 atrophy and deafness Driving licence, UK, 103
Clindamycin, 85 (DIDMOAD) syndrome, Drug treatment, for type 2 diabetes,
Closed-loop technology, 38 64 42
Collaborative Atorvastatin Diabetes Diabetes mellitus (DM), definition, Dulaglutide, 45
Study (CARDS), 98 3 Duodenal mucosa, 108
Coma, 61 Diabetes Mellitus Insulin Glucose Duodenal Mucosal Resurfacing
Coma, Hyperosmolar Nonketotic, infusion in Acute (DMR) technique,
61 Myocardial Infarction 107–109
Continuous ambulatory peritoneal (DIGAMI) study, 79 Dupuytren’s contracture, 94
dialysis (CAPD), 73 Diabetes Prevention Program, Dyslipidaemia, 98–99
Continuous glucose monitoring USA, 26
(CGM) systems, 38, 51, 101 Diabetic autonomic neuropathy, 76
E
Continuous glucose sensing Diabetic cheiroarthropathy, 94
technology, 35 Diabetic dermopathy., 92 Edmonton protocol, 105, 106
Continuous subcutaneous insulin Diabetic foot Empagliflozin, 46, 61
infusion (CSII), 35, 36 digital arterial calcification in, EMPA-REG study, 47
Coronary artery disease, 77 78 Enalapril, 80
Counterpoint study, 27 osteomyelitis in, 83 EndoBarrier duodeno-jejunal
Coxsackie B virus, 8, 9 Diabetic foot ulceration, risk factors bypass liner, 108, 110
C-peptide, 107 for, 80 Endocrine cells, 14
Creatinine level, 70, 71 Diabetic impotence, 89 End-stage diabetic retinopathy, 67
Critical-care admission, 53 Diabetic ketoacidosis (DKA), 59–61 End-stage renal disease (ESRD), 70
CTLA-4 gene, 8 Diabetic macular oedema, 67 Entrapment syndrome, 73, 75
Cushing’s syndrome, 4, 18, 19 Diabetic maculopathy, 66 Environmental factors
Cyclosporine A, 25 Diabetic neuropathy, 73 for children and adolescents, 51
Cystic fibrosis, 4, 22 Diabetic retinopathy, 69 viral infection, 8–10
Cytomegalovirus, 8, 17 Diabetic right-third cranial nerve Epstein–Barr virus, 8
palsy, 75 Equality Act 2010, 104
Diagnostic criteria of DM, 3, 4 Erectile dysfunction (ED), 76,
D
Dialysis, 73 86–89, 103
Dapagliflozin, 46, 61 Diazoxide, 4 causes, 86
Da Qing Study, China, 26 Dietary advice, 33 hypogonadism, 86
 Index 113

