STANDING TOGETHER AGAINST DIABETES

DIABETES MELLITUS Patofisiologi, Diagnosis, Management

Komplikasi

Dr. M a h a t m a SpPDSMF Penyakit Dalam F.K. UMS

SURAKARTA

-Cardiology-Pulmonology-Nephrology-Hematology-Gastrohepatoenterology-Endocrinology-Rheumatology-Infectious Diseases-Geriatri-Immunology-Psikosomatis

Presentation Point of View

1.Pendahuluan : Latar belakang

2.Anatomi, histologi, fisiologi,

Biokimia, Biomolekuler

3.Definisi, Klasifikasi4.Patofisiologi4. Gejala, Diagnosis5.Penatalaksanaan6.Komplikasi

Presentation Point of View

1.Pendahuluan/ Latar belakang

2. Anatomi, histologi, fisiologi, Biokimia, Biomolekuler 3. Definisi, Klasifikasi4. Patofisiologi4. Gejala, Diagnosis5. Penatalaksanaan6. Komplikasi

Mialgia / osteoartritis

Hipertensi

Tension Headache

Febris

Diabetes MellitusColic Abdomen : Gastritis / I S K

GREAT IMITATOR :

D M

SIPILIS

HIV/ AIDS

TBC?

?PRAKTEK SORE

RISKESDAS 20RISKESDAS 201010 RISKESDAS 20RISKESDAS 201010

Diagnosed patients

Undiagnosed patients

1,5%

MDGs : KIA

AIDS T B

D M

D M estimated ( WHO )

2000

>17 million

2020

8 million

LATAR BELAKANGLatar Latar BelakangBelakang

4,2%

Total DM = 5,7% E P I D E M I : Urgent need for Action

IGT = 10,2 %

SlametS 7

Negara maju

Negara berkembang

DuniaJum

lah

peng

idap

dia

bete

s de

was

a

1995

2000

2025

Jumlah Pengidap Diabetes di Dunia 1995-2025

Jumlah Pengidap Diabetes di Dunia 1995-2025

41%41%

170%170%

122%122%

P A N D E M I : Urgent need for Action

LATAR BELAKANGLatar Latar BelakangBelakang

350

300

250

200

150

100

50

0

Umur pasien diabetes paling banyak 35 th – 50 th

Umur pasien diabetes paling banyak 35 th – 50 th

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) :

INDONESIA 2000 5.6 million people with DM

2020 31.3 million people with DM

The 4th of world largest prevalence !!(International Diabetes Federation)

DM Prevalence

Diabetes50.1%

Hypertension

27%

Glomerulonephritis

13%

Other

10%

Primary Diagnosis for Patients Who

Start Dialysis EAGLE FLIES ALONE, MHT

Latar Latar BelakangBelakang

Presentation Point of View

1. Pendahuluan : Latar belakang

2.Anatomi, histologi, fisiologi,

Biokimia, Biomolekuler

3.Definisi, Klasifikasi4.Patofisiologi4. Gejala, Diagnosis5.Penatalaksanaan6.Komplikasi

EAGLE FLIES ALONE, MHT

PROINSULIN

C-PEPTIDEINSULIN

Anatomi/histologyAnatomi/histology

PANCREAS

Distribusi Glukosa ke JaringanF i s i o l o g iF i s i o l o g i

NO INSULIN

INS

INSINS

INS

Overview of Carbohydrate metabolism

INSINS

INS

INS

INS

INSINS

INS

INS

EAGLE FLIES ALONE, MHT

B i o k i m i B i o k i m i aa

promoter Coding reg

transcription

mRNA

Synthesis GLUT 4

translocation

PPAR

PPRE

Insulinreceptor

Insulin

RXR

Glucose

EAGLE FLIES ALONE, MHT

Bio MolekulerBio Molekuler

Presentation Point of View

1. Pendahuluan : Latar belakang2. Anatomi, histologi, fisiologi, Biokimia, Biomolekuler

3.Definisi Klasifikasi3. Patofisiologi4. Gejala, Diagnosis5. Penatalaksanaan6. Komplikasi

APAKAH D.M. ITU ?

Adalah suatu kumpulan gejala yang timbul pada seseorang disebabkan karena adanya

peningkatan kadar gula (glukosa) dalam darah akibat kekurangan insulin, mutlak maupun relatif.

