EPIDEMIOLOGI DAN

PATOFISIOLOGI DMT2

Luthfan Budi Purnomo

Divisi Endokrinologi Bagian Penyakit Dalam
FK UGM/RSUP Dr Sardjito
DEFINISI DIABETES MELITUS
 Diabetes melitus adalah kelompok penyakit
metabolik yang ditandai dengan hiperglikemia
kronik akibat gangguan sekresi insulin, aksinya
atau keduanya
 Ada istilah defisiensi insulin relatif dan
defisiensi insulin absolut
Diabetes Mellitus (DM) dilatarbelakangi oleh
 … predisposisi genetik

 … faktor lingkungan (pola hidup, lifestyle)

 Obesitas
 Bermalas-ria
 Nutrisi

 Kausa morbiditas dan mortalitas terutama

penyakit jantung kardiovaskular (PJK)

WDFDM2007 3
KELOMPOK RISIKO TINGGI DM TIPE 2

KELOMPOK RISIKO TINGGI DM TIPE 2

 Usia ≥45 th  Hipertensi T ≥140/90

 Kegemukan IMT ≥23 m2/kg, BBR >110%

 Riwayat DM kehamilan, abortus berulang

 Pernah melahirkan bayi dengan BBL ≥4000 g
 Gangguan glukosa puasa/gangguan toleransi glukosa
 Dislipidemia HDL ≤35 mg/dL, Trigliserid ≥250 mg/dL
 Riwayat keluarga DM

DM dapat diderita oleh siapa saja

CARDIOVASCULAR DISEASE IS THE PREDOMINANT CAUSE OF
DEATH AMONG PEOPLE WITH DIABETES

The WHO Multinational Study of Vascular Disease in Diabetes

Men Women

22% 20%
All others All others

54% 49%
8% Cardiovascular 14% Cardiovascular
Renal Renal

3%
Diabetes 14%
3% 14%
Cancer Diabetes Cancer

Adapted from Morrish NJ, et al. Diabetologia. 2001;44(suppl 2):S14–S21.

 ATHEROSCLEROSIS IS COMMON
IN NEWLY DIAGNOSED DIABETES MELLITUS

 Cardiovascular diseases:
common causes of morbidity & mortality in diabetics
 >50% of newly diagnosed type 2 diabetics show evidence
of cardiovascular disease
 Atherosclerosis:
major cause of death among diabetics
75% from coronary atherosclerosis
25% from cerebral / peripheral vascular disease
 >75% of hospitalizations of diabetics
 atherosclerotic disease

Adapted from Amos AF et al Diabet Med 1997;14:S7-S85; Hill Golden S Adv Stud Med 2002;2:364-370; Haffner SM et al
N Engl J Med 1998;339:229-234; Sprafka JM et al Diabetes Care 1991;14:537-543.
 Coronary Heart Disease (CHD) Risk in
Patients with Type 2 Diabetes
50
No diabetes (n=1373) 45
Type 2 diabetes (n=1059)
40

30
7-year
MI event Diabetes is regarded as a
rate† 20 CHD 19
20 risk equivalent

10
4

0
No prior MI Prior MI

CHD=coronary heart disease; MI=myocardial infarction

†Events/100 person-years
Haffner SM et al. N Engl J Med 1998; 339: 229–234
 ASPEK EPIDEMIOLOGIS
 Prevalensi DM bervariasi
 Prevalensi tertinggi: Pima Indians (USA) ~50%
 Samoa: traditional lifestyle 2-3%; western-lifestyle 34%
 Singapore: 18%; black Americans 10%; Indians 8%;
white Americans 6%; urban Chinese population 2%
 Indonesia:

WDFDM2007 8
PREVALENSI DM
Tahun 1994 2000 2010
Dunia 98.9 157.3 215.6
Asia 46.9 86.6 126.3