treatment, 86 Finnish Diabetes Prevention Study, Glitazones, 26, 44

vasoactive drug 26 Glomerulopathy, 70, 71
injection, 88 Finnish study, 73 GLP-1 receptor agonists, 52
transurethral application, Fluid replacement, 60 Glucagon, 58
88, 89 Food and Drug Administration Glucagon-like peptide-1 (GLP-1),
Eruptive xanthomata, 91, 92, 93 (FDA), 72, 106–107 14, 44, 45, 54, 90
Erythromycin, 77 Foot disorders Glucocorticoids, 4
Escherichia coli, 31, 81 burn injuries, 81 Glucogel, 57
Euglycaemic diabetic ketoacidosis callus, 81 Gluconeogenesis, 7, 58
(EDKA), 61 Charcot’s arthropathy, 81, 82, 83 Glucose
Euglycaemic ketoacidosis, 46 deep infection, 82 metabolism, brain, 57
European Association for the Study digital arterial calcification, 78 tolerance, impaired, 3, 4, 22,
of Diabetes (EASD), 72 gangrene, 78, 85 see also Blood glucose
Exercise, 35 osteomyelitis, 82, 83, 84, 85 Glucotoxicity, 14
and insulin sensitivity, 36 treatment, 85, 86 Glutamic acid decarboxylase
Exogenous insulin administration, ulcer, 82, 85 (GAD) antibodies, 9
54 weight-bearing reduction, 85 Gluten, 8
Eye disorders Fosinopril, 80 Glycaemic control, 34, 100
DIDMOAD syndrome, 64 Free fatty acids (FFAs), 14, 15, 90 Glycogenolysis, 7, 58
laser photocoagulation, 65, 66, Freestyle Libre 2 flash glucose Glycolysis, 59
67, 68, 69 monitoring system, 36 Glycosuria, 59
maculopathy, 63, 66 Frozen shoulder, 94 Granuloma annulare, 93
normal fundus, 63 Future developments GvokeHypoPen, 58
retinal detachment, 65, 69 β-cells, stem cell generated, 106
retinopathy, 63–69 insulin pumps, 106
H
thromboneovascular glaucoma, islet cell transplantation, 105
67 pancreatic transplantation, 105 Haemochromatosis, 4, 20, 22, 23
triamcinolone therapy, 68 Health-care costs, 3
vitreous haemorrhage, 65, 66, 69 Heart Outcomes Prevention
G
Ezetimibe, 99 Evaluation (HOPE) study,
Gabapentin, 77 80
Gastric inhibitory polypeptide Heart Protection Study (HPS), 98
F
(GIP), 44, 90 Hemoglobin (HbA1c) targets, 33
Faricimab, 67 Gastric Neurostimulator (GES) Hepatic gluconeogenesis, 59
Fasting plasma glucose (FPG), system, 77 Hepatic nuclear factors (HNFs), 5
3, 14 GCK-MODY, 16 Hepatic portal vein, isolated islet
Federal Aviation Administration, Genes administration, 106
104 DQB1, 8 Hereditary haemochromatosis, 20
Felodipine, 80 glucokinase, 16 Heterozygous mutations, 16
Fenofibrate, 99 INS (insulin gene), 16 High-density lipoprotein (HDL),
Fenofibrate Intervention and Event Genetic loci 98
Lowering in Diabetes IDDM2, 8 HNF1A-MODY, 16
(FIELD) trial, 99 Genome-wide association studies Human leukocyte antigen (HLA), 8
Fibrates, 99 (GWAS), 8, 24 HLA antigens, 8
Fibrocalculous pancreatopathy, 4 Geographic variation of DM, 1–2 Human proinsulin, 30
15-15 Rule, 57, 58 Gestational diabetes mellitus Hyalin deposition, 71
Finerenone in Reducing Kidney (GDM), 5, 26, 102 Hydroxymethylglutaryl-coenzyme
Failure and Disease O’Sullivan–Mahan criteria A reductase inhibitor, 98
Progression in Diabetic (USA), 5 Hyperbaric oxygen, 86
Kidney Disease WHO criteria, 5, see also Hyperglycaemia, 14, 49, 53, 59, 79
(FIDELIO-DKD) trial, 72 Pregnancy in pregnancy, 100
114 Index

Hyperglycaemia-driven osmotic plasma profile, non-diabetic, 33 Intermediate-density lipoprotein

diuresis, 61 proinsulin, protein sequence, 30 (IDL), 98
Hyperglycaemic Hyperosmolar rapid-acting, 47 Intraretinal microvascular
Nonketotic Coma requirements, children and abnormalities (IRMA), 64
(HONK), 61 adolescents, 51 Intravitreal triamcinolone, 67
Hyperinsulinaemia, 79 resistance, 2–3, 14–16 Irbesartan, 80
fetal, 101 Insulin analogs and formulations, Islet after kidney (IAK)
Hyperlipidaemia, 49, 98–99 30 transplantation, 106
Hyperosmolar Hyperglycaemic insulin aspart, 31 Islet amyloid polypeptide (IAPP),
Nonketotic Syndrome insulin detemir, 31 14
(HHNS), 61 insulin glargine, 31, 33 Islet cell antibodies (ICA), 9, 13
Hyperosmolar Hyperglycaemic insulin lispro, 31 Islet cell transplantation, 105, 106
State (HHS), 61–62 isophane, 31 Islet of Langerhans, 9, 30
Hyperosmolarity, 59 NPH (isophane), 31 Coxsackie B viral infection
Hyperosmolar Nonketotic Coma, porcine insulin, 31 (LM), 9
61 Insulin autoantibodies (IAA), 9 cystic fibrosis, pancreas (LM),
Hypertension, 71, 72–73, 79–80 Insulin crystals, 30 22
Hypertriglyceridaemia, 98 Insulin deficiency, 10 glucagon immunostained, 11
Hypoglycaemia, 31, 56, 58, 103, 106 Insulin degludec (Tresiba), 31 insulin immunostained, 11
brain glucose metabolism, 57 Insulin-dependent diabetes insulin storage granules, 11
causes of, 57 mellitus (IDDM), insulitis hyperexpression, 14
children and adolescents, 51 see Type 1 diabetes normal pancreas, 11
hypoglycaemia-induced cardiac Insulin detemir (Levemir), 31 somatostatin immunostained,
dysrhythmia, 57 Insulin independence, duration 11
neonatal, 100 of, 106 type 1 DM
self-treatment, 57 Insulin infusion rate, 60 β-cells, 11, 12
symptoms, 57 Insulin injection technique, 32 infiltrate, 12
Insulin-like growth factor (IGF)-1 lymphocyte infiltration, 12
receptors, 90 type 2 DM
I
Insulin lipoatrophy, 33 amyloid deposition, 15
IDDM2, 8 Insulinoma, 12 Isradipine, 80
Impaired fasting glucose (IFG), 2, 3 Insulin pump, 102 IV insulin, 55
Impaired glucose tolerance (IGT), Insulin-pump therapy, 51, 103
2, 3, 14, 19, 22, 26 Insulin regimes
K
Incretin-based treatments, 44–45 basal-bolus, 36
Indapamide, 80 continuous subcutaneous KCNJ11-NDM, 16
Inpatient management of diabetes, insulin infusion (CSII), Ketoacidosis, 46, 53, 59–62
53 35 causes of death, 60
Insulin, 30, 31, 47 twice-daily, 31 Ketoacids, 59
biosynthesis, 31 Insulin requirements in children Ketones, 53, 59, 60
biphasic response to glucose, 15 with T1DM, 51 Ketosis, in surgery, 54
crystals, 30 Insulin resistance, 79 ‘Ketosis-prone’ T2DM, 59
deficiency, biochemical Insulin resistance syndrome, 2–3, Klinefelter’s syndrome, 2, 4, 17, 21
consequences, 10 6, 14–16
discovery of, 1–3 definition, 14
L
impaired secretion, 14 Insulin therapy, patients on, 54
injection technique, 32 Insulin-treated diabetes, 54 Lactic acidosis, 43
lipid hypertrophy, 34 Insulitis, 9, 12 Laser photocoagulation, 65, 66, 67,
lipoatrophy, 33, 34 Insurance issues, 104 68, 69
longer-acting, 47 Interferon (IFN)γ, 9 Latent Autoimmune Diabetes in
pens, 32 Interleukin (IL)-2, 9 Adulthood (LADA), 4
 Index 115