EAGLE FLIES ALONE, MHT

Insulin Insulin kurang jumlahnya kurang jumlahnya Insulin Insulin kurang baik kerjanyakurang baik kerjanya

Diabetes Mellitus• Kelainan bersifat kronik progresif• 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

NutrisiEAGLE FLIES ALONE, MHT

D e f i n i s iD e f i n i s i

Tipe 1Destruksi sel beta, umumnya menjurus ke defisiensi insulin 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

Tipe LainDefek genetik fungsi sel betaDefek genetik kerja insulinPenyakit eksokrin pankreasEndokrinopatiKarena obat/zat kimiaInfeksiSebab imunologi yang jarangSindrom genetik lain yang berkaitan

dengan DM

DM

GestasionalEAGLE FLIES ALONE, MHT

KlasifikasiKlasifikasi

Presentation Point of View

1. Pendahuluan : Latar belakang2. Anatomi, histologi, fisiologi, Biokimia, Biomolekuler 3. Definisi, Klasifikasi

4.Patofisiologi

4. Gejala, Diagnosis5.Penatalaksanaan6.Komplikasi

CentralCentral Obesity Obesity

CHDCHD

glycemic disorders

( Prediabetes ) << HDL , >> LDL

– HypertriglyceridemiaHypertension

Endothel DisfunctionHiperuricemia

Microalbuminuriainflammation (hsCRP) Impaired thrombolysis

PAI-1

Insulin resistance

JARANG OLAHRAGAPENUAANOBAT OBATANSEBAB LAIN

DIABETES MELLITUSHIPERTENSIP C O S dan NAFLDHIPERURICEMIADISLIPIDEMIAATHEROSCLEROSISACANTHOSIS NIGRICANS

STROKESTROKEI

II

III

IVV

VI

VII

SlametS

Chronic hyperglycemiaChronic hyperglycemia

High circulating free fatty acids High circulating free fatty acids

PancreasPancreas

Amyloid

deposit

Glucotoxicity2Glucotoxicity2 Lipotoxicity3Lipotoxicity3

HGPHGP

UptakeUptake

Lipolysis

TNF

patofisiologipatofisiologi

Insulin resistance

Hyperinsulinemia to compensate for insulin resistance1,2

Hyperinsulinemia to compensate for insulin resistance1,2

Insulin deficiency

Insulin resistance Insulin deficiency

Normal glucose

Impaired glucose metabolism

Type 2 diabetes

30%

70%

100%

50%

150%

100%

IGT50% 70 %

Natural History of Type 2 Diabetes

No diabetes

Pre-diabetes

Time

Insulin secretion

Glycemia

Insulin resistance

patofisiologipatofisiologi

Insulin sensitivityTurun karena Resistensi Insulin

Insulin secretionTurun karena Glucotoxicity, Lipotoxicity

Problem Insulin Resistance

• Reseptor:

• “Post-receptor” (paling sering):

Translokasi GLUT 4

Sintesis GLUT 4

Kuantitas / kwalitas berkurang

ADA. Consensus Development on Insulin Resistance. 1997

Presentation Point of View

1. Pendahuluan : Latar belakang2. Anatomi, histologi, fisiologi, Biokimia, Biomolekuler 3. Definisi, Klasifikasi4. Patofisiologi

4. Gejala, Diagnosis

5.Penatalaksanaan6.Komplikasi

Gejala Klinis

polidipsia(sering haus) Berat

badan turun

poliuria(sering kencing)

gatal-gatalmata kaburimpotensia

poliphagia(cepat lapar)

kesemutan

Cepat Lelah

Luka pada Kaki Sukar

Sembuh

Luka pada Kaki Sukar

Sembuh

G e j a l aG e j a l a

FPG > 126

2-h PG > 200

CPG > 200with Classical Symptoms

IGT IFG T2DM

2h-PG

140-199

FPG110-125

FPG < 110

2-h PG < 140

Normal Pre - Diabetes Diabetes Mellitus(mg/dl) (mg/dl) (mg/dl)