WDFDM2007
Indonesia ? 5.6 ~8.2
Urban ~6 – ~20% Rural .8 – 2.3%

Cost of DM
CHD Blindness Gangrene ESRD
2-4x 10x 20x 17x
9
TYPE 2 DIABETES PREVALENCE IS PROJECTED TO REACH
300 MILLION BY 2025
 About 155 million adults worldwide diagnosed with diabetes in 2000
 83 million women and 72 million men
 Between 1995 and 2025,
the prevalence of diabetes in adults will increase by 35% and the
number of people with diabetes will increase by 122%

EUROPE ASIA
JAPAN
USA 2000: 30.8M 2000: 71.8M
2000: 6.9M
2000: 15M 2025: 38.5M 2025: 165.7M
AFRICA 2025: 8.5M
2025: 21.9M
AMERICAS 2000: 9.2M OCEANIA
(Ex-US)
2025: 21.5M 2000: 0.8M
2000: 20M
2025: 1.5M
2025: 42M

Adapted from King H et al Diabetes Care 1998;21:1414-1431.

KEJADIAN DIABETES DI DUNIA
2000 2030
Ranking Negara Jumlah diabetes Negara Jumlah diabetes
(juta)) (juta)

1 India 31.7 India 79.4

2 China 20.8 China 42.3
3 US 17.7 US 30.3
4 Indonesia 8.4 Indonesia 21.3
5 Japan 6.8 Pakistan 13.9
6 Pakistan 5.2 Brazil 11.3
7 Russia 4.6 Bangladesh 11.1
8 Brazil 4.6 Japan 8.9
9 Italy 4.3 Philippines 7.8
10 Bangladesh 3.2 Egypt 6.7

Wild S et al. Diabetes Care 2004;27:1047-53

PREVALENSI DI INDONESIA

 Urban 14,7%

 Rural 7,2%

(Perkeni, 2006)
KADAR GLUKOSA DARAH
DIATUR DAN DIKENDALIKAN
DALAM RENTANG YANG SEMPIT

Puasa: 80 - <100 mg/dl

2jPP/sesaat: 80 - <140 mg/dl

 HORMON PENGENDALI HOMEOSTASIS BAHAN BAKAR

 Insulin

 Counter-insulin hormone
-glucagon
-cathecolamine
-growth hormone
-glucocorticoids
INSULIN GLUCAGON
CATECHOLAMINE
GLUCOCORTICOID
GROWTH HORMONE

BLOOD GLUCOSE
FASE HOMEOSTASIS BAHAN BAKAR

 Fase I: 0-4 jam setelah makan

-Sumber glukosa darah : diit
-Jaringan pengguna : semua
-Sumber utama untuk otak: glukosa
 Fase II: 4-16 jam setelah makan
-Sumber glukosa darah : glikogen, glukoneogenesis hepar
-Jaringan pengguna : semua kecuali hepar, otot dan
jaringan lemak (mulai kurang)
-Sumber utama untuk otak: glukosa
 Fase III: 16-30 jam setelah makan
-Sumber glukosa darah : glukoneognesis hepar, glikogen
-jaringan pengguna : otak, eritrosit, medula ginjal; otot
menggunakan sedikit
-Sumber utama untuk otak: glukosa
FASE HOMEOSTASIS CONT.

 Fase IV: 30-48 jam setelah makan

Sumber glukosa darah: glukoneogenesis hepar & ginjal
Jaringan pengguna : sama fase III
Sumberutama otak : glukosa, benda keton
 Fase V: ≥48jam setelah makan
Sumber glukosa darah: glukoneogenesis hepar dan ginjal
Jaringan pengguna : otak mulai kurang, eritrosit, medula
ginjal
Sumber utama otak : benda keton, glukosa
BLOOD GLUCOSE
Fasting hyperglycemia

Post prandial hyperglycemia

A round the clock hyperglycemia
Breakfast Dinner
Lunch Fasting

Bed time
Day time
Fasting blood glucose

Blood glucose at bed time

+
Gluconeogenesis
POST PRANDIAL BLOOD GLUCOSE

Dietary glucose + Glucose of hepatic production

(gluconeogenesis)
_ _
Glucose uptake
 NORMAL PHASE OF INSULIN SECRETION
 Two phases of insulin secretion:
1. 3-5 minutes after bolus of glucose: immediately insulin secreted by
pancreatic beta cells by which the levels of plasma insulin increased
ten fold.
2. After 15 minutes when the levels of plasma insulin decreased by
half, and reached plateau after 2-3 hours.
GLUCOSE, INSULIN, AND GLUCAGON LEVELS AFTER
MEAL
 Progressive decline of -cell function over time –
unaffected by traditional agents in UKPDS

