DIABETES MELLITUS

Presented by
dr. Maysaa Nihad
to 5th year medical class
 ‫‪ ‬وفي يوم ‪ 20‬ديسمبر‪/‬كانون األول ‪ ، 2007‬اعتمدت الجمعية العامة لألمم‬
‫املتحدة القرار ‪ 61/225‬الذي أعلنت فيه يوم ‪ 14‬تشرين الثاني‪/‬نوفمبر من كل‬
‫عام باعتباره اليوم العاملي ملرض ى السكري‪ ،‬وذلك لالعتراف بالحاجة العاجلة‬
‫ملتابعة الجهود متعددة األطراف لتشجيع وتحسين الصحة البشرية‪ ،‬وإلتاحة‬
‫إمكانية الحصول على العالج والتثقيف في مجال الرعاية الصحية ‪.‬‬
‫‪ ‬ويشجع القرار كذلك الدول األعضاء على وضع سياسات وطنية للوقاية من‬
‫مرض السكري وعالج املصابين به ورعايتهم بما يتماش ى مع سبل التنمية‬
‫املستدامة في نظمها بمجال الرعاية الصحية‪.‬‬
‫‪ ‬بعد ‪ 100‬عام من اكتشاف األنسولين‬
‫‪ ‬موضوع اليوم العاملي للسكري للمدة ‪ 2023 - 2021‬هو الوصول إلى رعاية مرض ى‬
‫السكري‪.‬‬
 The earliest description of diabetes appeared in
a collection of medical texts in Egypt written
around 552 BC, the Ebers Papyrus.
 Diabetes mellitus and its medicinal remedies
were described in ancient India and China
 Aretaeus of Cappadocia, a Greek physician,
(129–199 AD) introduced the term “diabetes”
from the Greek word “siphon” as he noted that
diabetes causes constant flow of urine.
 Before the availability of insulin, the life
expectancy of children with diabetes mellitus
was short and the prognosis for the adult onset
diabetes was very poor.
 Diabetes mellitus (DM) is characterized by
hyperglycemia and glycosuria and is an end point
of a few disease processes.
 The most common type occurring in childhood is
type 1 DM (DM1), which is caused by
autoimmune destruction of the insulin-producing
beta cells (islets) of the pancreas leading to
permanent insulin deficiency.
 Type 2 DM (DM2) results from insulin resistance
and relative insulin deficiency, usually in the
context of exogenous obesity.
 Less common types of diabetes result from
genetic defects of the insulin receptor or
inherited abnormalities in sensing of ambient
glucose concentration by pancreatic beta cells
classification of diabetes

1- Type I diabetes (ß-cell destruction, usually leading to

absolute insulin deficiency).
Immune mediated
 Idiopathic

2-Type II diabetes* (may range from predominantly insulin

resistance with relative insulin deficiency to a
predominantly secretory defect with insulin resistance).
Dominant type2 due to sulfonylruea receptor1mutation
 TYPE 1 DIABETES MELLITUS

characterized by low or absent levels of endogenously

produced insulin & dependence on exogenous insulin to
prevent development of ketoacidosis

The natural history includes 4 distinct stages:

(1) preclinical β-cell autoimmunity with progressive defect of
insulin secretion.
(2) onset of clinical diabetes.
(3) transient remission “honeymoon period” .
(4) established diabetes associated with acute & chronic
complications & decreased life expectancy
The onset occurs predominantly in childhood, with median age
of 7 to 15 yr, but it may present at any age.

T1DM is characterized by autoimmune destruction of

pancreatic islet β cells.
Both genetic susceptibility & environmental factors contribute
to the pathogenesis.

Susceptibility to T1DM is genetically controlled by alleles of the

major histocompatibility complex (MHC) class II genes
expressing human leukocyte antigens (HLAs).
It is also associated with autoantibodies to islet cell cytoplasm
(ICA), insulin (IAA), antibodies to glutamic acid decarboxylase
(GADA or GAD65), and ICA512 (IA2).

T1DM is associated with other autoimmune diseases such as

thyroiditis, celiac disease, multiple sclerosis, and Addison
disease.

In some children and adolescents with apparent T 1DM, the

β-cell destruction is not immune mediated. This subtype of
diabetes occurs in patients of African or Asian origin & is
distinct from known causes of β-cell destruction such as
drugs or chemicals, viruses, mitochondrial gene defects,
pancreatectomy, & ionizing radiation. These individuals may
have ketoacidosis, but they have extensive periods of
remission with variable insulin deficiency, similarly to patients
with T2DM.
 TYPE 2 DIABETES MELLITUS

children & adolescents with this type of diabetes are

usually obese.
are not insulin dependent.
infrequently develop ketosis.