Late-onset diabetes mellitus, 2 Medtronic 780 G, 37 third cranial nerve palsy, 75

immune-mediated type 1, 2 Meglitinides, 44 treatment, 81
Levofloxacin, 85 Me proliferator-activated ulnar, 75
Lifestyle change, 25–26 receptorgamma (PPARγ), Niacin, 99
Linezolid, 85 44 Nitrosamines, 8
Lipid disorders, 98 Meropenem, 85 Non-alcoholic fatty liver disease
Lipid hypertrophy, 34 Metabolic syndrome, see Insulin (NAFLD), 90
Lipoatrophy, 33, 34 resistance syndrome Non-alcoholic steatohepatitis
Lipohypertrophy, 32, 34 Metformin, 41, 43, 44, 47, 72, 90 (NASH), 90
Lipolysis, 59 Metoclopramide, 77 Non-insulin-dependent diabetes
Lipoprotein abnormalities in Microalbuminuria, 71 mellitus (NIDDM),
T2DM, 98 Migratory necrolytic erythema, 93 see Type 2 diabetes
Lipoprotein A (Lp(a)) MiniMed continuous glucose Non-insulin treatment, patients
concentrations, 98 monitoring system, 35 on, 54
Liraglutide, 44 Minocycline, 85
Liraglutide Effect and Action in Mitochondrial diabetes, 16–17
O
Diabetes: Evaluation of Monitoring systems, blood glucose,
Cardiovascular Outcome 34–35, 37 Obesity
Results (LEADER) study, Monoclonal antibodies, 25 body mass index (BMI), 18
47 Monogenic diabetes childhood, 19
Lisinopril, 80 causes of, 17 energy expenditure, 20–21
Liver subtypes, 16–18 epidemic, 18–24
cirrhosis, 90 Multiple Risk Factor Intervention food consumption, 20
glucose output, 27 Trial (MRFIT), 77 food intake, 19–20
glucose production, 14, 15 Mumps, 8, 9, 17 genetics and, 21–24
hepatic nuclear factors (HNFs), 5 Myocardial infarction and sequelae of, 24
hepatic portal vein, isolated islet infection, 60 Obesity epidemic, 19
administration, 106 Myotonic dystrophy, 22 Obesity pandemic, 19
Losartan, 80 MySugarWatch glucose sensor Olmesartan, 80
Low-density lipoprotein (LDL), system, 37 Omnipod, 37
98–99 Oral glucose tolerance test (OGTT),
3
N
Osmotic diuresis, 59
M
National Diabetes Inpatient Audit Osteomyelitis, 82, 83, 84, 85
Macrophages, 9 (NaDIA), 53 foot, 85
Macrosomia, 100 NAVIGATOR study, 26 Osteomyelitis in diabetic foot,
Macrosomic babies, 101 Necrobiosis, 91 83
Maculopathy, 63, 66 Necrobiosis lipoidica diabeticorum, Osteoporosis, 83
Maggot debridement, ulcer, 86 91–92 O’Sullivan–Mahan criteria
Major histocompatibility complex Neovascular glaucoma, 67 (USA), 5
(MHC), 8 Nephropathy, 53, 69–73, 79, 80, 103 Outcome Reduction with Initial
antigens, 9 Neuropathic ulcer, 82 Glargine (ORIGIN) study,
Male excess, type 1, 6 Neuropathy, 71, 81, 103 26
Malignant otitis externa, 95 acute, 75
Massive eruptive xanthomata, 93 autonomic, 73, 76–77
P
Maturity onset diabetes, 41 chronic insidious sensory,
Maturity-onset diabetes of the 74–75 Pancreas, see also β-cells; Islet of
young (MODY), 4, 16 mononeuropathy, 75 Langerhans
Mealtime insulin, 36, 102 pathogenesis, 74 calcification, 23
Medicated Urethral System for prevalence, 74 cancer, 4, 24
Erection (MUSE), 88 proximal motor, 75–76 pancreatic duct, normal, 23
116 Index

