Dr.

M a h a t m a SpPD
SMF Penyakit Dalam F.K. UMS
SURAKARTA EAGLE FLIES ALONE, MHT
Topik
 LATAR BELAKANG
 TINJAUAN ANATOMIS FISIOLOGIS
 DEFINISI
 PATOFISIOLOGI
 DIAGNOSA
 PENATALAKSANAAN
 KOMPLIKASI
 Topik

 LATAR BELAKANG
 Latar Belakang
LATAR BELAKANG
RISKESDAS 2008
STANDING TOGETHER AGAINST DIABETES

Diagnosed patients

Undiagnosed patients

Indonesian Basic Health D M estimated ( WHO )

Research (RISKESDAS) 2020
>17 million
Total DM = 5,7%
Diagnosed DM = 1,5%
Undiagnosed DM = 4,2% 8 million
IGT = 10,2 % 2000
 Diabetes Mellitus ( DM ) :
 WHO (1993) : prevalensi DM 6%, >100 jt. 2003 : 177jt, 2025 : 300jt.
 Indonesia 1998 : 3,5 juta, 8,5 juta (tahun 2020)
 Pre-diabetes ??
 Faktor yg berperan dlm  jml DM : usia >40 tahun yg ,
kemakmuran, pola hidup serba berkecukupan,  penyakit infeksi,
angka harapan hidup 
 Nefropati Diabetika (ND) :
 Prevalensi 20-30%
 17 kali >> Non-DM
 Di AS > 50.000/ thn (GGT, ESRD)  ND tertinggi
 Biaya dialisis  :
- Pencegahan komplikasi DM
- Menghambat progresivitas ND Absolut
 DM Prevalence
INDONESIA
2000  5.6 million people with DM
2020  31.3 million people with DM

The 4th of world largest prevalence !!

(International Diabetes Federation)

Pre-diabetes ??
 Faktor yg berperan dlm  jml DM : usia >40 tahun yg ,
kemakmuran, pola hidup serba berkecukupan,  penyakit infeksi,
angka harapan hidup  Other Glomerulonephritis
10%
Nefropati Diabetika (ND) :
13%

Diabetes Hypertension
Primary Diagnosis for Patients Who Start
50.1% 27%
Dialysis
EAGLE FLIES ALONE, MHT
Proyeksi WHO tentang Struktur Umum
Populasi Diabetes
1995-2025

Negara maju Negara berkembang

Umur pasien diabetes Umur pasien diabetes

paling banyak > 65 th paling banyak 45-65 th
(40-59 th)*

Umur non produktif Umur produktif

EAGLE FLIES ALONE, MHT

 Topik
 TINJAUAN ANATOMIS FISIOLOGIS
 PROINSULIN

C-PEPTIDE
INSULIN

EAGLE FLIES ALONE, MHT

Overview of Carbohydrate metabolism
Makanan (Nasi/tepung/gula)

Kadar gula
darah normal

Insulin (I)

LEMAK

HATI
OTOT
EAGLE FLIES ALONE, MHT
 Overview of Carbohydrate metabolism

INS

INS INS

INS
INS
INS INS

INS
 Insulin Glucose

Insulin
receptor

Synthesis GLUT 4
PPARg mRNA
RXR

PPRE transcriptio
promoter n
Coding reg

EAGLE FLIES ALONE, MHT

Topik
 DEFINISI
 Apakah Diabetes itu ?
Faktor
Faktor Lingkungan/
keturunan Cara hidup
Gaya hidup
berisiko:
Makan
berlebihan
Insulin kurang jumlahnya Kurang sport
Insulin kurang baik kerjanya Stres

DIABETES = penyakit dengan

kadar gula (glukosa) darah meningkat

Insulin = hormon pengatur kadar glukosa darah

yang yang dikeluarkan oleh pankreas
14
 Diabetes Mellitus
• Kelainan bersifat kronik
• Gangguan metabolisme KH-L-P
• Komplikasi Makro & Mikro Vaskuler
• Berkaitan dengan faktor genetik
• Gejala Utama Intoleransi Glukosa

Faktor 2  Fungsi Endo. Pank ( DM )