100
Randomization to intensive
treatment
75
Β-cell
Function
(%) 50

IGT Postprandial T 2 D
Hyperglicemia Phase I
25 T2D
Phase 2
T2D
Phase 3
0
-12 -10 -6 -2 0 2 6 10 14
Years from Diagnosis

Lebovitz H. Diabetes Review 1999;7:139-53

UK Prospective Diabetes Study Group. Diabetes 1995; 44:1249–1258.
UNDERLYING FACTORS IN TYPE 2 DM :
IR AND -CELL DYSFUNCTION

Genetic susceptibility
obesity, sedentary lifestyle

Insulin Resistance -cell dysfunction

 insulin
secretion
 glucose  hepatic gluc
uptake production

Type 2 diabetes
Adapted from DeFronzo RA. Diabetes 1988; 37: 667–87.
 PANCREATIC ISLET CELLS DYSFUNCTION LEADS TO
HYPERGLYCEMIA IN T2DM

Fewer -Cells
-Cells hypertrophy

Insufficient Excessive
insulin glucagon
+ –
+

↑ Glucose
↓ Glucose ↑ HGO
uptake

HGO=hepatic glucose output

Adapted from Ohneda A, et al. J Clin Endocrinol Metab. 1978; 46: 504–510; Gomis R, et al. Diabetes Res Clin Pract. 1989; 6:
191–198.
STAGES OF BETA CELLS DYSFUNCTION PROGRESSION

Stage 1: stage of compensation, increased insulin

secretion to maintain normoglycemia against
insulin resistance and decreased beta cells mass
Stage 2: stage of adaptation to the loss of beta cells mass
and the loss of glucose stimulated insulin
secretion (GSIS)
Stage 3: stage of de-compensation
Stage 4: stage of de-compensation
Stage 5: stage of ketosis progression

(Mauvais-Jarvis et al., 2004)

 PERKEMBANGAN DIABETES TIPE 2
Resistensi Insulin Fungsi Sel-Beta

Resistensi Insulin &

Hiperinsulinemia dg
Toleransi Glucosa Normal

Resistensi Insulin &

Kadar Insulin Menurun dg Toleransi
Glucosa Terganggu (IGT)

Diabetes Tipe 2
Adapted from Diabetes 1996;45:1661
NATURAL HISTORY OF TYPE 2 DIABETES

Obesity IFG* Diabetes Uncontrolled Hyperglycemia

350
300 Post-meal Glucose
250
(mg/dL)
Glucose

200
150 Fasting Glucose
100
50

250
Insulin Resistance
Function (%)

200
Relative

150
Insulin Level
100 -cell Failure
50
-10 -5 0 5 10 15 20 25 30
*IFG = impaired fasting Years of Diabetes
glucose
Adapted from International Diabetes Center (IDC), Minneapolis, Minnesota.
NATURAL HISTORY OF TYPE 2 DIABETES

Insulin sensitivity Insulin secretion

Type 2 diabetes
30% 50%

50% IGT 70-100%

70% Impaired glucose 150%

metabolism
100% Normal glucose metabolism 100%

Diabetes Obes Metab 1999; 1(1): S1

 INSULIN RESISTANCE AND -CELL DYSFUNCTION ARE LINKED AND ARE
UNDERLYING FACTORS IN TYPE 2 DIABETES

Increased
Elevated
lipolysis and
release of free circulating FFA
fatty acids

High insulin demand

Insulin -Cell
resistance dysfunction

Decreased glucose
uptake into muscle
and adipose tissue and Hyperglycemia
raised hepatic glucose
output