transplantation, 105 DREAM (Ramipril and S

trauma, 4 Rosiglitazone), 26
Scandinavian Simvastatin Survival
Pancreatectomy, 4 NAVIGATOR (Nateglinide and
Study (4S Trial), 98
Pancreatitis, 4 Valsartan), 26
Semaglutide, 45
Panretinal laser photocoagulation, ORIGIN (Insulin Glargine),
Serious diabetic retinopathy, 65
68 26
SGLT (sodium/glucose
Panretinal photocoagulation, 67 Priapism, 87
cotransporter) inhibitors,
Papaverine, 87 Problem Areas in Diabetes (PAID)
61
Patient education, 33–34 Scale, 103
SGLT-2 inhibitors, 46, 54
PCSK9 inhibitors, 99 Proinsulin, 30
Shoulder dystocia, 100
PDE5 inhibitors, 87 Proliferative diabetic retinopathy,
Sildenafil, 87
Percutaneous coronary 67
Simvastatin, 98
intervention (PCI), 79 Proteinuria, 69–71
Sitagliptin, 44
Perioperative management, 53–54 Pseudomonas, 80
Skin abnormalities in diabetic
Peripheral vascular disease, 71, 77, Pump-treated patients, 60
patients, 91
78, 79, 80
Skin disorders
Permanent prenatal diabetes
Q acanthosis nigricans, 90, 91
mellitus (PNDM), 16
balanitis, 95
Peroxisome proliferator-activated Quality of life issues, 104
bullae, 92
receptors (PPARγ)
candidiasis, 95
agonists, 44
R dermopathy, 92
Phaeochromocytoma, 4
eruptive xanthomata, 91, 92, 93
Phentolamine, 87 Rabson–Mendenhall syndrome, 22
granuloma annulare, 93
Phosphate, 60 Ramipril, 80
migratory necrolytic erythema, 93
Phosphodiesterase inhibitors, 87 Random plasma glucose
necrobiosis lipoidica
Phosphodiesterase type 5 (PDE concentration, 3
diabeticorum, 91–92
5), 87 Ranibizumab, 67
severe bacterial infection, 95
Photocoagulation, 67 Rapilose, 57
uncommon, 91
Pioglitazone, 44 Reaven’s syndrome, see Insulin
vitiligo, 91, 92
Pitavastatin, 98 resistance syndrome
Sodium-glucose co-transporter-2
Plasma glucose, 60 Regulatory T cells (Tregs), 25
(SGLT2) inhibitors, 72
Platelet-derived growth factor, 86 Renal
Sodium valproate, 77
Polymorphisms, 8 artery stenosis, 71, 80
Somatostatin, 11
Postoperative infection, 54 failure, 71–72
Spina bifida, 100
Postprandial lipids, 98 glomerulopathy, 70, 71
Staphylococcus aureus, 80
Potassium, 61 transplantation, 73
Statin therapy, 98–99
Potassium loss, 59 Renal-angiotensin-aldosterone
lipid-lowering combination
Prader–Willi syndrome, 17, 18 system (RAAS), 71
therapy
Prandial glucose regulators, 44 Retinopathy, 52, 63–69, 71, 103
statin/ezetimibe, 99
Pravastatin, 98 background, 63
statin/fibrate, 99
Prediabetes, 3, 6 end-stage, 67
Steatohepatitis, 90
Pregabalin, 77 exudative, 65
Stress response, 53
Pregnancy, 5, 100–102, see also peripheral proliferative, 66
Study to Prevent Non-Insulin
Gestational diabetes serious, 69
Dependent Diabetes
mellitus (GDM) severe, 67
Mellitus (STOP-NIDDM)
Caesarean section rates, 101 Revita Duodenal Mucosal
Trial, multinational, 26
insulin regimes, 101 resurfacing technique,
Sulphonylureas, 42–43, 54, 56, 57
perinatal problems, 100 107–109
Surgery, 53–55
Preproliferative retinopathy, 65 Rosiglitazone, 44
perioperative management, 53–54
Prevention trials, pharmacological Rosuvastatin, 98
postoperative infection, 54
ACTNOW (pioglitazone), 26 Rubella, congenital, 8
 Index 117