Some may develop ketosis during severe infections or other

stresses & may then need insulin for correction of
symptomatic hyperglycemia.
The presentation of T2DM is typically more insidious than that
with T1DM.

children with T2DM often seek medical care because of

excessive weight gain & fatigue as a result of insulin
resistance &/or an incidental finding of glycosuria during
routine physical examination.

The incidence of T2DM in children has increased by more than

10-fold in many diabetes centers, in part as a result of the
epidemic of childhood obesity
Acanthosis nigricans (dark pigmentation of skin
creases/flexural areas), a sign of insulin resistance, is present
in the majority of patients with T2DM & is accompanied by a
relative hyperinsulinemia at the time of the diagnosis

In some children with strong family history of T2DM, impaired

glucose tolerance may occur in a pattern implying dominant
inheritance. This pattern of diabetes has been termed
maturity-onset diabetes of the young (MODY) and may require
insulin treatment.

In MODY, there is no apparent autoimmune destruction of β

cells and no HLA association.
Diagnostic Criteria for Diabetes Mellitus

1) Fasting serum glucose concentration ≥126 mg/dL,,

mg/dL, and

(2) a random venous plasma glucose ≥200 mg/dL with

symptoms of hyperglycemia
(3) an abnormal oral glucose tolerance test (OGTT)
with a 2-hour postprandial serum glucose
(concentration ≥200

(4) a HgbA1c ≥6.5%.

A patient is considered to have
impaired fasting glucose
if fasting serum glucose concentration
is 100 to 125 mg/dL or
impaired glucose tolerance if 2-hour
plasma glucose following
an OGTT is 140 to 199 mg/dL.
 DIAGNOSIS.

the most important clue is an inappropriate polyuria in any

child with dehydration, poor weight gain, or “the flu.”
Hyperglycemia, glycosuria, & ketonuria can be determined
quickly.
Nonfasting blood glucose greater than 200 mg/dL (11.1
mmol/L) with typical symptoms is diagnostic with or without
ketonuria. In the obese child, T2DM must be considered.
Once hyperglycemia is confirmed, it is prudent to determine
whether DKA is present (especially if ketonuria is found) and
to evaluate electrolyte abnormalities—even if signs of
dehydration are minimal.
A baseline hemoglobin A1C (HbA1C) allows an estimate of
the duration of hyperglycemia & provides an initial value by
which to compare the effectiveness of subsequent therapy.
In the non obese child, testing for autoimmunity to β cells is
not necessary.
Other autoimmunities associated with type 1 diabetes should
be sought, including celiac disease (by tissue
transglutaminase IgA and total IgA) and thyroiditis (by
antithyroid peroxidase and antithyroglobulin antibodies).
Because significant physiologic distress can disrupt the
pituitary-thyroid axis, free thyroxine (T4) and TSH levels
should be checked after the child is stable for a few weeks.

Rarely, a child has transient hyperglycemia with glycosuria

while under substantial physical stress. This usually resolves
permanently during recovery from the stressors.
Routine screening procedures, such as postprandial
determinations of blood glucose or screening oral glucose
tolerance tests, have yielded low detection rates in healthy,
asymptomatic children, even among those considered at risk, such
as siblings of diabetic children. Accordingly, such screening
procedures are not recommended in children.
IT IS TREATABLE
NON-CURABLE
DISEASE
Insulin Therapy

Children with long-standing diabetes & no insulin reserve

require ~ 0.7 U/kg/d if prepubertal
1.0 U/kg/d at midpuberty
1.2 U/kg/d by the end of puberty.

