Diabetes Mellitus

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 vessels.

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

urinary bladder
slow healing
blurred vision
pruritus vulvae
erectile dysfunction

Diagnosis Criteria

Symptoms plus one of the following

Random glucose >200mg/dL
Fasting Blood glucose >126mg/dL
2 hour glucose tolerance test
>200mg/dL
Need to confirm results on a
subsequent day

Diabetes Mellitus

HYPERGLYCEMIA: fluid/electrolyte
imbalance.

Polyuria

Sodium, chloride, potassium excreted

Polydipsia from dehydration

Polyphagia: cells are starving, so
person feels hungry despite eating huge
amounts of food. Starvation state
remains until insulin is available.

2010 Diagnosis of Diabetes and

Categories of Increased Risk for
Diabetes
NORMAL

IFG or IGT
(Predabetes)

DIABETES

FPG < 100 mg/dl

IFG
FPG > 100 - 125
mg/dl

FPG > 126 mg/dl

2-h PG < 140

mg/dl

A1C

IGT
2-h PG > 140 199 mg/dl
5.7% to 6.4%

ADA, Diabetes Care 33: Suppl. 1, S11-S61, 2010

2-h PG > 200 mg

Random PG > 200
+ symptoms
6.5%

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
on previous testing, had IGT or IFG
have other clinical conditions associated with insulin resistance
have a history of vascular disease

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 (GDM)

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),
autoantibodies to the tyrosine phosphatases IA-2 and IA-2.

Idiopathic diabetes.

no known etiologies

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 (IPF1; 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

Acromegaly; Cushings syndrome; Glucagonoma; Pheochromocytoma;

Hyperthyroidism; Somatostatinoma; Aldosteronoma.

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; Friedreichs ataxia;
Huntingtons chorea; Laurence-Moon-Biedl syndrome;
Myotonic dystrophy; Porphyria; Prader-Willi 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 814 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

Differential Diagnosis
Type 1 and Type 2 Diabetes

Type 1 Diabetes

Type 2 Diabetes

Usual clinical course

Insulin-dependent

Initially non-insulindependent

Usual age of onset

<20 years (but ~50%

over 20 years)

>40 years but

increasingly earlier

Body weight

Usually lean

Usually obese

Clinical onset

Often acute

Subtle, slow

Ketosis-prone

Yes

No

Family history

15% with 1 relative

Common

Ethnicity
minorities

Predominantly white

More common in

Frequency of HLA-DR3,
DR4, DQB1*0201, *0302

Increased

Not increased

Islet autoantibodies
(GADA, ICA, IA-2A, IAA)

Present

Absent

Etiology of Type 2 Diabetes

Impaired Insulin Secretion and Insulin Resistance

Genes and environment
Impaired insulin
secretion

Insulin resistance

Impaired glucose
tolerance

Type 2 diabetes

Pathophysiology of Type 2 DM
Insulin resistance
insulin receptor number
insulin receptor kinase activity
Post-receptor defects
GLUT4 translocation from impaired signaling
Impaired islet function
Loss of first phase insulin secretion
secretion of proinsulin
Defective pulsatile insulin secretion
Deposition of islet amyloid polypeptide

Pathogenesis of Type 2 Diabetes

Two Defects

Hepatic
insulin
resistance
Excessive
glucose production

More glucose enters

the blood stream

Impaired
insulin
secretion

Hyperglycemia

Glycosuri

Muscle/fat
insulin
resistance
Impaired glucose
clearance

Less glucose enters

peripheral tissues
16

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.

Insulin resistance and -cell

dysfunction are fundamental to
IGT
Type 2
typeNormal
2
diabetes
diabetes
Insulin
resistan
ce

Increased insulin
resistance

Insulin
secreti
on
Postprandial
glucose

Hyperinsulinaem
then -cell failur

Fasting
glucose

Hyperglycaemia

Abnormal
glucose toleranc

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
Aging
Obesity and
inactivity

Genetic
abnormalities

Type 2
diabetes

Medications

INSULIN
RESISTANCE

Rare
disorders

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

Reduced

ability of -cells to
compensate for insulin
resistance

Impaired

Genetic

and environmental
pathophysiology

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

(genetic background)

Amyloid
deposition

lipotoxicity
elevated FFA,TG

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
Adjust meals & medications accordingly
3-4 times per week usually recommended
(30 minute)

Nutritional
Recomendation

Energy needs

Basal energy requirements (BER) : 25-30 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 20-30% of BER

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 transunsaturated 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
Cholesterol intake <300 mg/d

Physical exercise and insulin

resistance
Exercise

muscle glucose uptake

acute &
whole body glucose disposal longterm
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.

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
Glucos
e uptake

Oral Drug Therapy for

Type 2 DM

Sulfonylureas

Repaglinide
Nateglinide

Biguanides

Thiazolidinediones

Acarbose

Insulin
secretagogues

}
}

Insulin
sensitizers

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 insulin-stimulated
perpheral glucose utilization in both adipose tissue
and skeletal muscle.

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 1.25e
2.50
Glipizide
2.5-40
Glipizide XL
5-20
Gliclazide
40-320
Glimepiride
4-8

20
40
20
320
8

1-2
1-2
1
1-2
1

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 Generation- Metformin

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 5AMP-activated
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)

Prostanoid 15-deoxy 12,14PG J2
Polyunsaturated fatty acids, such as linoleic acid

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

Clinicalrise
use in postprandial glucose
Smaller
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
5-15
lispro/aspart 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
Ultra
fast/ultra
short-acting

regular

Plasma [Insulin]

Short-acting

Lispro/aspart

NPH

Intermediateacting

lente
ultralente

Long-acting
Ultra long-

glargine

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, non-enzymatic

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

Before breakfast (fasting)

2 hour post prandial

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
Women

> 40 mg/dl (1.1 mmol/l)

> 50 mg/dl (1.3 mmol/l)

Triglycerides

< 150 mg/dl (1.7 mmol/l)

Konsensus PERKENI
2005