DIABETES MELLITUS

ALI SANTOSA.
 Definisi

 Suatu kelompok penyakit metabolik

 Hiperglikemia
 Karena kelainan sekresi insulin, kerja
insulin atau keduanya
 s@di
3
 Masalah Diabetes di Indonesia

Kecenderungan meningkat terutama didaerah perkotaan

Jakarta : 1.6% (1983) 5.69%( 1993) 14.7% (2005)

Makassar : 1.5% (1984) 3.5% (1998) 12.5% (2005)
Padang : 1.5 % (1984) 5.12% (2005)

Di pedesaan masih rendah

Tasikmalaya : West Java 1.1%

Toraja : Sulawesi 0.8%
Jawa Timur : East Java Urban = rural 1.45%
 Prevalences of IGT and DM in Indonesia
(Basic Health Research – 2007)
Recruited 24.417 person – across 438 districts

12,0

10,0 10,2
(percentage)

8,0

6,0 5,7

4,0 4,2

2,0
1,5

0,0
IGT New-onset DM DM Total DM

5 5 s.@di
(Indonesia Ministry of Health Affair– 2007)
T2DM Is Characterised by Decreased Insulin
Secretion and Increased Insulin Resistance

Genetic and Environmental Factors

Lack of exercise/high-fat diet

 Insulin  Insulin
secretion resistance
 Liver glucose
production

Glucose toxicity Glucose toxicity

 Blood glucose
 FISIOLOGI INSULIN

Menekan produksi gula hati

Meningkatkan sintesa Glikogen
Menekan Glikogenolisis
Meningkatkan glukosa uptake
Menekan lipolisis
Insulin signal transduction pathway in
skeletal muscle
 RESISTENSI INSULIN

 PRE-RESEPTOR
- insulin abnormal
 RESPTOR
- jumlah reseptor menurun
- afinitas reseptor menurun
 POST-RESEPTOR
- GLUT-4 menurun
- transduksi signal terganggu
- fosforilasi abnormal
 Faktor penyebab RI

 Hormon strees :
- katekolamin
- kortisol
- glukagon
- hormon pertumbuhan

 Sitokin :
- interleukin-6
- TNF-alfa

 Asam lemak bebas

 The progressive nature of
type 2 diabetes
Normal Impaired Type 2 Late type 2
glucose diabetes diabetes
tolerance complications
Insulin
sensitive
Hyperglycaemia

Normal insulin
secretion Insulin
resistance
Normoglycaemia
β-cell
exhaustion

Insulin resistance

Fasting plasma glucose

Insulin sensitivity
Insulin secretion Adapted from Bailey CJ et al. Int J Clin Pract 2004;58:867–876.
Groop LC. Diabetes Obes Metab 1999;1 (Suppl. 1):S1–S7.
 The progressive nature of
type 2 diabetes
Normal Impaired Type 2 Late type 2
glucose diabetes diabetes
tolerance complications
Insulin
sensitive
Hyperglycaemia

Normal insulin
secretion Insulin
resistance
Normoglycaemia
β-cell
exhaustion

Insulin resistance

Fasting plasma glucose

Insulin sensitivity
Insulin secretion Adapted from Bailey CJ et al. Int J Clin Pract 2004;58:867–876.
Groop LC. Diabetes Obes Metab 1999;1 (Suppl. 1):S1–S7.
 Insulin and Glucagon Response to a Large
Carbohydrate Meal in Type 2 Diabetes
Type 2 diabetes mellitus (n=12)*
360 Nondiabetic controls (n=11)
(mg/100 ml)

330
Meal
Glucose

300
270
240
110
80
150 Depressed/delayed insulin response
120
(µU/ml)
Insulin

90
60
30
0
140
130
Glucagon
(µµg/ml)

120 Nonsuppressed glucagon

110
100
90
–60 0 60 120 180 240

Time (minutes)
*Insulin measured in five patients
Adapted from Müller WA et al N Engl J Med 1970;283:109–115.
15
 Model of underlying factors in type 2 diabetes:
insulin resistance and -cell dysfunction
Diabetes genes
Adipokines
-CELL Inflammation
DYSFUNCTION Hyperglycaemia
Free fatty acids
Other factors