A reasonable dose in the newly diagnosed child, then, is about

60–70% of the full replacement dose based on pubertal
status.
 During the early part of the 20th century,
before insulin became available,
physicians Allen and Joslin endorsed
fasting and calorie-restricted diets for
diabetes (4).
 This resulted in some improvement of
glucosuria and acidosis, decreased coma,
and delayed death among children with
diabetes. All diabetics were advised to
decrease their sugar and dietary starch
intake, and those who were obese were
advised to lose weight.
 The discovery of insulin in 1922 marked a major
breakthrough in medicine and therapy in patients with
diabetes.
 Long before the discovery of insulin, it was hypothesized
that the pancreas secreted a substance that controlled
carbohydrate metabolism.
 For years, attempts at preparing pancreatic extracts to
lower blood glucose were unsuccessful due to impurities
and toxicities.
 Frederick Banting, an orthopedic surgeon, had the idea
of isolating pancreatic islet extracts by ligating the
pancreatic duct of dogs, keeping them alive until the
acini degenerated, leaving the islets for isolation.
 .
 He approached John Macleod, professor of
physiology and department head at the University
of Toronto, for laboratory space. Macleod granted
him laboratory space, ten dogs for his experiments,
a student research assistant (Charles Best), and
provided supervision and guidance. The
experiments began on May 17, 1921, and by
September they showed that the depancreatized
dog developed diabetes and that intravenous
injection with their pancreatic extract, which they
named isletin, lowered the blood glucose
 By late 1921, the biochemist J.B. Collip joined the group
and helped purify the isletin for human use. The first
injection of the pancreatic extract to a 14-year-old boy
by Banting and Best on January 11, 1922, caused a
sterile abscess, had no effect on ketosis, and resulted in
mild blood glucose reduction.
 Subsequent injections of the purified extract by Collip
had promising results that same year. Blood glucose and
glucosuria decreased, and ketonuria disappeared.
Rosenfeld reported encouraging results in six more
patients.
 Several months later, in 1923, Banting, Best, and
Macleod were awarded the Nobel Prize.
The Miracle Drug
 In 1923, August Krogh, from the University
of Copenhagen, met with Banting and
Macleod to learn more about insulin
because his wife had diabetes mellitus. He
received authorization from the University
of Toronto to bring insulin to Scandinavia. A
non-profit body, Nordisk Insulin Laboratory,
began insulin production
 In 1982, the first insulin utilizing rDNA
technology, Humulin® R (rapid) and N
(NPH, intermediate-acting), were marketed.
 Once patients with diabetes started to
live longer, chronic complications of
diabetes became prevalent.
 In 1993, the Diabetes Control and
Complications Trial showed for the first
time without any doubt the linear
relation between the degree of glycemic
control and complications
 The discovery of pancreatic crude extracts
gave hope to patients with diabetes mellitus.
The subsequent development of precisely
engineered insulin analogs, which are more
physiologic, improved diabetes control and
reduced or delayed complications. Insulin
continues to be the cornerstone of therapy.
Newer medications complement and
enhance insulin action tailored toward
different mechanisms in the
pathophysiology of diabetes mellitus.
All preanalog insulins form hexamers, which must dissociate
into monomers subcutaneously before being absorbed into
the circulation.
Thus, a detectable effect for regular (R) insulin is delayed by
30–60 min after injection.
This, in turn, requires delaying the meal 30- 60 min after the
injection for optimal effect-a delay rarely attained in a busy
child's life.

Regular insulin R has a wide peak & a long tail for bolus
insulin.
This profile limits postprandial glucose control, produces
prolonged peaks with excessive hypoglycemic effects between
meals, & increases the risk of nighttime hypoglycemia.
These unwanted between-meal effects often necessitate
“feeding the insulin” with snacks and limiting the overall
degree of blood glucose control.

NPH and Lente insulins also have inherent limits because they
do not create a peakless background insulin level

This produces significant hypoglycemic effect during the

midrange of their duration. Thus, it is often difficult to predict
their interaction with fast-acting insulins.
lispro/aspart + Glargine
The rapid onset and short duration of
L or A reduce overlap between pre-
meal injections, and there is no
extended nighttime action. This
reduces the risk of hypoglycemia.
Glargine provides a steady basal
profile that simplifies prediction of
lispro/aspart+
bolus ultralente
insulin effect.

lispro/aspart+ NPH or Lente

lispro/aspart+ NPH or Lente

Regular and NPH or Lente

Lispro (L) & aspart (A), insulin analogs, are absorbed much
quicker because they do not form hexamers. They provide
discrete pulses with little if any overlap and short tail effect.
This allows better control of post-meal glucose increase and
reduces between-meal or nighttime hypoglycemia.

The long-acting analog glargine (G) creates a much flatter 24-

hr profile, making it easier to predict the combined effect of a
rapid bolus (L or A) on top of the basal insulin, producing a
more physiologic pattern of insulin effect.
Postprandial glucose elevations are better controlled, &
between-meal & nighttime hypoglycemia are reduced.
Ultralente (UL) given twice a day provided a reasonable basal
profile & was quite effective when used with lispro or aspart.
Since UL is no longer available, G may be given every 12 hours
in young children if a single daily dose of G does not produce
complete 24-hr basal coverage.