 Genetik
 Virus & Bakteri
 Bahan Toksik
 Nutrisi
EAGLE FLIES ALONE, MHT
 Klasifikasi DM
Destruksi sel beta, umumnya menjurus ke defisiensi insulin
Tipe 1 absolut
Autoimun
Idiopatik
Tipe 2 Bervariasi, mulai yang terutama dominan resistensi insulin
disertai defisiensi insulin relatif sampai yang terutama defek
sekresi insulin disertai resistensi insulin

Defek genetik fungsi sel beta

Tipe Lain
Defek genetik kerja insulin
Penyakit eksokrin pankreas
Endokrinopati
Karena obat/zat kimia
Infeksi
Sebab imunologi yang jarang
Sindrom genetik lain yang berkaitan dengan DM

DM
Gestasional
EAGLE FLIES ALONE, MHT
 DIABETES Tidak Ada Insulin
TIPE 1
Gluc Gluc
Gluc Gluc Gluc

Kadar glukosa
Gluc
Gluc darah meningkat

Tidak ada insulin yang

membuka pintu
masuk sel
Tenaga

Tak ada yang dibakar

Sel otot

Gluc Glukosa darah

SlametS
Pintu masuk sel
EAGLE FLIES ALONE, MHT
 DIABETES Kerja Insulin Kurang Baik
TIPE 2
Gluc Gluc
Gluc Gluc Gluc Insulin

Gluc Gluc Kadar glukosa

darah meningkat

Ada insulin tapi

tak mampu membuka
pintu masuk sel
Tenaga

Tak ada yang dibakar

Sel otot

Gluc Glukosa darah

SlametS
Pintu masuk sel
EAGLE FLIES ALONE, MHT
 Gejala
Klinis

poliuria poliphagia polidipsia

(sering kencing) (cepat lapar) (sering haus) Cepat Lelah berat
badan
turun

Luka pada Kaki kesemutan mata kabur impotensia gatal-gatal

Sukar Sembuh
 Topik

 PATOFISIOLOGI
 Leptin

Adiponectin

Resistin

Adipsin (ASP)

Angiotensinogen/AT-II

Cytokines
(TNF-, IL-6)

Insulin kurang baik kerjanya

EAGLE FLIES ALONE, MHT

 patofisiologi
Insulin deficiency

Hyperinsulinemia
to compensate for insulin
resistance1,2

Glucotoxicity2 Lipotoxicity3
Amyloid
deposit

Pancreas High circulating

Chronic
free fatty acids
hyperglycemia

Lipolysis
HGP

TNF 
Uptake Insulin resistance
SlametS
 patofisiologi
Natural History of Type 2 Diabetes

Insulin sensitivity Insulin secretion

Insulin resistance

Glycemia

30% Type 2 50%

diabetes
50% IGT 70 %
Impaired glucose Insulin secretion
70% metabolism 150%
Time
100% Normal glucose 100% No Pre-
diabetes diabetes
 Hyperglycemia

AGE formation Glucose auto oxidation Sorbitol pathway

 Antioxidants
 Oxidative Sress

Lipid peroxidation Endothelial dysfunction Hypercoagulability

 Leukocyte adhesion  NO  Endothelin Fibrinolysis
 Foam cell formation  Prostacyclin  Coagulability
 TNF a  TXA2  Platelet reactivity

Vascular complications

Retinopathy Nephropathy Neuropathy

SlametS
Topik
 DIAGNOSA
 Stages of type 2 Diabetes in relationship to
100 -cell function

75
Beta cell function (%)

50

IGT Postprandial
Hyperglycemia Type 2
Type 2
25 Diabetes
Diabetes
Phase 1 Type 2
Phase 3
Diabetes
Phase 2
0
8 - 10
- 12 6 -4
6 -2
2 00 2 46 8
10 12
14
1 hypoX-jsk-7-99
Years from diagnosis
EAGLE FLIES ALONE, MHT
 Criteria for the Diagnosis of Pre-DM
(IGT & IFG) and DM

Normal Pre - Diabetes Diabetes Mellitus

(mg/dl) (mg/dl) (mg/dl)

IGT IFG T2DM

2h-PG FPG FPG > 126

FPG < 110
2-h PG < 140 140-199 110-125 2-h PG > 200
New IFG*: CPG > 200
100-125 with Classical Symptoms

A Dx of Diabetes must be confirmed on a subsequent day by any one of the 3 Methods.