 Insulin
secretion INSULIN
RESISTANC
E
 Lipolysis  Glucose  Glucose
production uptake

 Free fatty  Blood

acids glucose
Adapted from Stumvoll M et al. Lancet 2005;365:1333–1346.
 Asal gula darah meningkat

 Asupan makanan
 Produksi gula hati (glikogenolisis dan glukoneogenesis)
 penurunan up take glukosa oleh adiposit dan otot
 Insulin

Pengendalian Reseptor
incretin
glukosa insulin

Post reseptor
PPAR gama
 Pathogenesis of Type 2 Diabetes

Inherited/acquired factors Overweight, inactivity

(acquired/inherited)

Insulin deficiency Insulin resistance

 FFA

 Glucose  Production of glucose

and TG in the liver In blood vessels Platelets, fibrinolysis
uptake

Diabetic
dyslipidaemia  PAI-1

Endothelial dysfunction
Hyperglycaemia

Type 2 diabetes

FFA=free fatty acid; TG=triglycerides; PAI-1=plasminogen-activator inhibitor-1.

Adapted from Yki-Järvinen H. In: Textbook of Diabetes 1. 3rd ed. Oxford, UK: Blackwell; 2003:22.1-22.19.
 Excessive Hepatic Glucose Production
Causes Fasting Hyperglycaemia
Fasting plasma glucose (mmol/L)
5 10 15

4.0 Control
production (mg/kg • min)

T2DM
Hepatic glucose

3.5

3.0

2.5
r = 0.847
P<0.001
2.0

0
1.5
0 100 200 300
Fasting plasma glucose (mg/dL)
Adapted from DeFronzo RA. Diabetes. 1988;37:667-687.
 Impaired Insulin Effect at the Liver Causes
Fasting Hyperglycaemia

Production 2 mg/kg/min
Normal

Plasma glucose 5 mmol/L

(90 mg/dL)
Normal
insulin Other
action tissues

Type 2 diabetes
Production
2.5 mg/kg/min

Plasma glucose 10 mmol/L

(180 mg/dL)
Impaired
Increased insulin Other
liver fat action tissues

Insulin deficiency exacerbates hyperglycaemia.

DeFronzo RA. Diabetes. 1988;37:667-687.
 Failure to Suppress Hepatic Glucose Production
Causes Post-prandial Hyperglycaemia
Defect in suppression of hepatic glucose production
by insulin → increased need for insulin during a meal

Rate of glucose appearance Rate of glucose disappearance

98 98
100 100
75 75 18 Urine
Glucose
from oral 80
g/5 h

glucose*
50 50
Other
20 tissues
Hepatic
glucose
production
0 0
Normal Diabetes Normal Diabetes
P<0.01 P<0.01
*Not significant.
Data from Mitrakou A et al. Diabetes. 1990;39:1381-1390.
 Pathogenesis of Type 2 Diabetes

Inherited/acquired factors Overweight, inactivity

(acquired/inherited)

Insulin deficiency Insulin resistance

 FFA

 Glucose
 Production of glucose
and TG in the liver In blood vessels Platelets, fibrinolysis
uptake

Dyslipidaemia  PAI-1

Endothelial dysfunction
Hyperglycaemia

Type 2 diabetes

FFA=free fatty acid; TG=triglycerides; PAI-1=plasminogen-activator inhibitor-1.

Adapted from Yki-Järvinen H. In: Textbook of Diabetes 1. 3rd ed. Oxford, UK: Blackwell; 2003:22.1-22.19.
 Basal Insulin Therapy Decreases Overnight
Free Fatty Acid Concentrations
Bedtime Insulin (23 ± 3 IU) Plus Oral Therapy

800 Overnight free fatty acid levels

Plasma free fatty acids (mol/L)

600
*

400

Before treatment
After treatment
200

N = 15; T2DM

22 24 2 4 6 8
Time of day (h)
*P<0.05, except for first 3 measurements.
Adapted from Taskinen MR et al. Diabetes. 1989;38:580-588.
 Pathogenesis of Type 2 Diabetes

Inherited/acquired factors Overweight, inactivity

(acquired/inherited)

Insulin deficiency Insulin resistance

 FFA

 Glucose
 Production of glucose
and TG in the liver In blood vessels Platelets, fibrinolysis
uptake

Dyslipidaemia  PAI-1

Endothelial dysfunction
Hyperglycaemia

Type 2 diabetes

FFA=free fatty acid; TG=triglycerides; PAI-1=plasminogen-activator inhibitor-1.