The basal insulin glargine should be

25–30% of the total dose in toddlers
40–50% in older children.
The remaining portion of the total daily dose is divided evenly
as bolus injections for the 3 meals.
A simple 3- or 4-step dosing schedule is begun based on the
blood glucose level. As soon as the family is taught to
calculate the carbohydrate content of meals, bolus insulin
can be more accurately dosed by both the carbohydrate
content of the meal as well as the ambient glucose.
 SUBCUTANEOUS INSULIN DOSING

BOLUS INSULIN

AGE (YR TARGET TOTAL BASAL Units Units

GLUCOSE DAILY INSULIN, Added per Added per
(MG/DL) INSULIN % OF 100 15 g at
(U/KG/D) TOTAL mg/dL Meal
DAILY above
DOSE Target
0-5 100-200 0.6-0.7 25-30 0.50 0.50

5-12 80-150 0.7-1.0 40-50 0.75 0.75

12-18 80-150 1.0-1.2 40-50 1.0-2.0 1.0-2.0

 Management
 Management of DM1 in children requires a
comprehensive approach with attention to
medical, nutritional, and psychosocial issues.
 Therapeutic strategies should be flexible
with the individual needs of each patient and
the family taken into account.

 Optimal care involves a team of diabetes

professionals, including a physician, a
diabetes nurse educator, a dietitian, and a
social worker or psychologist.
 Goals
 The Diabetes Control and Complications Trial
established that intensive insulin therapy, with
the goal of maintaining blood glucose
concentrations as close to normal as possible,
 can delay the onset and slow the progression of
complications of diabetes (retinopathy,
nephropathy, neuropathy).
 Attaining this goal using intensive insulin therapy
can increase the risk of hypoglycemia.
 The adverse effects of hypoglycemia in young
children may be significant because the
immature CNS may be more susceptible to
glycopenia
 For children younger than 5 years old, an
appropriate goal is maintenance of blood
glucose concentrations between 80 and 180
mg/dL.
 For school-age children, 80 to 150 mg/dL is
a reasonable target range.
 For adolescents, the goal is 70 to 130
mg/dL.
 Goals of therapy also should take into
account other individual characteristics,
such as a past history of severe
hypoglycemia and the abilities of the patient
and family.
 Honeymoon Period
 In some patients with new onset of DM1, the beta
cell mass
has not been completely destroyed. The remaining
functional beta cells seem to recover function with
insulin treatment.
 When this occurs, exogenous insulin requirements
decrease. This is a period of stable blood glucose
control, often with nearly normal glucose
concentrations.
 This phase of the disease, known as the
honeymoon period, usually starts in the first weeks
of therapy, often continues for 3 to 6 months, and
can last 2 years.
Nutrition
It is recommended that
Carbohydrates contribute 50% to 65% of
the total calories,
 protein 12% to 20%, and
 fat <30%. Saturated fat should
contribute <10% of
 the total caloric intake, and cholesterol
intake should be less than 300 mg/24
hours.
 High fiber content is recommended.
 Children using a twice-aday
 combination of intermediate-acting and fast-
acting insulins
 need to maintain a relatively consistent meal
schedule so
 that carbohydrate absorption and insulin
action peaks correspond.
 Typical meal schedule for a patient using this
type of
 regimen involves three meals and three
snacks daily.
 The total carbohydrate content of the meals
and snacks should be kept constant.
 Blood Glucose Testing
 Blood glucose should be routinely monitored
before each meal and at bedtime.
 Hypoglycemia during the night or excessive
variability in the morning glucose
concentrations should prompt additional
testing at 2 or 3 am to ensure that there is no
consistent hypoglycemia or hyperglycemia.
 ( Somogy & Dawn Syndrom )
 During periods of illness or when blood
glucose concentrations are higher than 300
mg/dL, urine ketones also should be tested

 Long-Term Glycemic Control

 Complications
 Patients with DM1 for more than 3 to 5 years should
receive an annual ophthalmologic examination for
retinopathy.
 Urine should be collected annually for assessment
of microalbuminuria, which suggests early renal
dysfunction and indicates a high risk of progression
to nephropathy.
 Treatment with ACE inhibitors may halt the
progression of microalbuminuria.
 In children with DM1, annual cholesterol
measurements and periodic assessment of blood
pressure are recommended. Early detection of
hypertension and hypercholesterolemia with
appropriate intervention can help limit future risk of
coronary disease.
 Other Disorders
 Chronic autoimmune lymphocytic thyroiditis
is particularly common and can result in
hypothyroidism
 Because symptoms can be subtle, thyroid
function tests should be performed
annually.
 Other disorders that occur with increased
frequency in children with DM1 include
celiac disease, IgA deficiency, Addison
disease, and peptic ulcer disease.
THANK YOU