New IFG*:100-125

EAGLE FLIES ALONE, MHT

D i a g n o s i D i a g n o s i ss

with Classical Symptoms

T T G O : 75 g Anhydrous Glucose in Water

Criteria for the Diagnosis PreDiabetes (IGT & IFG) and DM

hypoX-jsk-7-99

IGT Postprandial Hyperglycemia Type 2

DiabetesPhase 1 Type 2

DiabetesPhase 2

Type 2DiabetesPhase 3

- 12 - 10 - 6 - 2 0 2 6 10 14Years from diagnosis

Bet

a ce

ll fu

ncti

on (%

)Stages of type 2 Diabetes in relationship to

-cell function

25

0

50

75

100

8 6 4 02 4 6 10

EAGLE FLIES ALONE, MHT

D i a g n o s i D i a g n o s i ss

Rata rata Px DM terdiagnosa

D M

2

KomplikasiCardioMetabolik +++

PREDIABETIK

MASALAH DIAGNOSA

Presentation Point of View

1. Pendahuluan : Latar belakang2. Anatomi, histologi, fisiologi, Biokimia, Biomolekuler 3. Definisi, Klasifikasi4. Patofisiologi4. Gejala, Diagnosis

5.Penatalaksanaan

6.Komplikasi

Treatment : stepwise approach

( dulu )

1

2

3

4

5

Combination of2 oral medicines

Insulin

One oral medicine

EducationExercise

Diet

+

++

PenatalaksanaanPenatalaksanaan

Combination of3 oral medicines

The New Paradigm of (Type 2) Diabetes Treatment

Aggressive Treatment Driven by Target ( A1C < 7 % )

Early Insulinisation Combination Oral – insulin

PenatalaksanaanPenatalaksanaan

Treat to Target

Individualized Treatment Driven by Patient 0riented

Saat diagnosis:

Gaya hidup

+

Metformin

Gaya hidup +

Metformin +

Insulin basal

Gaya hidup +

Metformin +

Sulfonilurea

Gaya hidup +

Metformin +

Insulin intensif

Gaya hidup +

Metformin +

Pioglitazon

Gaya hidup +

Metformin +

GLP-1 agonis

Gaya hidup +

Metformin +

Pioglitazon + sulfonilurea

Gaya hidup +

Metformin +

Basal insulin

Well validated core therapies

Less well validated core

therapies

Tahap 1

Tahap 3Tahap 2

ADA/EASD consensus algorithmU S A & Eropa )

a Sulfonylureas other than glibenclamide or chlorpropamideb Insufficient clinical safety data; CHF = congestive heart failure

Check HbA1C every3 months until <7%. Change

treatmentif HbA1C ≥7%

Basal plusBasal +

1 prandialBasal insulinonce daily

(treat-to-target)

Basal plusBasal +

2 prandial

Basal bolus Basal +

3 prandial

Metformin

SU, TZDAGH, GLP1

HbA1c ≥7.0%, FBG on targetPPG ≥160 mg/dL

HbA1c ≥7.0%

PenatalaksanaanPenatalaksanaan

STEP 1

STEP 2

STEP 3

STEP 2

L i f e s t y l e c h a n g e s

?

STEP 3

STEP 3

A 1 c ?

EAGLE FLIES ALONE, MHT

< 7 % ?

C I N A : A1c .. 6,7J E P A N G : A1c .. 6,5I N D I A : Stepwise treatmentS I N G A P U R A : A D AINGGRIS & SKANDINAVIA : ?AMERIKA LATIN : ??

SlametS

Hb A1c = Kadar Gula Dalam Sel Darah Merah,Menggambarkan Kadar Rata – Rata Gula Darah

Selama 2-3 Bulan Yang Lalu

Hb A1c = Kadar Gula Dalam Sel Darah Merah,Menggambarkan Kadar Rata – Rata Gula Darah

Selama 2-3 Bulan Yang Lalu

8%

Target pengendalian = 7%Target pengendalian = 7%

7%

6%

Gula darahmg/dl

Gula darahmg/dl

160

130

HbA1cHbA1c

200

100

PenatalaksanaanPenatalaksanaan

37

Basal Insulin menurunkan A1C antara 2 % – 3,5 %

OAD menurunkan A1C antara 0,5 % – 1,5%

Microvascular complications

Myocardial infarction

HbA1c Deaths related to diabetes

Stratton IM, et al. BMJ 2000; 321: 405–412. 15

11 %

redu

ces

% r

edu

ces

A1

C

A1

C

-21%

-37%

-14%

PenatalaksanaanPenatalaksanaan

38

Expected HbA1c reduction accordingto intervention

Intervention Expected ↓ in HbA1c (%)