Adapted from Yki-Järvinen H. In: Textbook of Diabetes 1. 3rd ed. Oxford, UK: Blackwell; 2003:22.1-22.19.
 Pathogenesis of Type 2 Diabetes

Inherited/acquired factors Overweight, inactivity

(acquired/inherited)

Insulin deficiency Insulin resistance

 FFA

 Glucose
 Production of glucose
and TG in the liver In blood vessels Platelets, fibrinolysis
uptake

Dyslipidaemia  PAI-1

Endothelial dysfunction
Hyperglycaemia

Type 2 diabetes

FFA=free fatty acid; TG=triglycerides; PAI-1=plasminogen-activator inhibitor-1.

Adapted from Yki-Järvinen H. In: Textbook of Diabetes 1. 3rd ed. Oxford, UK: Blackwell; 2003:22.1-22.19.
 Hepatic Insulin Resistance Leads to
Hypertriglyceridaemia

Normal TG
Normal
Normal
insulin
action

Type 2 diabetes High TG

Impaired
Low HDL cholesterol
insulin Small dense LDL
Increased action (diabetic dyslipidaemia)
liver fat to inhibit
VLDL
production
Insulin deficiency exacerbates hypertriglyceridaemia
TG=triglycerides; HDL=high-density lipoprotein; LDL=low-density lipoprotein; VLDL=very low-density lipoprotein.
 Pathogenesis of Type 2 Diabetes

Inherited/acquired factors Overweight, inactivity

(acquired/inherited)

Insulin deficiency Insulin resistance

 FFA

 Glucose
 Production of glucose
and TG in the liver In blood vessels Platelets, fibrinolysis
uptake

Dyslipidaemia  PAI-1

Endothelial dysfunction
Hyperglycaemia

Type 2 diabetes

FFA=free fatty acid; TG=triglycerides; PAI-1=plasminogen-activator inhibitor-1.

Adapted from Yki-Järvinen H. In: Textbook of Diabetes 1. 3rd ed. Oxford, UK: Blackwell; 2003:22.1-22.19.
 Decline of -Cell Function in the UKPDS
Illustrates Progressive Nature of Diabetes

100 Time of diagnosis

-Cell function (% of normal by HOMA)

?
80

60

Pancreatic function
40 = 50% of normal

20

0
–10 –9 –8 –7 –6 –5 –4 –3 –2 –1 0 1 2 3 4 5 6
Time (y)

UKPDS=United Kingdom Prospective Diabetes Study; HOMA=homeostasis model assessment.

Adapted from Holman RR. Diabetes Res Clin Pract. 1998;40(suppl):S21-S25.
U.K. Prospective Diabetes Study Group. Diabetes. 1995;44:1249-1258.
 Better Insulin Secretion
After Improved Metabolic Control
Response to Oral Glucose Before and After 3 Therapies

Diet Sulfonylureas Insulin Before

(n = 17) (n = 26) (n = 7) After
Plasma insulin (U/mL)

50

* *
* * * *
* *
* *
* *
25 * *

* *

0
0 1 2 3 0 1 2 3 0 1 2 3
Time (h)
*P<0.05.
Adapted from Kosaka K et al. Diabetologia. 1980;18:23-28.
 Pathogenesis of Type 2 Diabetes

Inherited/acquired factors Overweight, inactivity

(acquired/inherited)

Insulin deficiency Insulin resistance

 FFA

 Glucose
 Production of glucose
and TG in the liver In blood vessels Platelets, fibrinolysis
uptake

Dyslipidaemia  PAI-1

Endothelial dysfunction
Hyperglycaemia

Type 2 diabetes

FFA=free fatty acid; TG=triglycerides; PAI-1=plasminogen-activator inhibitor-1.

