Resistensi Insulin :

Apa & Mengapa Perlu Ditangani pada DM tipe 2

Sepuluh Negara dengan Perkiraan Jumlah Pasien DM Dewasa Terbanyak, 1995 and 2025
Negara Urutan
1 India 2 China 3 U.S. 4 Russian Fed. 5 Japan 6 Brazil 7 Indonesia 8 Pakistan 9 Mexico 10 Ukraine Negara Lainnya Total 19.4 16.0 13.9 8.9 6.3 4.9 4.5 4.3 3.8 3.6 49.7 135.3 India China U.S. Pakistan Indonesia Russian Fed. Mexico Brazil Egypt Japan 57.2 37.6 21.9 14.5 12.4 12.2 11.7 11.6 8.8 8.5 103.6 300.0

1995 (juta)

Negara

2025 (juta)

Type 2 Diabetes Is NOT a Mild Disease

Microvascular complication
Diabetic Retinopathy
Leading cause of blindness in working age adults1

Macrovascular complication
Stroke
2 to 4 fold increase in cardiovascular mortality and stroke3

Cardiovascular Disease
8/10 diabetic patients die from CV events4

Diabetic Nephropathy
Leading cause of end-stage renal disease2

Diabetic Neuropathy
Leading cause of non-traumatic lower extremity amputations5

1 Fong

DS, et al. Diabetes Care 2003; 26 (Suppl. 1):S99S102. 2Molitch ME, et al. Diabetes Care 2003; 26 (Suppl. 1):S94S98. 3 Kannel WB, et al. Am Heart J 1990; 120:672676. 4Gray RP & Yudkin JS. In Textbook of Diabetes 1997. 5Mayfield JA, et al. Diabetes Care 2003; 26 (Suppl. 1):S78S79.

When Macrovascular & Microvascular Complication in T2DM?

Obesity IGT Diabetes (Uncontrolled) Prediabetes Type 2 diabetes
Macrovascular complications Microvascular complications

Plasma glucose (mg/dl)

Postprandial
126 Fasting

Insulin resistance

Relative function

Insulin level 100

Diabetes duration (years)

20

10

10

20

30

Adapted from Bergenstal RM, et al. Diabetes mellitus, carbohydrate metabolism and lipid disorders. In Endocrinology. 4th ed. 2001.

Underlying factors in type 2 DM :

IR and -cell dysfunction

Genetic susceptibility obesity, sedentary lifestyle

Insulin Resistance

-cell dysfunction
insulin secretion

glucose
uptake

hepatic gluc production

Type 2 diabetes
Adapted from DeFronzo RA. Diabetes 1988; 37: 66787.

GLUCOSE ABSORPTION
INTESTINE

GLUCOSE PRODUCTION
LIVER

GLUCOSE UPTAKE

Glucose

MUSCLE ADIPOSE TISSUE

INSULIN SECRETION

PANCREAS
Modified: Ann Intern Med 1999;131:281

Patofisiologi DM tipe 2
1. Defek sekresi insulin

2. Resistensi insulin

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 Glucose (mg/dL) 250 200 150 100 50 250 200 150 100 50 -cell Failure Insulin Level Fasting Glucose Post-meal Glucose

Relative Function (%)

Insulin Resistance

-10
*IFG = impaired fasting glucose

-5

10

15

20

25

30

Years of Diabetes

Adapted from International Diabetes Center (IDC), Minneapolis, Minnesota.

The UKPDS demonstrated that loss of glycemic control correlates with progressive loss of -cell function
-Cell function (%, HOMA analysis) 60

40

20 0 -1 0 1 2 3 4 Time from randomization (years) 5 6

UK Prospective Diabetes Study Group. Diabetes 1995; 44:12491258.

Patofisiologi DM tipe 2
1. Defek sekresi insulin

2. Resistensi insulin

Definisi RESISTENSI INSULIN Gangguan respon terhadap efek fisiologis insulin, meliputi gangguan metabolisme: glukosa lipid protein fungsi endotel.

(Diabetes Care 2000; 23(Suppl 1):54

Natural History of Type 2 Diabetes

Insulin sensitivity
30% 50% 70% 100% Type 2 diabetes IGT Impaired glucose metabolism Normal glucose metabolism

Insulin secretion
50% 70-100% 150% 100%

Diabetes Obes Metab 1999; 1(1): S1

Insulin Resistance: Associated Conditions

Type 2 diabetes

Atherosclerosis
Dyslipidemia Decreased fibrinolytic activity Insulin Resistance

Impaired glucose tolerance Hypertension

Obesity (central)

Acanthosis nigricans

Polycystic ovary disease Hyperuricemia

KLINIS

Insulin resistance and -cell dysfunction are linked and are underlying factors in type 2 diabetes
Increased lipolysis and release of free fatty acids
High insulin demand

Elevated circulating FFA

Insulin resistance
Decreased glucose uptake into muscle and adipose tissue and raised hepatic glucose output

-Cell dysfunction

Hyperglycemia

Type 2 diabetes

Elevated circulating FFA is a central factor in the development of type 2 diabetes

Insulin resistance

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

High insulin demand and insulin resistance in pancreas

Increased lipolysis

Hyperglycemia

Elevated circulating FFA

-cell dysfunction

Arner P. Diabetes Obes Met 2001;3 (Suppl.1); S11S19.

Management DM tipe 2
1. Non-Farmakologis: Pola makan & OR 2. Farmakologis : Obat (OAD)

Major Metabolic Defects in Type 2 Diabetes

Peripheral insulin resistance in muscle and fat Impaired pancreatic insulin secretion

Increased hepatic glucose output

Diabetes Care, 1999; 22:562
ref version 2.1

Sites of Action of Current OAD

GLUCOSE ABSORPTION
INTESTINE -glucosidase inhibitors

GLUCOSE PRODUCTION
LIVER

PERIPHERAL GLUCOSE UPTAKE & UTILIZATION

Glucose
Biguanides
Thiazolidinediones ADIPOSE TISSUE MUSCLE

Biguanides

Thiazolidinediones
INSULIN SECRETION
Sulphonylureas Meglitinides PANCREAS
Modified: Ann Intern Med 1999;131:281

Terima Kasih
Atas Perhatiannya

Batasan kadar glukosa darah

(Konsensus PERKENI 2006)

(mg/dL, darah Vena)

Bukan DM Belum Pasti DM Tes GD Sewaktu 100 - 199 < 100 GD puasa 100 125* < 100
TTGO

DM > 200 > 126

* Glukosa darah puasa terganggu

TG normal
< 140

TGT / IGT 140 - 199

DM
> 200

TTGO = Tes Toleransi Glukosa Oral (Puasa 8 jam, minum 75g glukosa 2 jam di test TGT / IGT = Toleransi Glukosa Terganggu / Impaired Glucose Tolerance