Lifestyle interventions 1 to 2%

Metformin 1 to 2%

Sulfonylureas 1 to 2%

Insulin 1.5 to 3.5%

Glinides 1 to 1.5%1

Thiazolidinediones 0.5 to 1.4%

-Glucosidase inhibitors 0.5 to 0.8%

GLP-1 agonist 0.5 to 1.0%

Pramlintide 0.5 to 1.0%

DPP-IV inhibitors 0.5 to 0.8%

1. Repaglinide is more effective than nateglinideAdapted from Nathan DM, et al. Diabetes Care 2009;32:193-203.

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

Olah Raga

Latihan Fisik (Olah Raga)

Dampak Positif

Sensitifitas Insulin - Reseptor Perbaikan profil lipid Perbaikan kondisi kardiovaskulerDampak

Negatif

Ketosis Hipoglikemi Komplikasi kronik Trauma sendi

Sesuai kondisi• Fisik• Metabolik

HYPERGLYCEMIA

Glucotoxicity

Lipotoxicity

IncreasedFree Fatty

Acids

INSULIN RESISTANCE DEFECTIVE INSULINSECRETION

-GlucosidaseInhibitors

Delay IntestinalCarbohydrate

Absorption

LiverIncreased Glucose

Production

Adipose TissueIncreased Lipolysis

Thiazolidinediones(TZDs)

Increase GlucoseUptake

TZDs?

BiguanidesDecrease

Hepatic GlucoseProduction

TZDsDecreaseLipolysis

OAD/ ORAL ANTI DIABETIC

Pancreatic Beta CellsDecreased Insulin

Secretion

Sulfonylureasand

NonsulfonylureaSecretagogues

Increase InsulinSecretion

Small IntestineCarbohydrateAbsorption

Skeletal MuscleDecreased

Glucose Uptake Lipotoxicity

(type 2 diabetes)

Vascular benefits of metformin

Reduced cardiovascular risk

Metformin

ImprovedInsulin sensitivity

Fibrinolysis

Nutritive capillary flow

Haemorrheology

Postischaemic flow

ReducedHypertriglyceridaemia

AGE formation

Cross-linked fibrin

Neovascularisation

Oxidative stress

Model showing the potential contribution of the related loss of visceral adipose tissue to the beneficialeffects of metformin on the features of the metabolic syndrome FFA : free fatty acids

HepaticGlucoseproduction

FFA ?

VisceralAdipose tissue ?

Insulinsensitivity

METFORMIN

Insulinsensitivity

Muscleglucose uptake

Glucose

(—)

(+)

(=)

↓ ↓ INSULIN RESISTANCEINSULIN RESISTANCE1 ↓ 1 h PP (↓ PmH)

METFORMINMIRACLE

56EFFECTS

51

50

49

48

47

46

45

44

43

42

41

40

39

38

37

36

35

34

33

32

31

30

29

28

27

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

↓ FPG↓ VAT

↓ WC

↓ Glucose Absorption

↑ Glycogenesis

↑ Insulin Rec. Binding

↑ GUT : GLUT-5 Expression

↑ Post-Receptor Effect

↓ Glucolipotoxicity

↓ Oxidative Stress

↓ Inflammation

↓ FFA

↓TG, ↑ HDL-C, ↓Tot-C, ↓ LDL-C

Synthesis & Secretion of GLP-1

↓ AGE

↓ Fibrinogen

↓ Factor-VII (TF)

↓ PAI-1

↓ Factor-XVIIIA

↓ TSH

↓ Respiratory Complexl

↑ Erythrocyte Deformability

↓ Platelet Aggregation

26 ↓ Hyperinsulinemia

↓ AMPK

β-Endorphin

↓ ADMA

↑ Apn

↓ Resistin

↓ Leptin

↓ NFKB

↓Cytosolic Ca++

↓SMC Fibroblast

↑ Plaque Regression

↑ NO (↑ HSP-90, ↑ eNOS)

↓ Capillary Permeability

↓MMP-9

↑ Peripheral A. Blood Flow

↑ PTEN

↓HT-29

↓ LNCaP

↓ PC-3

↓DU 145

↓ cyclin D1

↑ TSC2

↑ TSC1

↓ mTORC1

↑ LBK1

↑ p53

IIIustrated : Tjokroprawiro 1994-2011

FIGUREFIGURE MET with Metabolic-Cardiovascular-Carner (MMC) MET with Metabolic-Cardiovascular-Carner (MMC) Protective EffectsProtective Effects

↓ ↓ FOXO1/ ↓FABP4FOXO1/ ↓FABP456

M E T F O R M I

N ?

