REVIEW OF DIABETES MELLITUS

LOO HARIYANTO RAHARJO, dr., Msi.

Ketua Program Studi Pendidikan Dokter
FK-UWKS
 Diabetes mellitus (DM) is a group of diseases characterized by
high levels of blood glucose resulting from defects in insulin
production, insulin action, or both.

 The term diabetes mellitus describes a metabolic disorder of

multiple aetiology characterized by chronic hyperglycaemia
with disturbances of carbohydrate, fat and protein metabolism
resulting from defects in insulin secretion, insulin action, or
both.

 The effects of diabetes mellitus include long–term damage,

dysfunction and failure of various organs.
 Diabetes mellitus may present with characteristic symptoms
such as thirst, polyuria, blurring of vision, and weight loss.

 In its most severe forms, ketoacidosis or a non–ketotic

hyperosmolar state may develop and lead to stupor, coma
and, in absence of effective treatment, death.

 Often symptoms are not severe, or may be absent, and

consequently hyperglycaemia sufficient to cause pathological
and functional changes may be present for a long time before
the diagnosis is made.
 The long–term effects of diabetes mellitus include progressive
development of the specific complications of retinopathy with
potential blindness, nephropathy that may lead to renal
failure, and/or neuropathy with risk of foot ulcers,
amputation, Charcot joints, and features of autonomic
dysfunction, including sexual dysfunction.

 People with diabetes are at increased risk of cardiovascular,

peripheral vascular and cerebrovascular disease.
 The development of diabetes is projected to reach pandemic
proportions over the next10-20 years.

 International Diabetes Federation (IDF) data indicate that by the year

2025, the number of people affected will reach 333 million –90% of
these people will have Type 2 diabetes.

 In most Western societies, the overall prevalence has reached 4-6%,

and is as high as 10-12% among 60-70-year-old people.

 The annual health costs caused by diabetes and its complications

account for around 6-12% of all health-care expenditure.
 Type 1 Diabetes Mellitus
 Type 2 Diabetes Mellitus
 Gestational Diabetes
 Other types:
LADA (Latent Autoimmune Diabetes in Adults )
MODY (maturity-onset diabetes of youth)
Secondary Diabetes Mellitus
 Was previously called insulin-dependent diabetes mellitus (IDDM)
or juvenile-onset diabetes.
 Type 1 diabetes develops when the body’s immune system
destroys pancreatic beta cells, the only cells in the body that make
the hormone insulin that regulates blood glucose.
 This form of diabetes usually strikes children and young adults,
although disease onset can occur at any age.
 Type 1 diabetes may account for 5% to 10% of all diagnosed cases
of diabetes.
 Risk factors for type 1 diabetes may include autoimmune, genetic,
and environmental factors.
 Was previously called non-insulin-dependent diabetes mellitus (NIDDM) or
adult-onset diabetes.
 Type 2 diabetes may account for about 90% to 95% of all diagnosed cases of
diabetes.
 It usually begins as insulin resistance, a disorder in which the cells do not
use insulin properly. As the need for insulin rises, the pancreas gradually
loses its ability to produce insulin.
 Type 2 diabetes is associated with older age, obesity, family history of
diabetes, history of gestational diabetes, impaired glucose metabolism,
physical inactivity, and race/ethnicity.
 African Americans, Hispanic/Latino Americans, American Indians, and some
Asian Americans and Native Hawaiians or Other Pacific Islanders are at
particularly high risk for type 2 diabetes.
 Type 2 diabetes is increasingly being diagnosed in children and adolescents.
 A form of glucose intolerance that is diagnosed in some
women during pregnancy.
 Gestational diabetes occurs more frequently among
African Americans, Hispanic/Latino Americans, and
American Indians. It is also more common among obese
women and women with a family history of diabetes.
 During pregnancy, gestational diabetes requires treatment
to normalize maternal blood glucose levels to avoid
complications in the infant.
 After pregnancy, 5% to 10% of women with gestational
diabetes are found to have type 2 diabetes.
 Women who have had gestational diabetes have a 20% to
50% chance of developing diabetes in the next 5-10 years.
 Other specific types of diabetes result from specific genetic
conditions (such as maturity-onset diabetes of youth),
surgery, drugs, malnutrition, infections, and other illnesses.

 Such types of diabetes may account for 1% to 5% of all

diagnosed cases of diabetes.
 Latent Autoimmune Diabetes in Adults (LADA) is a form of
autoimmune (type 1 diabetes) which is diagnosed in
individuals who are older than the usual age of onset of type
1 diabetes.
 Alternate terms that have been used for "LADA" include Late-
onset Autoimmune Diabetes of Adulthood, "Slow Onset Type
1" diabetes, and sometimes also "Type 1.5
 Often, patients with LADA are mistakenly thought to have
type 2 diabetes, based on their age at the time of diagnosis.
 About 80% of adults apparently with recently diagnosed Type
2 diabetes but with GAD (Glutamic Acid Decarboxylase) auto-
antibodies (i.e. LADA) progress to insulin requirement within 6
years.