Adapted from Yki-Järvinen H. In: Textbook of Diabetes 1. 3rd ed. Oxford, UK: Blackwell; 2003:22.1-22.19.
 Endothelial Function

ACh  Endothelium releases NO,

Endothelial cell which promotes vasodilation
M
Ca2+  NO production reflects
eNOS
endothelial function
NO
NADPH  Endothelial dysfunction
characterises type 2
diabetes patients
guanylate  Endothelial dysfunction
cyclase
GTP cGMP predicts cardiovascular
events1,2
Vascular smooth muscle cell

ACh=acetylcholine; M=muscarinic receptor; eNOS=endothelial nitric oxide synthase; NADPH=nicotinamide adenine dinucleotide
phosphate; GTP=guanosine triphosphate; cGMP=cyclic guanosine monophosphate; NO=nitric oxide.
1. Perticone F et al. Circulation. 2001;104:191-196.
2. Heitzer T et al. Circulation. 2001;104:2673-2678.
 Faktor Risiko

 Usia > 45 tahun

 Obesitas
 Jarang beraktivitas fisik
 Orang tua DM
 Riwayat melahirkan bayi > 4000gram
atau riwayat DM gestasional
 Hipertensi
 HDL < 35 mg/dL dan atau trigliserida >
250 mg/dL
 Riwayat TGT atau GDPT
 Riwayat peny kardiovaskular
G
E
J
A
L
A
 Diagnosis

1. Gejala klasik DM + GDS > 200mg/dl

2. Gejala klasik DM + GDP > 126 mg/dl
3. Tanpa gejala klasik DM > Kadar glukosa darah
abnormal 2 kali
4. Atau hasil pada TTGO > 200mg/dl
 Klasifikasi
I. Type I diabetes, insulin-dependent diabetes mellitus (IDDM) or "juvenile-onset
diabetes"
A. Immune mediated
B. Idiopathic
II. Type II diabetes, non-insulin-dependent diabetes (NIDDM) or "adult-onset diabetes"
III. Other specific types
A. Genetic defects of beta-cell function (e.g., maturity-onset diabetes of the young
[MODY] types 1-3 and point mutations in mitochondrial DNA)
B. Genetic defects in insulin action
C. Disease of the exocrine pancreas (e.g., pancreatitis, trauma, pancreatectomy,
neoplasia, cystic fibrosis, hemochromatosis, fibrocalculous pancreatopathy)
D. Endocrinopathies (e.g., acromegaly, Cushing's syndrome, hyperthyroidism,
pheochromocytoma, glucagonoma, somatostinoma, aldosteronoma)
E. Drug or chemical induced (e.g., glucocorticosteroids, thiazides, diazoxide,
pentamidine, vacor, thyroid hormone, phenytoin, beta-agonists, oral
contraceptives)
F. Infections (e.g., congenital rubella, cytomegalovirus)
G. Uncommon forms of immune-mediated diabetes (e.g., "stiff-man" syndrome,
anti-insulin receptor antibodies)
H. Other genetic syndromes (e.g., Down, Klinefelter's, Turner's syndrome,
Huntington's disease, myotonic dystrophy, lipodystrophy, ataxia-telangiectasia)
 Komplikasi

Akut :
 Hipoglikemi
 Koma Lakto-Asidosis
 Ketoasidosis Diabetik–Koma Diabetik
 Koma Hiperosmoler Non-Ketotik
Kronis :
 Mikroangiopati (nefropati DM, retinopati DM)
 Makroangiopati (PJK, diabetic feet, stroke)
 Mikro-makroangiopati (neuropati, mudah infeksi)
 Lain-lain (artropati, kardiomiopati)
Hiperglikemia dikenal sebagai penyebab timbulnya radikal
bebas

Melalui 4 rute yang berbeda, yaitu :

• peningkatan glikolisis
• peningkatan aktivitas jalur sorbitol
• glukosa auto-oksidasi
• non-enzimatik protein glikasi
(glikosilasi)
 Kejadian Komplikasi Vaskular DM

Dibandingkan dengan non DM

 Penyakit Jantung Koroner : 2-4 x
 Stroke : 2–5 x
 Luka Gangren : 5x
 Gagal Ginjal : 7x
25x
 Buta :
Manifestasi Klinis Komplikasi Vaskular