SULFONILUREA

Metabolik

Vaskuler

Mencegah angiopati

membersihkan

radikal bebas

Memperbaiki

fungsi trombosit

Memacu

fibrinolisis

PengendalianKadar glukosa darah

Dasar Pemikiran Terapi Sulfonilurea

Bilamana Terapi dimulai

Bagaimana cara Pemberian obat

Memacu sekresi insulin Memperbaiki Glucose Clearance Memperbaiki profil lipid

BB Normal Glukosa darah puasa 140 mg/dl Diit, OR biguanid gagal Belum butuh Insulin

Mulai dosis kecil tunggal

dosis

terbagi/berulang Ditelan 30 mnt AC

Berikatan dengan

reseptor 65 kDa

Pengeluaran K+

dihambat

Depolarisasi

Saluran Ca++

terbuka

[Ca++] intrasel meningkat

Sekresi insulin

M

eta

bolis

m

[ATP] [ADP]

K+_

cAMP+

ADP

Ca++K+

[Ca++]i

Sekresi Insulin

DepolarisasiDepolarisasi

glimipiride

GlukosaGlukosa&&

Asam AminoAsam Amino

+

+

Pro-insulin Sel b

eta

pan

kre

as

Sel b

eta

pan

kre

as

65 kDa65 kDaSU lain

reseptor SUreseptor SU

140 140 kDakDa

MEKANISME KERJA SULFONILUREA

K - ATP Channel

Farmakokinetik dari SulfonilureaObat

WaktuParuh( Jam )

JangkaWaktuKerja

( Jam )

Dosis/hari

( mg )Tablet/

hariMetabolit

Aktif

ACETOHEXAMIDE

CHLORPROPAMIDE

GLICLAZIDE

GLIPIZIDE

GLIBURIDE

TOLBUTAMIDE

TOLAZAMIDE

0.8 - 2.4

24 - 48

6 - 15

1 - 5

2 - 4

3 - 28

4 - 7

12 - 18

24 - 72

10 - 15

14 - 16

20 - 24

6 - 10

16 - 24

250 - 1500

100 - 500

40 - 320

2.5 - 20

2.5 - 20

500 - 3000

100 - 1000

2

1

1 - 2

1 - 2

1 - 2

2 - 3

1 - 2

-

-

-

-

-

-

-

Glimepiride(Generasi 3)• Potensi ekstra pankreas > efektif

• Kerja cepat & bertahan lama

• Dosis kecil

• IP adalah suatu mekanisme IP adalah suatu mekanisme endogen jantung untuk endogen jantung untuk melindungi dirinya dari melindungi dirinya dari suatu kejadian iskemisuatu kejadian iskemikk

yang mematikan (parah) yang mematikan (parah)

• IP IP : : kanal/saluran kanal/saluran KKATPATP di di jantung terbuka jantung terbuka

secara secara otomatisotomatis menyusul kejadian iskemik menyusul kejadian iskemik

miokard yang singkatmiokard yang singkat

• Obat-obatan yang Obat-obatan yang menghambat terbukanya menghambat terbukanya

KKATPATP di jantung dapat di jantung dapat membahayakan kondisi membahayakan kondisi

iskemik miokardiskemik miokard

Ischemic Preconditioning Ischemic Preconditioning (IP)(IP)

Oklusi/hambatan yang Oklusi/hambatan yang singkat dan berulang-singkat dan berulang-ulang pada pembuluh ulang pada pembuluh

darah yang sama darah yang sama menyusul oklusi yang menyusul oklusi yang berkepanjangan akan berkepanjangan akan

menghasilkan luas infark menghasilkan luas infark yang lebih kecil yang lebih kecil

(ischemic (ischemic preconditioning) preconditioning)