Type 2 diabetes
 ELEVATED CIRCULATING FFA IS A CENTRAL FACTOR IN THE DEVELOPMENT
OF TYPE 2 DIABETES

Insulin resistance

High insulin demand and

Decreased glucose uptake insulin resistance in
pancreas Increased
into muscle and adipose
lipolysis
tissue and raised hepatic
glucose output

Hyperglycemia Elevated circulating FFA

-cell dysfunction Arner P. Diabetes Obes Met

2001;3 (Suppl.1); S11–S19.
 GLUT 4 (Glucose transporters 4) and insulin action

Synthesis

Adapted from Shepherd PR et al. Glucose transporters and insulin action. NEJM, July 22, 1999
 Septicidal Septet DeFronzo ADF 2006

Decreased
Incretin effect



Impaired Insulin Increased
secretion lipolysis

Islet -cell ??
Hyperglycemia


Increase Neurotransmitter
Glucagon Increased Decreased Glucose dysfunction
secretion HGP uptake

 Septem = seven
 Kelompok risiko tinggi DM

Usia ≥45 tahun

Kegemukan (BB >120% BB idaman/IMT ≥23 kg/m2)
Kebiasaan tidak aktif (sedentary)
Hipertensi (T ≥140/90 mmHg)
Turunan pertama dari orang tua dengan DM
Riwayat melahirkan bayi dg BBL >4000 gram
Riwayat DM pada kehamilan
Riwayat TGT atau GDPT
Penderita PJK, TBC, hipertiroidisme
Dislipidemia (HDL ≤35 mg/dl; TG ≥250 mg/dl)
Keluhan DM

Poliuri
Polidipsi Khas DM
Polifagi
BB turun

Kesemutan
Gatal di daerah genital
Keputihan
Infeksi sulit sembuh
Bisul hilang timbul
Penglihatan kabur
Cepat lelah
Mudah mengantuk
 Diagnosis DM

Keluhan khas DM + 1 kali kriteria lab. terpenuhi

Tanpa keluhan khas DM dibutuhkan 2 kali kriteria lab
terpenuhi atau
Tes beban glukosa
Kriteria laboratorium

Puasa (mg/dl) 2jPP (mg/dl)

Normal <100 <140

Terganggu 100-125 140-199

DM ≥126 ≥200
TEST TOLERANSI GLUKOSA ORAL
 3 hari makan dan aktivitas seperti biasa
 Berpuasa paling sedikit 8 jam
 Diperiksa kadar glukosa darah puasa
 Diberikan 75 g glukosa anhidrous dalam 250 ml
air dan diminum dalam waktu 5 menit
 Berpuasa kembali sampai pengambilan darah
untuk pemeriksaan 2 jam setelah pembebanan
 Diperiksa kadar glukosa darah 2 jam sesudah
pembenanan
 Selama proses pemeriksaan,subyek tetap
istirahat dan tidak boleh merokok
 DIAGNOSIS

Saat sekarang kadar A1c dijadikan kriteria

diagnosis diabetes melitus
Syarat pemeriksaan A1c dilakukan dengan
metode yang disertifikasi oleh the National
Glycohemoglobin Standardization Program
(NGSP) atau sesuai metode yang digunakan DCCT

A1c ≥6,5% diabetes

A1c 5,7-6,4 prediabetes
KLASIFIKASI DM (ETIOLOGI)
Tipe 1: destruksi sel B, biasanya menyebabkan
defisiensi insulin absolut
Tipe 2: defek sekresi insulin progresif disertai
resistensi insulin
Tipe lain:
penyebab lain seperti defek genetik pada
fungsi sel B, pada aksi insulin; penyakit
pankreas eksokrin (fibrosis kistik); obat
atau bahan kimiawi
Diabetes gestasional:
diagnosis selama kehamilan
KASUS
 Seorang laki-laki 45 th, ayah kandung diketahui
meninggal karena diabetes. Pada saat
pemeriksaan kesehatan diketahui GDN 120
mg/dl; GD2JPP 190 mg/dl dan HbA1c 6,7%.
 Seorang wanita 50 th, pada pemeriksaan
kesehatan diketahui GDN 115 mg/dl; GD2JPP
210 mg/dl tanpa gejala khas DM.