Fasting means : No Calorie intake for at least 8 hours *IGT by OGTT; *IFG by FPG
Glucose Load : 75g Anhydrous Glucose in Water
 Topik
 PENATALAKSANAAN
Criteria for Diabetes Control

Good Fair Poor

Fasting blood glucose (mg/dl) 80-109 110-125 ≥126

2hpp blood glucose (mg/dl 80-144 145-179 ≥180

A1C (%) <6.5 6.5-8 >8

Total- cholesterol (mg/dl) <200 200-239 ≥240

LDL-cholesterol (mg/dl) <100 100-129 >130

HDL-cholesterol (mg/dl) >45

Triglyceride (mg/dl) <150 150-199 ≥200

Body mass index (kg/m2) 18.5-22.9 23-25 >25

Blood pressure (mmHg) <130/80 130-140/80-90 >140/90

Perkeni, 2009
Treatment :
stepwise approach Blood
Glucose Control
+
+ 5
+ 4
3
2

1
 Latihan Fisik (Olah Raga)

Olah Raga Dampak Positif

Sesuai kondisi
• Fisik  Sensitifitas
• Metabolik Insulin - Reseptor 
 Perbaikan profil lipid
 Perbaikan kondisi
Dampak kardiovaskuler
Negatif

 Ketosis
 Hipoglikemi
 Komplikasi kronik 
 Trauma sendi
Sites/Mechanisms of Action
hypoglycemic Agents

Decreased digestion of
complex sugars
Alpha-glucosidase
inhibitors Sulfonylureas
Meglitinides

Normoglycemia
Biguanides
Thiazolidinediones Increased insulin
secretion
Decrease in hepatic Thiazolidinediones
glucose production Biguanides

Increase in glucose uptake

 Insulin Target Tissues
Biguanides TZDs Sulfonylureas
Decrease Decrease and
Hepatic Glucose
Thiazolidinediones
Lipolysis Nonsulfonylurea
TZDs Production
(TZDs) Secretagogues
?
Increase Glucose Adipose Tissue Increase Insulin
Uptake Liver Increased Lipolysis Secretion
Increased Glucose
Production
Skeletal Muscle Increased Pancreatic Beta Cells
Decreased Free Fatty Decreased Insulin
Glucose Uptake Acids Secretion
Lipotoxicity Lipotoxicity

INSULIN RESISTANCE DEFECTIVE INSULIN

SECRETION

-Glucosidase Glucotoxicity
Inhibitors
Delay Intestinal
Carbohydrate
Absorption

Small Intestine
Carbohydrate HYPERGLYCEMIA
Absorption
(type 2 diabetes)
SULFONILUREA Generasi 1  Generasi 2  Generasi 3
Paling banyak digunakan • Makin efektif
dalam praktek • Efek samping > kecil

• Normoglikemi
Komplikasi Glimepiride
• Hiperinsulinemi 
! DOSIS 
Hipoglikemi
vaskuler (Generasi 3)

• Potensi ekstra pankreas

> efektif
• Kerja cepat & bertahan lama
• Dosis kecil

Efek samping
minimal
 Pengendalian
Metabolik
Kadar glukosa darah

SULFONILUREA

Mencegah angiopati
 membersihkan
Vaskuler radikal bebas
 Memperbaiki
fungsi trombosit
 Memacu
fibrinolisis
 Metformin

Improved Reduced
Insulin sensitivity Hypertriglyceridaemia
Fibrinolysis AGE formation
Nutritive capillary flow Cross-linked fibrin
Haemorrheology Neovascularisation
Postischaemic flow Oxidative stress

Reduced cardiovascular risk

AGE : advanced glycation end-products

Vascular benefits of metformin

Effects of metformin on non-conventional factors
(Grant PJ, 2003).

