Diabetes Mellitus

Mardianto
Division of Endocrine and
Metabolic
Departement of Internal Medicine
Haji Adam Malik General Hospital

Countries with the highest

numbers of estimated cases of
diabetes for 2030
Egypt

Philippines
Japan
Bangladesh
Brazil
Pakistan
Indonesia
USA
China
India
0

20

40

60

80

100

People with diabetes (millions)

Adapted from Wild SH et al. Diabetes Care 2004; 27: 256970.

DEFINITION OF DIABETES
MELLITUS

Diabetes mellitus is a group of

metabolic diseases characterized by
hyperglycemia resulting from
defects in insulin secretion, insulin
action, or both.
The chronic hyperglycemia of
diabetes is associated with long-term
damage, dysfunction, and failure of
various organs, especially the eyes,
kidneys, nerves, heart, and blood

Common Symptoms
Classic symptoms Others sympmtoms
fatigue
increased hunger
tingling or numbness in
increased thirst
hands and feet
frequent urination recurring infections
gums, skin, lung,
weight loss

urinary bladder
slow healing
blurred vision
pruritus vulvae
erectile dysfunction

Diagnosis of Diabetes
Mellitus
1.

2.

3.

Symptoms of diabetes and a casual plasma glucose

200 mg/dl (11.1 mmol/l). Casual is defined as any
time of day without regard to time since last meal.
The classic symptoms of diabetes include polyuria,
polydipsia, and unexplainedweight loss.
OR
FPG 126 mg/dl (7.0 mmol/l). Fasting is defined as no
caloric intake for at least 8 h.
OR
2-h plasma glucose 200 mg/dl (11.1 mmol/l) during
an OGTT. The test should be performed as described
by the World Health Organization, using a glucose
load containing the equivalent of 75-g anhydrous
In thedissolved
absence of unequivocalin
hyperglycemia,
these criteria should be confirmed by
glucose
water.
repeat testing on a different day. The OGTT is not recommended for routine clinical use,
but may be required in the evaluation of patients with IFG (see text) or when diabetes is
still suspected despite a normal FPG as with the postpartum evaluation of women with
GDM.

ADA definition of
hyperglycaemic states

Criteria for the diagnosis of diabetes

Symptoms of diabetes plus casual plasma glucose 200 mg/dl (11.1 mmol/l)
or
FPG
< 100 mg/dl (5.6 mmol/l)

normal fasting glucose

100125 mg/dl (5.66.9 mmol/l)

126 mg/dl (7.0 mmol/l)

impaired fasting glucose

diabetes

or
OGTT 2-h post-load glucose
< 140 mg/dl (7.8 mmol/l)
140199 mg/dl (7.811.1 mmol/l)

normal glucose tolerance

impaired glucose tolerance

200 mg/dl (11.1 mmol/l)

diabetes

ADA = American Diabetes Association

Adapted from American Diabetes Association. Diabetes Care 2004; 27:S5S10.

Criteria for screening for

diabetes in asymptomatic
adult individuals
Testing for diabetes should be considered in
all individuals :
at age 45 years (BMI >25 kg/m2)
at a younger age ; overweight (BMI >23
kg/m2*) and have additional risk factors, as
follows:
are habitually physically inactive
have a first-degree relative with diabetes
have delivered a baby weighing >4 kg or have been
diagnosed
with GDM
are hypertensive (>140/90 mmHg)
have an HDL-C level 35 mg/dl and/or a TG level
250 mg/dl
have PCOS

CLASSIFICATION OF DIABETES
MELLITUS
1.

2.

3.
4.

Type 1 diabetes (cell destruction,

usually leading to absolute insulin
deficiency)
Type 2 diabetes (ranging from
predominantly insulin resistance
with relative insulin deficiency to
predominantly an insulin secretory
defect with insulin resistance)
Other specific types of diabetes
Gestational diabetes mellitus

Type 1 diabetes

Immune-mediated diabetes.

510% of those with diabetes;

absolute insulin deficiency (insulin
dependent diabetes, type I diabetes, or
juvenile-onset diabetes)
cellular-mediated autoimmune
destruction of the - cells of the
pancreas.
markers of the immune destruction of
the -cell include

islet cell autoantibodies, autoantibodies to

insulin,
autoantibodies to glutamic acid
decarboxylase (GAD65),

Other specific types of

diabetes

A. Genetic defects of -cell function

Chromosome 12, HNF-1 (MODY3);

Chromosome 7, glucokinase (MODY2);
Chromosome 20, HNF-4 (MODY1);
Chromosome 13, insulin promoter factor-1
(IPF-1; MODY4); Chromosome 17, HNF-1
(MODY5); Chromosome 2, NeuroD1
(MODY6); Mitochondrial DNA

B. Genetic defects in insulin action

Type A insulin resistance; Leprechaunism;

Rabson-Mendenhall syndrome; Lipoatrophic
diabetes.