 The potential value of identifying this group at high risk of

progression to insulin dependence includes:
◦ the avoidance of using metformin treatment
◦ the early introduction of insulin therapy
 MODY – Maturity Onset Diabetes of the Young

 MODY is a monogenic form of diabetes with an autosomal dominant

mode of inheritance:
◦ Mutations in any one of several transcription factors or in the enzyme
glucokinase lead to insufficient insulin release from pancreatic ß-cells, causing
MODY.
◦ Different subtypes of MODY are identified based on the mutated gene.

 Originally, diagnosis of MODY was based on presence of non-ketotic

hyperglycemia in adolescents or young adults in conjunction with a
family history of diabetes.

 However, genetic testing has shown that MODY can occur at any age
and that a family history of diabetes is not always obvious.
 Permanent Neonatal Diabetes Mellitus

DEND syndrome is a very rare, generally severe form of neonatal diabetes mellitus (NDM,
see this term) characterized by a triad of developmental delay, epilepsy, and neonatal
diabetes.
 Within MODY, the different subtypes can essentially be
divided into 2 distinct groups: glucokinase MODY and
transcription factor MODY, distinguished by characteristic
phenotypic features and pattern on oral glucose tolerance
testing.

 Glucokinase MODY requires no treatment, while transcription

factor MODY (i.e. Hepatocyte nuclear factor -1alpha) requires
low-dose sulfonylurea therapy and PNDM (caused by Kir6.2
mutation) requires high-dose sulfonylurea therapy.
Secondary causes of Diabetes mellitus include:

 Acromegaly,
 Cushing syndrome,
 Thyrotoxicosis,
 Pheochromocytoma
 Chronic pancreatitis,
 Cancer
 Drug induced hyperglycemia:
◦ Atypical Antipsychotics - Alter receptor binding characteristics, leading to increased insulin
resistance.
◦ Beta-blockers - Inhibit insulin secretion.
◦ Calcium Channel Blockers - Inhibits secretion of insulin by interfering with cytosolic calcium
release.
◦ Corticosteroids - Cause peripheral insulin resistance and gluconeogensis.
◦ Fluoroquinolones - Inhibits insulin secretion by blocking ATP sensitive potassium channels.
◦ Naicin - They cause increased insulin resistance due to increased free fatty acid mobilization.
◦ Phenothiazines - Inhibit insulin secretion.
◦ Protease Inhibitors - Inhibit the conversion of proinsulin to insulin.
◦ Thiazide Diuretics - Inhibit insulin secretion due to hypokalemia. They also cause increased
insulin resistance due to increased free fatty acid mobilization.
 Prediabetes is a term used to distinguish people who are at
increased risk of developing diabetes. People with prediabetes
have impaired fasting glucose (IFG) or impaired glucose
tolerance (IGT). Some people may have both IFG and IGT.

 IFG is a condition in which the fasting blood sugar level is

elevated (100 to 125 milligrams per decilitre or mg/dL) after
an overnight fast but is not high enough to be classified as
diabetes.

 IGT is a condition in which the blood sugar level is elevated

(140 to 199 mg/dL after a 2-hour oral glucose tolerance test),
but is not high enough to be classified as diabetes.
 Progression to diabetes among those with prediabetes is not
inevitable. Studies suggest that weight loss and increased physical
activity among people with prediabetes prevent or delay diabetes
and may return blood glucose levels to normal.

 People with prediabetes are already at increased risk for other

adverse health outcomes such as heart disease and stroke.
 Management of
Diabetes Mellitus
 Studies have shown that medications have been successful in preventing
diabetes in some population groups.
 In the Diabetes Prevention Program, people treated with the drug metformin
reduced their risk of developing diabetes by 31% over 3 years.
 Treatment with metformin was most effective among younger, heavier
people (those 25-40 years of age who were 50 to 80 pounds overweight)
and less effective among older people and people who were not as
overweight.
 Similarly, in the STOP-NIDDM Trial, treatment of people with IGT with the
drug acarbose reduced the risk of developing diabetes by 25% over 3 years.
 Other medication studies are ongoing. In addition to preventing progression
from IGT to diabetes, both lifestyle changes and medication have also been
shown to increase the probability of reverting from IGT to normal glucose
tolerance.
 Research studies have found that lifestyle changes can
prevent or delay the onset of type 2 diabetes among high-
risk adults.

 These studies included people with IGT and other high-risk

characteristics for developing diabetes.

 Lifestyle interventions included diet and moderate-intensity

physical activity (such as walking for 2 1/2 hours each
week).