CombinationCombinationCardioprotectiveCardioprotective

SURSUR 22

SURSUR 11

• Ingested with meals

• Delay the digestion of complex carbohydrate

• Competitive inhibition of alpha glucosidase in the intestine

• Blunts postprandial glucose spikes

• Gastrointestinal side effects

• Ingested with meals

• Delay the digestion of complex carbohydrate

• Competitive inhibition of alpha glucosidase in the intestine

• Blunts postprandial glucose spikes

• Gastrointestinal side effects

Alpha Glucosidase Inhibitors (AGIs)

Alpha Glucosidase Inhibitors (AGIs)

PPAR

promoter Coding reg

+RXR

Modified from Howard L. Foyt et al. Thiazolidinediones. Diabetes Mellitus: a Fundamental and Clinical Text, 2 nd Ed.

PPRE

receptor

Insulin

Resistensi InsulinGlucose

mRNA

Synthesis GLUT 4

X

X

transcription

promoter Coding reg

transcription

mRNA

Modified from Howard L. Foyt et al. Thiazolidinediones. Diabetes Mellitus: a Fundamental and Clinical Text, 2 nd Ed.

Synthesis GLUT 4

translocation

PPRE

Insulinreceptor

Insulin Glucose

Pioglitazone reduced Insulin resistance

Pio

PPAR+RXR

Comparison of therapies for T2DM when used as monotherapy (Nathan 2003)

Diet Sulfonylurea

Biguanide

Glucosidase Inhibitor

Thiazoli -dinedione

Insulin

Metabolic effectsImproves resistanceImproves secretionOvernight HGPPostprandial excursionHbA1cLowers FFAWeight gainHypoglycemiaAllergic phenomena

++++++---

+

++++++++++++++

++++++++++--+

+++++++++--

+++++++++-+

++++++++++++++++++

Other side effectsAnabuse effectHyponatremiaLactic acidosisGastrointestinal 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)

55

Glimepiride improves beta-cell function and increases insulin synthesis and release.

Glimepiride reduces HGO through suppression of glucagon from alpha cells.

Metformin decreases HGO by targeting the liver to decrease

gluconeogenesis and glycogenolysis.

Metformin has insulin- sensitizing properties.Beta-Cell

Dysfunction

Hepatic Glucose Overproduction

(HGO)

The Combination of Glimepiride and MetforminThe Combination of Glimepiride and Metformin

Insulin Resistance

53

Presentation Point of View

1. Pendahuluan : Latar belakang2. Anatomi, histologi, fisiologi, Biokimia, Biomolekuler 3. Definisi, Klasifikasi4. Patofisiologi4. Gejala, Diagnosis5. Penatalaksanaan

6.Komplikasi

KOMPLIKASI DIABETES MELLITUS

• Akut :

- Hipoglikemia - Koma Asidosis Dia- betika - Hiperosmoler Non Ketotik - Koma Laktat Asi- dosis

• Kronik :

- Mikroangiopati : - Nefropati D M - Retinopati DM - Kardiomiopati DM - Neuropati DM - Makroangiopati : - PJK + hipertensi - CVA - Ulkus/ ganggren - Neuropati DM - Rentan Infeksi : - TB Pulmo, dll.

Overview

KOMPLIKASI AKUT DM

LIFE THREATENING METABOLIC DISORDERS(KEGAWATAN)

HIPERGLIKEMI HIPOGLIKEMI

KETOASIDOSIS LAKTOASIDOSIS HIPEROSMOLER

• Kontraktilitas miokard • Cardiac output • Tensi • Perfusi ke organ2 • Respons vaskuler thd katekolamin • Syok hipovolemi

• Syok hipovolemi• Trombo-emboli

• Edema cerebri• Kerusakan SSP

• Infeksi akut

• Penghentian Insulin / dosis kurang

• New onset DM

• Gangguan metabolisme KH, L, P

• Gangguan keseimbangan cairan, elekt, asam-basa

• Hiperglikemi berat• Ketonemi• Asidosis metab• Dehidrasi s/d syok• nafas kussmaul• kesadaran s/d koma