C. Diseases of the exocrine pancreas

Pancreatitis; Trauma/pancreatectomy;
Neoplasia; Cystic fibrosis; Hemochromatosis;
Fibrocalculous pancreatopathy.

D. Endocrinopathies

Other specific types of

diabetes
E. Drug- or chemical-induced

Vacor; Pentamidine; Nicotinic acid;

Glucocorticoids; Thyroid hormone; Diazoxide;
adrenergic agonists; Thiazides; Dilantin;
Interferon.

F. Infections

Congenital rubella; Cytomegalovirus.

G. Uncommon forms of immune-mediated

diabetes

Stiff-man syndrome; Antiinsulin receptor

antibodies.

H. Other genetic syndromes sometimes

associated with diabetes

Downs syndrome; Klinefelters syndrome;

Turners syndrome; Wolframs syndrome;

Gestational diabetes
mellitus (GDM)

Any degree of glucose intolerance with

onset during pregnancy
Return to normal glucose regulation after
delivery is common
Increased perinatal morbidity and mortality
if untreated
Risk assessment for GDM
should be undertaken at the
first prenatal visit.
Women with clinical
characteristics consistent with a
high risk for GDM (those with
marked obesity, personal history
of GDM, glycosuria, or a strong

Gestational diabetes
mellitus (GDM)

Diagnostic criteria for the 100-g

OGTT are as follows:
95 mg/dl fasting, 180mg/dl at 1 h,
155 mg/dl at 2 h, and 140 mg/dl at 3
h.
Two or more of the plasma glucose
values must be met or exceeded for a
positive diagnosis.

The test should be done in the

morning after an overnight fast of 8
14 h.

Type 2 diabetes
Type 2 diabetes is characterised by:

chronic hyperglycaemia with

disturbances of carbohydrate, fat
and protein metabolism

defects in insulin secretion (-cell

dysfunction) and insulin action
(insulin resistance)

Definition, Diagnosis and Classification of Diabetes Mellitus and its Complications. Department of Noncommunicable
Disease Surveillance, World Health Organization, Geneva 1999.

What is insulin resistance?

Definition of Insulin Resistance :
Impaired response to the
physiological effects of insulin,
including those on glucose, lipid,
protein metabolism and vascular

Receptor:
endothelial
function

Quantity / function

Post-receptor (mostly):

Translocation of GLUT
Synthesis of GLUT

ADA. Consensus Development on Insulin Resistance. 1997

Insulin
Insulin
receptor

PPAR

Glucose
transloca

tion

RXR

Synthesis GLUT 4

mRNA

PPRE

transcription

promoter

Coding reg

Modified from Howard L. Foyt et al. Thiazolidinediones. Diabetes Mellitus: a Fundamental and Clinical Text, 2nd Ed.

Insulin resistance

Glucose

Insulin

Insulin
receptor

Translocation

X Synthesis GLUT 4
mRNA

PPAR +RXR

PPRE

promoter
Muscle
Cells

transcription

Coding reg

Modified from Howard L. Foyt et al. Thiazolidinediones. Diabetes Mellitus: a Fundamental and Clinical Text, 2nd Ed.

dysfunction are fundamental to

type 2 diabetes
Normal
diabetes
Insulin
resistan
ce
Insulin
secreti
on
Postprandial
glucose
Fasting
glucose

IGT

Type 2

Increased insulin
resistance

Hyperinsulinaemia
then -cell failure
Abnormal
glucose tolerance
Hyperglycaemia

Adapted from Type 2 Diabetes BASICS. International Diabetes Center, Minneapolis, 2000.