Swedish Obesity Study, 107 pathogenesis, 7–10 U

Syndrome X, see Insulin resistance pre-insulin treatment, 2
UK National Pregnancy in Diabetes
syndrome prevention, 24–25, 107
Audit, 100
Systolic blood pressure (SBP), 80 towards a cure for, 105–107
United Kingdom Prospective
treatment
Diabetes Study (UKPDS),
dietary, 33
T 41, 43, 63
dietary management and
Blood Pressure Control Study,
Tachycardia, 76 patient education, 33–34
80
Tadalafil, 87 glucose monitoring, 34–35
HbA1c target, 33
T-cell depletion, 106 insulin, 47
T1DM TrialNet Study Group trial, insulin preparations,
25 development of, 30–33 V
Teplizumab, 107 insulin pump treatment
Vancomycin, 85
T-helper cells, 9 and closed-loop insulin
Vardenafil, 87
Thiazide, 4 delivery, 35–37
Vascular endothelial growth factor
Thiazolidinediones, 44 psychological aspects, 37–38
(VEGF) inhibitors, 67
Thiazolineidiones (glitazones), 44 Type 2 diabetes, 10
Vertex, 106, 107
Tirzepatide, 45 childhood, 4, 52
Very-low-density lipoprotein
T lymphocytes, 8–9 classification, 4
(VLDL), 27, 98
Total-contact cast (TCC), 84 dietary treatment, 42
ViaCell, 106
Transient neonatal diabetes drug treatment, 42, 43
Vibration controlled transient
mellitus (TNDM), 16 epidemiology, 6
elastography (VCTE), 90
Transplantation histological abnormality in,
Viral associations
islet cell, 105, 106 15
adenovirus, 17
renal, 73 incidence, 1
Coxsackie B virus, 8, 9, 17
whole-pancreas, 105 insulin resistance in, 14–16
cytomegalovirus, 8, 17
Treatment Options for Type 2 insulin secretion in, 14
Epstein–Barr virus, 8
Diabetes in Adolescents lipoprotein abnormalities in,
Visual impairment, 103
and Youth (TODAY), 52 98
Vitiligo, 91, 92
Triamcinolone, 68 pathogenesis, 14
Vitreoretinal surgery, 67
Tricyclic antidepressants, 77 prevention, 25–26
Vitreous haemorrhage, 69
Triglycerides, 98 reversal of, 27
Trimethoprim-sulphamethoxazole, surgical and endoscopic
85 interventions, 107–110 W
Troglitazone, 44 treatment
Weight-bearing forces, reduction
Troglitazone in Prevention of α-glucosidase inhibitors, 44
of, 85
Diabetes (TRIPOD) biguanides (metformin), 43
Weight loss, 25, 26, 42
study, 26 cardiovascular outcome
Whole-pancreas transplantation,
Truncal radiculopathy, 75 studies, 47
105
Tumor necrosis factor (TNF)-α, 10 drugs, 44
Wolfram’s syndrome, 17
Turner’s syndrome, 4, 17, 21 HbA1c targets, 33
World Health Organization (WHO)
Type 1 diabetes, 2 incretin-based treatments,
diagnostic criteria, 3
classification, 4 44–45
dietary advice, 33 insulin, 41, 47
environmental factors, 8–10 meglitinides, 44 Z
epidemiology, 6 SGLT-2 inhibitors, 46
Zinc transporter, 9
genetic factors, 7–8 sulphonylureas, 42–43
incidence, 3 thiazolineidiones
insulin requirements in children (glitazones), 44
with, 51 treatment strategies and
male excess, 6 guidelines, 47–48