Risk marker Effect

PlAI-1 Marker reduction
Factor VII Reduction
Fibrinogen Equivocal , some studies report reduction, others
no effect
Factor XIII Reduces A and B subunit
Fibrin Alters structure / function
C-reactive protein Reduction
Platelets Reduction platelet growth factor 4 and
thromboglobulin, stabilises platelet and antioxidant
effect
Blood flow Metformin increases hemodynamic responses to L-
arginine. Lowers levels of asymptomatic
dimethylarginine, improves post ischemic blood
flow and improves blood flow in both sekeletal
muscle and adipose tissue
 Alpha Glucosidase Inhibitors
(AGIs)

• Ingested with meals

• Delay the digestion of complex
carbohydrate
• Competitive inhibition of alpha
glucosidase in the intestine
• Blunts postprandial glucose spikes
• Gastrointestinal side effects
 The use of acarbose
1. It has direct effect on postprandial glucose
2. Does not cause hypoglycemia when given alone
3. Does not cause weight gain
4. Side effects are trivial
5. It can be used as first - line drug therapy
6. It can be used as an adjunct to existing and
conventional therapy
7. Modulates peaks and delays glucose absorption
8. Hypothesized that AGI administration to IGT cases
may delay or prevent T2DM and CVD risks
Comparison of therapies for T2DM when used as
monotherapy (Nathan 2003)
Diet Sulfonyl Bigua Glucosidase Thiazoli - Insulin
urea nide Inhibitor dinedione

Metabolic effects
Improves resistance + + ++ + +++ ++
Improves secretion + ++ + + + +
Overnight HGP + + ++ + + +
Postprandial excursion + ++ + ++ + ++
HbA1c + ++ ++ + + +++
Lowers FFA + + + + + ++
Weight gain - + - + + ++
Hypoglycemia - + - - - ++
Allergic phenomena - + + - + +

Other side effects

Anabuse effect - +* - _ - -
Hyponatremia - +* - _ - -
Lactic acidosis - - + _ - -
Gastrointestinal - - + ++ - -
Hepatic dusfunction - - - - +# -

* common with 2nd generation sulfonylureas (glipizide, gliburide), most common chlorpropamide
# severe idiosyncratic failure in 1/35.000 – 1/50000 patients treated with troglitazons (others less)
 Topik
KOMPLIKASI
 Overview

KOMPLIKASI DIABETES MELLITUS

• Akut : • Kronik :

- Hipoglikemia - Mikroangiopati :
- Koma Asidosis Dia- - Nefropati D M
betika - Retinopati DM
- Hiperosmoler Non - Kardiomiopati DM
Ketotik - Neuropati DM
- Koma Laktat Asi- - Makroangiopati :
dosis - PJK
- CVA
- Ulkus/ ganggren
- Neuropati DM
- Rentan Infeksi :
- TB Pulmo, dll.
 Koma Hipoglikemi

Insulin 
Koma

Diet  OHO 

 lapar  Berdebar
 Lemah  Pusing
 Gemetar  Gelisah
 Keringat dingin  Kesadaran 
 Diabetes and Vascular
Complications
Diabetes

Macroangiopathy Microangiopathy

Coronary artery disease Nephropathy

Peripheral vascular Retinopathy
disease Neuropathy
Stroke
 Glukosa
Mortalitas
Post Prandial
Kardiovaskuler
Korelasi

 Hiperglikemi  Disfungsi
 Hipertrigliseridemi endotel PJK
 Aterogenesis
Produksi
Prostasiklin 

Produksi
• Viskositas
Aktivator
• Mikrotrombus
Fibrinolisis 
• Penyempitan vaskuler
Produksi Hambatan
Thromboxane A2  Deformabilitas aliran darah
eritrosit
 Perjalanan penyakit pd nefropati diabetik

Perubahan fungsi
• GFR  Incipiens Nephropathy
• Albuminuria reversible
• Ginjal membesar • Hiperfiltrasi
• Hyperfiltration • Mikroalbuminuria
• Hipertensi

0 2 5 Waktu (tahun) 15 20 25

Awal DM 
ESRD
ACE Inhibitor

Perubahan struktur Overt nephropathy

• Penebalan membrana basalis  Makroalbuminuri/ gross protein
• Ekspansi mesangium  Kreatinin 
• Hyperperfusion
 GFR ml/mnt 150 120 60 < 10
 Serum
creat mg/dl 0,8 1 > 2,0 >5