 In the Diabetes Prevention Program, a large prevention

study of people at high risk for diabetes, the development
of diabetes was reduced 58% over 3 years.
 The major components of the treatment of
diabetes are:

A • Diet and Exercise

• Oral hypoglycaemic
B therapy

C • Insulin Therapy
 Diet is a basic part of management in every case. Treatment
cannot be effective unless adequate attention is given to
ensuring appropriate nutrition.

 Dietary treatment should aim at:

◦ ensuring weight control
◦ providing nutritional requirements
◦ allowing good glycaemic control with blood glucose levels as close to
normal as possible
◦ correcting any associated blood lipid abnormalities
The following principles are recommended as dietary guidelines for
people with diabetes:

 Dietary fat should provide 25-35% of total intake of calories but

saturated fat intake should not exceed 10% of total energy.
Cholesterol consumption should be restricted and limited to 300
mg or less daily.

 Protein intake can range between 10-15% total energy (0.8-1

g/kg of desirable body weight). Requirements increase for
children and during pregnancy. Protein should be derived from
both animal and vegetable sources.

 Carbohydrates provide 50-60% of total caloric content of the

diet. Carbohydrates should be complex and high in fibre.

 Excessive salt intake is to be avoided. It should be particularly

restricted in people with hypertension and those with
nephropathy.
 Physical activity promotes weight reduction and improves
insulin sensitivity, thus lowering blood glucose levels.

 Together with dietary treatment, a programme of regular

physical activity and exercise should be considered for each
person. Such a programme must be tailored to the
individual’s health status and fitness.

 People should, however, be educated about the potential risk

of hypoglycaemia and how to avoid it.
 There are currently four classes of oral anti-diabetic agents:

i. Biguanides
ii. Insulin Secretagogues – Sulphonylureas
iii. Insulin Secretagogues – Non-sulphonylureas
iv. α-glucosidase inhibitors
v. Thiazolidinediones (TZDs)
 If glycaemic control is not achieved (HbA1c > 6.5%
and/or; FPG > 7.0 mmol/L or; RPG >11.0mmol/L) with
lifestyle modification within 1 –3 months, ORAL ANTI-
DIABETIC AGENT should be initiated.

 In the presence of marked hyperglycaemia in newly

diagnosed symptomatic type 2 diabetes (HbA1c > 8%,
FPG > 11.1 mmol/L, or RPG > 14 mmol/L), oral anti-
diabetic agents can be considered at the outset together
with lifestyle modification.
As first line therapy:

 Obese type 2 patients, consider use of metformin, acarbose or TZD.

 Non-obese type 2 patients, consider the use of metformin or insulin

secretagogues

 Metformin is the drug of choice in overweight/obese patients. TZDs and

acarbose are acceptable alternatives in those who are intolerant to
metformin.

 If monotherapy fails, a combination of TZDs, acarbose and metformin is

recommended. If targets are still not achieved, insulin secretagogues
may be added
Combination oral agents is indicated in:

 Newly diagnosed symptomatic patients with HbA1c >10

 Patients who are not reaching targets after 3 months on

monotherapy
 If targets have not been reached after optimal dose of combination
therapy for 3 months, consider adding intermediate-acting/long-
acting insulin (BIDS).

 Combination of insulin+ oral anti-diabetic agents (BIDS) has been

shown to improve glycaemic control in those not achieving target
despite maximal combination oral anti-diabetic agents.

 Combining insulin and the following oral anti-diabetic agents has been
shown to be effective in people with type 2 diabetes:
◦ Biguanide (metformin)
◦ Insulin secretagogues (sulphonylureas)
◦ Insulin sensitizers (TZDs)(the combination of a TZD plus insulin is not an
approved indication)
◦ α-glucosidase inhibitor (acarbose)

 Insulin dose can be increased until target FPG is achieved.

 Diabetes
Management
Algorithm
 In elderly non-obese patients, short acting insulin secretagogues can be
started but long acting Sulphonylureas are to be avoided. Renal function
should be monitored.

 Oral anti-diabetic agent s are not recommended for diabetes in pregnancy

 Oral anti-diabetic agents are usually not the first line therapy in diabetes
diagnosed during stress, such as infections. Insulin therapy is
recommended for both the above

 Targets for control are applicable for all age groups. However, in patients
with co-morbidities, targets are individualized

 When indicated, start with a minimal dose of oral anti-diabetic agent, while
reemphasizing diet and physical activity. An appropriate duration of time
(2-16 weeks depending on agents used) between increments should be
given to allow achievement of steady state blood glucose control
Short-term use:
 Acute illness, surgery, stress and emergencies
 Pregnancy
 Breast-feeding
 Insulin may be used as initial therapy in type 2 diabetes
 in marked hyperglycaemia
 Severe metabolic decompensation (diabetic ketoacidosis, hyperosmolar
nonketotic coma, lactic acidosis, severe hypertriglyceridaemia)

Long-term use:
 If targets have not been reached after optimal dose of combination
therapy or BIDS, consider change to multi-dose insulin therapy. When
initiating this,insulin secretagogues should be stopped and insulin
sensitisers e.g. Metformin or TZDs, can be continued.
 The majority of patients will require more than one daily injection if good
glycaemic control is to be achieved. However, a once-daily injection of an
intermediate acting preparation may be effectively used in some patients.