Insulin Resistance and -Cell

Dysfunction Produce
Hyperglycemia in Type 2 Diabetes
-Cell Dysfunction

Insulin Resistance

Pancreas

Increased
Lipolysis

Elevated
Plasma FFA

Liver

Islet -Cell Degranulation;

Reduced Insulin Content
Increased Glucose Output

Muscle

Adipose Tissue

Reduced
Plasma Insulin

Hyperglycemia
Courtesy of S. Smith, GlaxoSmithKline

Decreased Glucose Transport

& Activity (expression) of GLUT4

Role of Free Fatty Acids in

Hyperglycemia
Adipose
tissue insulin
resistance
ADIPOSE TISSUE
MUSCLE
Muscle
insulin
resistance

Lipolysis

LIVER

FFA mobilization
Liver insulin
resistance

FFA oxidation

FFA oxidation
Gluconeogenesis

Glucose utilization
Hyperglycemia
Boden G. Proc Assoc Am Physicians. 1999;111:241-248.

Insulin Resistance: An
Underlying Cause of Type 2
Diabetes
Obesity and
inactivity

Aging

Medications
Rare
disorders

Genetic
abnormalities

INSULIN
Type 2
diabetes

RESISTANCE
PCOS

Hypertension
Atherosclerosis
Dyslipidemia
Reaven GM. Physiol Rev. 1995;75:473-486
Clauser, et al. Horm Res. 1992;38:5-12.

-cell dysfunction
ability of -cells to
secrete insulin
Impaired ability of -cells to
compensate for insulin
resistance
Genetic and environmental
pathophysiology
Reduced

DeFronzo RA et al. Diabetes Care 1992; 15: 31854.

Multiple factors may drive

progressive decline of b-cell
function
Hyperglycaemia
(glucose toxicity)

Insulin resistance
Protein
glycation

-cell
lipotoxicity
elevated FFA,TG
(genetic background)
Amyloid
deposition

Management of
Diabetes Mellitus

General Therapeutic
Objectives

Achieve a normal blood glucose level (reduced

symptoms)
Minimize risk of long-term complications
(microvascular and macrovascular) resulting from
sustained high blood sugar.
Gain adequate control of diabetes by ensuring
compliance with a management plan.
Maintain a healthy lifestyle as near normal as
possible.

The principle of
management

Education of diabetes
Lifestyle management
Diet
Exercise

Interventional of pharmacology
Oral treatment
Insulin

Basic education
1.

Survival skills

How to make prescribe medication

How to test blood glucose

Warning sign of hypo/hyperglycemia
Basic nutrition guidelines

2.

Timing, action of medication, technique

for administration (insulin)

Food types, timing of meal, balancing

content and quantity

Lifestyle management issues

Lifestyle Management
Diet & Exercise

Diet -- Three important components

Enough

nutrition to meet energy

demands
Food intake distributed throughout the
day
Feeding pattern and amounts should be
consistent

Exercise
Helps

decrease blood glucose levels

Have physician approve exercise
program

Nutritional
Recomendation

Energy needs

Basal energy requirements (BER) : 2530 kcal/kg of desirable body weight

Desirable body weight/Ideal body
weight (IBW) :

Formula Brocca modified: 90%x {Body

Length (cm)-100}x1kg

Additional energy required :

Activity level

Sedentary 10% of BER

Moderate 20% of BER
Strenuous 50% of BER

Infections :10-20%

Obese patients : reduced energy 20-

Nutritional Recommendations
for All Persons with Diabetes

Protein : 1520% of kcal/d (10% for those

with nephropathy)
Saturated fat : <7% of kcal/d (7% for those
with elevated LDL)
Polyunsaturated fat :<10% of kcal;avoid
trans-unsaturated fatty acids
Carbohydrate : 6070% of total calories
Use of caloric sweeteners, including
sucrose, is acceptable.
Fiber (2035 g/d) and sodium (<3000
mg/d) levels as recommended for the
general healthy population

Physical exercise and insulin

resistance
Exercise

acute &
long whole body glucose disposal
term
risk of developing Type 2 DM
GLUT4 is recruited to the plasma
membrane independently of insulin
Effective in Type 2 diabetics because
muscle GLUT4 expression is normal
Regular exercise has been shown to
improve blood glucose control, reduce
cardiovascular risk factors, contribute to
weight loss, and improve well-being.
muscle glucose uptake

Recommendations of
physical activity

Initial physical activity

recommendations should be modest,
based on the patients willingness
and ability, gradually increasing the
duration and frequency to 30 45
min of moderate aerobic activity 35
days per week, when possible.
Greater activity levels of at least 1
h/day of moderate (walking)or 30
min/day of vigorous (jogging)
activitymay be needed to achieve
successfullong-term weight loss.