Pembuluh darah kecil Pembuluh darah besar

Mata Stroke

Ginjal Penyakit
jantung koroner

Syaraf Kaki diabetes

KRITERIA PENGENDALIAN DM
BAIK SEDANG BURUK
GD Puasa (mg/dl) 80 - 109 110 - 139 > 140
GD 2-JSM (mg/dl) 110 - 159 160 - 199 > 200
HbA1C (%) 4 - 5,5 6-8 >8
Kolesterol Total < 200 200 - 239 > 240
Kolesterol LDL
Tanpa PJK < 130 130 - 159 > 160
Dengan PJK < 100 100 - 129 > 130
Kolesterol HDL > 45 35 - 45 < 35
Trigliserida
Tanpa PJK < 200 200 - 249 > 250
Dengan PJK < 150 150 - 199 > 200
BMI : Wanita 18,5 - 22,9 23 - 25 > 25 atau < 18,5
Pria 20 - 24,9 25 - 27 > 27 atau < 20
Tekanan Darah (mmHg) < 130 / 85 130-160 / 85-95 > 160 / 95
 Cara Mencapai Tujuan Pengobatan

1.Mengatur makan

4. Penyuluhan

2. Gerak badan 3. Obat-obatan

 Pengobatan Diabetes pada Usia Lanjut

Tujuan :
Bila harapan hidup tidak terlalu panjang
• Menghilangkan gejala
• Perbaikan kualitas hidup
• Atur kadar glukosa darah
• Cegah hipoglikemia

Bila harapan hidup cukup panjang:

• Mencegah komplikasi akut dan kronik
• Menurunkan angka kesakitan dan kematian
• Mengurangi efek samping obat
Modified from Heine RJ Current perspective 2000
 Prioritas
Pengobatan
Diabetes

Pengendalian kadar Pengendalian kolesterol,

gula darah sampai trigliserid, tensi dan
mendekati normal kegemukan
Gerak Badan

30 menit : 3 - 4 kali/minggu
(tiap hari lebih baik)
Olah raga Meningkatkan Uptake Glukosa di Sel Otot
dan Lemak

 Cinnulin PF®

 Cinnulin PF®

 Cinnulin PF®

(B.Mang, et al., Effects of a Cinnamon Extract on Plasma Glucose, HbA1C, and serup lipids in diabetes mellitus Type 2,
(B.Mang, et al., Effects of a Cinnamon
EuropeanExtract
Journalon
of Plasma
Clinical Glucose, HbA1C,
Investigation and
(2006) serup
36, lipids in diabetes mellitus Type 2,
340-344
European Journal of Clinical Investigation (2006) 36, 340-344
Manfaat Gerak Badan

 Menurunkan kadar gula darah

 Menurunkan berat badan
 Mengurangi kemungkinan terjadinya
komplikasi
 Bukan sekedar bergerak, ada aturannya
(hati-hati bila ada
penyakit jantung)
 CommonNew Oral
Oral Antidiabetic
Antidiabetic Agents
Agents Do
Directly Target Islet
Not Directly (  and
Target Islet Dysfunction
cell ) Dysfuntion

GLP-1 analogue
Thiazolidinedione
(exenatide
s
injectable)/DPP-4 Increase glucose uptake in
inhibitors skeletal muscle and
Improves glucose-dependent insulin decrease lipolysis in
secretion from pancreatic β-cells, adipose tissue
suppresses glucagon secretion from
Meglitinides
-cells, slows gastric emptying
Increase insulin secretion
from pancreatic -cells

Sulfonylureas
Increase insulin secretion
from pancreatic -cells
-Glucosidase
inhibitors
GLP = glucagon-like peptide. Delay intestinal carbohydrate
Adapted from Cheng and Fantus. CMAJ. 2005;172:213–226.
absorption
 Schematic Representation of DPP IV - modulated
Incretin Action
Meal

DPP IV
Liver Stomach

Pancreas
GIP GLP-1 Minutes
-
- cells
cells
 Insulin  Glucagon
Small intestine
 Glucose
DPP IV = diphenylpeptidase IV
Adapted from Demuth HU et al 2005
Terima Kasih