(dikutip dari Harrison Ed 16 : Adapted RA defronzo 1998 )

DIABETIC RETINOPATHY
ERECTILE DYSFUNCTION

Kita lahir & besar

bersama.
Tapi mengapa
kamu mati
duluan ?
 Patofisiology

Mekanisme Rentan Infeksi Pada DM

• Keadaan Nutrisi intra sel berkurang
(malnutrisi, dehidrasi)
• Insufisiensi Vaskular
( makro dan mikroangiopati )
• Neuropati
• Fungsi Leukosit Berkurang
- Penurunan kemampuan Intracelluler Killing PMN, MN
- Defisiensi Komplemen
- Berkurangnya jumlah T- helper
- Disfungsi Makrofag
 Patofisiology

Mekanisme Rentan Infeksi TB

Pada DM
• Fungsi Leukosit Berkurang

Penurunan Intracelluler Killing PMN, MN

Defisiensi Komplemen

Berkurangnya jumlah T- helper

Disfungsi Makrofag
Disfungsi Makrofag
Penurunan kemampuan Intracelluler Killing PMN, MN

Kemotaksis
Perlekatan

Fagositosis
H2O2, spesies oksigen aktif

Intracellular Killing

Eksositosis
 Insulin secretion in normal individu
 An amount of insulin will be secreted by human pancreas
about 49-50 units insulin / day
 Two phases of insulin secretion :
 Basal insulin secretion :
fasting 10 microU/ml
post prandial 100 microU/ml
peak at 30 – 40 minutes
without eksogen stimuli
 Stimulated insulin secretion
with eksogen stimuli
burst insulin release
decreased with gradually
 Breakfast Lunch Supper
75 –

50 – INSULIN
(U/mL)
Insulin

25 –
Basal
0– insulin
150 –
GLUCOSE

100 –
(mg/dL)
Glucose

50 – Basal
glucose

0–
7 8 9 10 11 12 1 2 3 4 5 6 7 8 9
a.m p.m
Time of day

Twenty four hours profiles of blood insulin and

glucose concentration in normal Human
 Breakfast Lunch Supper
75 –

50 – INSULIN
(U/mL)
Insulin

25 –
Basal
0– insulin
150 –
GLUCOSE

100 –
(mg/dL)
Glucose

50 – Basal
glucose

0–
7 8 9 10 11 12 1 2 3 4 5 6 7 8 9
a.m p.m
Time of day

Twenty four hours profiles of blood insulin and

glucose concentration in normal Human
 60 ng/ml

Individu normal
Insulin
plasma FAS E 1 FAS E-2

waktu
3-5 mnt 50-60 menit

Penderita DM tipe-2

Insulin (Tumpul) Lebih tinggi dan lama

plasma
FAS E- 1 FAS E-2
Comparative profiles Secretion of bloodWaktu
insulin Normally and
(Delayed Insulin D M
secretion)
Metabolic benefit of insulin therapy
(Edelman 1995)

1. Reduce fasting and postprandial glucose levels

2. Suppresses HGP hepatic glucose production
3. Stimulates peripheral glucose utilization
4. Increase glucose oxidation/storage in muscles
5. Improves lipoprotein composition
6. Reduces AGEP advanced glycosylation end products
7. Reduces glucose toxicity
8. Improves endogenous insulin secretion ability

1-4 maintain normoglycemia

5-6 prevent complications
7-8 preserving β-cell function
Profiles of injectable insulin
 Early Insulinisation
DCCT & UKPDS :
1. Reducing hyperglycaemia reduces incident risk &
progression of diabetic complications
2. Target HbA1C 6.5% to 7%

UKPDS Data – Lowered 1% HbA1C leads to

reduction of :
• 21% diabetes-related mortality
• 14% MI
• 37% microvascular complications
• 43% PVD
 Early Insulinisation
Challenge of Type 2 DM Control
Type 2 DM – a progressive disease

• Progressive decline of –cell function

• Late diagnosis – average 12 years
• Loss of initial BG control within few years
• Exogenous Insulin becomes necessary
• Often, Insulin therapy need intensified
Be a Good Doctor’s with Active Learning and Share Knowledge Each Other
Think Globally but Act Locally (WHO Statement)