 Twice-daily mixtures of short- and intermediate-acting insulin is a

commonly used regimen.

 In some cases, a mixture of short- and intermediate-acting insulin may be

given in the morning. Further doses of short-acting insulin are given before
lunch and the evening meal and an evening dose of intermediate-acting
insulin is given at bedtime.

 Other regimens based on the same principles may be used.

 A regimen of multiple injections of short-acting insulin before the main

meals, with an appropriate dose of an intermediate-acting insulin given at
bedtime, may be used, particularly when strict glycaemic control is
mandatory.
 Patients should be educated to practice self-care. This allows
the patient to assume responsibility and control of his / her own
diabetes management. Self-care should include:

◦ Blood glucose monitoring

◦ Body weight monitoring
◦ Foot-care
◦ Personal hygiene
◦ Healthy lifestyle/diet or physical activity
◦ Identify targets for control
◦ Stopping smoking
“Newer” Diabetes
Therapies
WHERE DO THEY FIT IN?
Therapeutic Options for
Type 2 Diabetes Therapeutics over time
1995 2018
Sulfonylureas
Sulfonylureas GLP1 receptor
Insulin (NPH, Regular, ultralente) agonists
Insulin (NPH, DPP-4 inhibitors
Regular, analogues,
peakless basal, etc)
Metformin Amylin analogues

TZDs Bile Acid

Sequestrants
Alpha-glucosidase Bromocriptine
inhibitors
Meglitinides SGLT2 inhibitors
 Class Mechanism Advantages Disadvantages Cost
Biguanides / • Activates AMP-kinase • Extensive experience • Gastrointestinal Low
Metformin •  Hepatic glucose • No hypoglycemia • Lactic acidosis
production • Weight neutral • B-12 deficiency
• ?  CVD • Contraindicated if GFR <
30mL/min
SUs / • Closes KATP channels • Extensive experience • Hypoglycemia Low
Meglitinides •  Insulin secretion •  Microvasc. risk • Weight gain
• Poor durability
• Do NOT use Glyburide

TZDs • PPAR-g activator • No hypoglycemia • Weight gain Mod

•  insulin sensitivity • Durability • Edema / heart failure
•  TGs,  HDL-C • Bone fractures
• ?  CVD (pio) • ?  MI (rosi)
• ? Bladder ca (pio)
a-GIs • Inhibits a-glucosidase • No hypoglycemia • Gastrointestinal Mod
• Slows carbohydrate • Nonsystemic • Dosing frequency
absorption •  Post-prandial glucose • Modest  A1c
• ?  CVD events
 Class Mechanism Advantages Disadvantages Cost
DPP-4 • Inhibits DPP-4 • No hypoglycemia • Modest  A1c High
inhibitors • Increases GLP-1, GIP • Well tolerated • ? Pancreatitis
• Urticaria
GLP-1 receptor • Activates GLP-1 R • Weight loss • GI High
agonists •  Insulin,  glucagon • No hypoglycemia • ? Pancreatitis
•  gastric emptying • ? Beta cell mass • Medullary ca
•  satiety • ? CV protection • Injectable
Amylin mimetics • Activates amylin receptor • Weight loss • GI High
•  glucagon •  PPG • Modest  A1c
•  gastric emptying • Injectable
•  satiety • Hypo w/ insulin
• Dosing frequency
Bile acid • Bind bile acids • No hypoglycemia • GI High
sequestrants •  Hepatic glucose production • Nonsystemic • Modest  A1c
•  Post-prandial glucose • Dosing frequency
•  CVD events
Dopamine-2 • Activates DA receptor • No hypoglyemia • Modest  A1c High
agonists • Modulates hypothalamic control • ?  CVD events •Dizziness, syncope
of metabolism • Nausea, fatigue
•  insulin sensitivity
 Class Mechanism Advantages Disadvantages Cost

Insulin • Activates insulin receptor • Universally effective • Hypoglycemia Variable

•  peripheral glucose uptake • Unlimited efficacy • Weight gain
•  Microvascular risk • ? Mitogenicity
• Injectable
• Training requirements
• “Stigma”

Table 1. Properties of anti-hyperglycemic agents Diabetes Care, Diabetologia. 19 April 2012