Oral Therapy for Type 2

Diabetes
Target Sites of Action
Adipose
tissue

Sulfonylureas
Repaglinide

Pancreas

Gut

Insulin secretion

Glucose
uptake

Acarbose
Miglitol

FFA output

Hyperglycemia

Rosiglitazone
Pioglitazone

Metformin
Rosiglitazone
Pioglitazone

Liver
Hepatic
glucose
output

Rosiglitazone
Pioglitazone
Metformin

Glucose
absorption

Muscle
Gluco
se
uptake

Oral Drug Therapy for

Type 2 DM

Sulfonylureas

Repaglinide
Nateglinide

Biguanides

}
}

Insulin
Thiazolidinedionesensitizers

Insulin
secretagogues

Acarbose

Inhibitors of
CHO
absorption

Sulfonylureas :
Mechanism action

Pancreatic effect

Specific receptor on the surface of

pancreatic beta cell bind the
suflfonilurea receptors (SUR)
There is a family of SUR, Sur
1/Kir6.2 is found in B cellsand the
brain.
SUR 2A/Kir6.2 is found in cardiac
and skeletal muscle

Extrapancreatic effect

Studied in vitro and vitro

In human studies; enhances insulinstimulated perpheral glucose
utilization in both adipose tissue

Sulfonylureas: Mechanism
of Action
Na+

GLUT2

Na+

K+

K+

KIR K+
K

Ca2+

Pancreatic
cell
Insulin granules

Sulfonylureas

Vm

Ca2+
Ca2+

Voltage-gated
Ca2+ channel

First Generation
Sulfonylureas
Name

Tolbutamide*
Chlorpropam
ide
Tolazamide *
Acetohexami
de*
*not available

Daily
dose
range
5003000
100500
1001000
2501500

Max daily Doses/day

dose
(mg/day)
3000
2-3
500
1
1000
1-2
1500
1-2

Second Generation
Sulfonylureas
Name

Daily Max daily Doses/day

dose
dose
range (mg/day)
(mg/da
y)
Glibenclamid 1.2520
1-2
e
2.50
40
1-2
Glipizide
2.5-40
20
1
Glipizide XL
5-20
320
1-2
Gliclazide
40-320
8
1
Glimepiride
4-8

Adverse Effects of
Sulfonylureas

Severe hypoglycemia

Overdose
Early in treatment
Most common with glybenclamide

Weight gain
Erythema, skin reactions
Blood dyscrasias (abnormal cellular
elements)
Hepatic dysfunction and other GI
disturbances

Contraindications for
Sulfonylureas

Pregnancy

Surgery

Severe infections

Severe stress or trauma

Severe hepatic or renal failure

Insulin therapy should be used in

all of these

Repaglinide and
Nateglinide

Mechanism of action:
decrease ATP-sensitive K+
conductance
Additional high affinity binding site
identified in mouse -cells for
repaglinide

Action is glucose dependent

High potency
Elicited insulin release is rapid
and brief

Taken with meals for postprandial

hyperglycemia

Biguanide
s

First

Generation- Phenformin

Phenethylbiguanide
Adverse Effects

Lactic acidosis
Risk of cardiovascular disorder

Second GenerationMetformin

1,1-Dimethylbiguanide

Rarely produces lactic

acidosis except under
predisposing conditions

Biguanides

Mechanism of action:
antihyperglycemic

Correct elevated hepatic glucose

output
Inhibit gluconeogenesis
Inhibit glucose-6-phosphatase activity
glycogen sparing

insulin resistance
Mediated by activation of 5AMPactivated protein kinase (AMPK) in
hepatocytes and muscle
Do not increase insulin secretion

Not hypoglycemic, even at high doses

Thiazolidinediones

Antihyperglycemic

Do not increase

CH3

ROSIGLITAZONE

insulin secretion

O
NH

Increase insulin
sensitivity in liver

and muscle

PIOGLITAZONE

Reduce hepatic glucose output

Improve lipid profiles

O
NH

Thiazolidinediones: Mechanism
of Action
Ligands

for PPAR:

(Peroxisome proliferator-activated

receptor

Nuclear hormone receptor superfamily

Expressed primarily in fat, regulates
differentiation
More limited expression in muscle,
heart, liver,
kidney, gut,
macrophages
Heterodimerizes with RXR, binds to
hormone
response elements,
regulates gene transcription

Known

natural ligands (low affinity)

Insulin resistance

Glucose

Insulin

Insulin
receptor

Translocation

X Synthesis GLUT 4
mRNA

PPAR +RXR

PPRE

promoter
Muscle
Cells

transcription

Coding reg

Modified from Howard L. Foyt et al. Thiazolidinediones. Diabetes Mellitus: a Fundamental and Clinical Text, 2nd Ed.

TZD reduce insulin resistance

Insulin

Insulin
receptor

Glucose
Transloca
ti

on

Synthesis GLUT 4

PPRE

transcription

promoter
Muscle
Cells

mRNA

+ RXR

TZ
D

A
TZV
D

PPAR

Coding reg

Modified from Howard L. Foyt et al. Thiazolidinediones. Diabetes Mellitus: a Fundamental and Clinical Text, 2nd Ed.

 glucosidase inhibitors
(Acarbose)
Mechanism of action: competitive and
reversible inhibitors of a glucosidase in the
small intestine
Delay carbohydrate digestion and
absorption
Smaller

Clinical rise
use in postprandial glucose
For

mild to moderate fasting hyperglycemia with

significant postprandial hyperglycemia
Taken with the first bite of a meal

Adverse

effects:

Gastrointestinal

disturbances; Flatulence,

nausea, diarrhea
Use gradual dose titration

Clinical Uses of Insulin

Type 1 diabetes mellitus

Type 2 diabetes mellitus uncontrolled on
maximal combination therapy with oral
agents
Gestational diabetes
Hyperglycemic
emergencies
Total pancreatectomy patients
Acute or chronic hyperglycemia provoked
by:

Infection or trauma
Steroid therapy
Endocrinopathies such as hyperthyroidism
Other types of secondary diabetes

Summary of bioavailability
characteristic of the insulin
Insulin Type

Onset

Peak Action

Duration

Ultra short
acting

Insulin
lispro/aspart

5-15
minutes

1-1,5 hours

3-4 hours

Short-acting

regular

15-30
minutes

1-3 hours

5-7 hours

Intermediate Lente, NPH

acting

2-4 hours

8-10 hours

18-24 hours

Long acting

Ultralente

4-5 hours

8-14 hours

25-36 hours

Insulin
glargine

6-8 hours

24 hours

Insulin Preparations
Lispro/aspa
rt

Short-acting

regular

Plasma [Insulin]

Ultra
fast/ultra
short-acting

NPH

Intermediateacting

lente
ultralente

Long-acting
Ultra long-

glargine
0

12

16

20

24

Assesment of glycemic
control

Urinalysis

Glycosuria

Urinary ketones

Semi-quantitatif test for acetoacetat; Ketosis-prone

diabetes

Glycated haemoglobin

Limitations of urinalysis : renal threshold (varies between

individual); urinary concentration (fluid intake and urine
concentration may effect); neuropathic bladder (reduce
the accuracy); hypoglycemia (this can not be detect)

HbA1c is formed by the post-translational, nonenzymatic glycation

Glycaemic targets
Frequency of measurement (every 3 or 6 months)
Limitations of HbA1c measurements : daily patern of
blood glucose levels?; blood loss/haemolysis/reduced
red cell (low HbA1c)

Blood glucose

ADA, AACE and IDF glycaemic goals

Biochemical
index
HbA1c (%)

ADA1,2

AACE
3

<7

< 6.5

IDF4
(Western
Pacific
region)

< 6.5

mg/dl mmol/l mg/dlmmol/lmg/dlmmol/l

Fasting/prepra 90130 5.07.2 < 110 < 6.0 < 110 < 6.1
ndial plasma
glucose
Postprandial
< 180 < 10.0 < 140 < 7.8 < 145 <8.0
plasma
glucose

1. ADA. Diabetes Care 2004; 27: S1535; 2. ADA Diabetes Care 2002; 25: S3549;
3. Feld S. Endocrine Pract 2002; 8 (Suppl 1): 4082; 4. Asian-Pacific Type 2 Diabetes Policy Group.
Type 2 diabetes: Practical targetsand treatment. 4th Edn; Hong Kong: Asian-Pacific Type 2 Diabetes Policy Group, 2005.

Current Indonesian Society of

Endocrinology (Perkeni) treatment targets
HbA1c

< 7%

Fasting BG

< 100 mg/dl

Post prandial BG < 140 mg/dl

Blood pressure
< 130/80 mmHg
LDL-cholesterol

< 100 mg/dl (2.6 mmol/l)

HDL-cholesterol
Men
> 40 mg/dl (1.1 mmol/l)
Women > 50 mg/dl (1.3 mmol/l)
Triglycerides
< 150 mg/dl (1.7 mmol/l)
Konsensus PERKENI
2005