30% kasus dapat tampilDalam kondisi hiperosmoler

KETOASIDOSIS

Poliuri, PolidipsiPoliuri, Polidipsi Nausea, VomitusNausea, Vomitus Kulit & Mukosa keringKulit & Mukosa kering Nafas kuszmaulNafas kuszmaul Dehidrasi Dehidrasi syok syok Lemah, Depresi, KejangLemah, Depresi, Kejang Kesadaran Kesadaran koma koma

Diagnosis laborat Hiperglikemi berat Glukosuri berat Ketonuri berat pH darah PO O2 Tekanan osmose plasma

0.3 – 0.4 unit/KgBB50% i.v

50% s.c

• Continous infusion

Banyak diminati efek terapi cepat komplikasi minimal

• Hipoglikemi• Hipokalemi

• 0.1 u/kgBB/jam — me insulin plasma — memenuhi (100 – 200 µ u/mL) kapasitas maksimal

reseptor insulin

LANSIA

½ dosis dari pro

gram

KALIUM

BIKARBONAT

ANTIBIOTIKA

• Indikasi K+ < 5.5 mEq/L

• KCL ( 2/3 )• Preparat

• KPO4 ( 1/3 )

• Indikasi • pH < 7,1 (darah arteri) • HCO3 < 5.0 mEq/L • K+ > 6.5 mEq/L • Hipotensi respon ( - ) thd pemb. cairan • Payah jantung kiri • Depresi pernafasan

• Indikasi infeksi akut

Data Laboratorium klinik

LABORATORIUM KAD HONK

Glukosa plasma (mg/dl) > 250 > 600

pH < 7.3 > 7.3

HCO3 serum (mEq/L) < 15 > 20

Keton urine 3+ 1+

Keton serum (+) pengenceran 1:2 (-) pada pengenceran 1:2

Osmolalitas serum (mOsm/Kg) Bervariasi 330

Natrium serum (mEq/L) 130 – 140 145 – 155

Kalium serum (mEq/L) 5 – 6 4 – 5

BUN (mg/dl) 18 - 25 20 - 40

Panduan klinik praktis untuk membedakan KAD & HONKDengan pengertian sekitar 30% penderita KAD dapatTampil dalam kondisi HONK

LAKTOASIDOSIS

Hipoksia jaringan

Hipovolemia

Disfungsi miokard

Syok sepsis

Gangguan fungsi hepar

laktic hepatic clearance

Biguanid

laktat

DM lansia

PERBEDAAN DENGANKETOASIDOSIS & HIPEROSMOLER

Koma Koma HipoglikemiHipoglikemi

Insulin

Koma

Diet OHO , Nephropathy

lapar Berdebar

Lemah Pusing

Gemetar Gelisah

Keringat dingin Kesadaran

Reaksi tubuh yang normal akibat keadaan hipoglikemi :

Aktivasi saraf otonom :Berdebar, lapar, gemetar, keringat dingin, nausea

Neuro-glycopenia :Mengantuk, perilaku aneh, sukar konsentrasi

inkoordinasi, sulit bicara.

Akibat berat : hemiparesis, konvulsi, chore-atetosis

ataxia, dekortikasi.

Otak dalam keadaan normal : butuh 50% produksi glukosa basal

( 1 mg/kg/menit )

KOMPLIKASI DIABETES MELLITUS

• Kronik :

- Mikroangiopati : - Nefropati D M - Retinopati DM - Kardiomiopati DM - Neuropati DM - Makroangiopati : - PJK + hipertensi - CVA - Ulkus/ ganggren - Neuropati DM - Rentan Infeksi : - TB Pulmo, dll.

Overview

SlametS

Hyperglycemia

Glucose auto oxidationGlucose auto oxidation Sorbitol pathwaySorbitol pathwayAGE formationAGE formation

Oxidative Sress Oxidative Sress Antioxidants Antioxidants

Lipid peroxidation Leukocyte adhesion Foam cell formation

TNF a

Lipid peroxidation Leukocyte adhesion Foam cell formation

TNF a

Endothelial dysfunction NO Endothelin

Prostacyclin TXA2

Endothelial dysfunction NO Endothelin

Prostacyclin TXA2

HypercoagulabilityFibrinolysis

Coagulability Platelet reactivity

HypercoagulabilityFibrinolysis

Coagulability Platelet reactivity

Vascular complicationsVascular complications

RetinopathyRetinopathy NephropathyNephropathy NeuropathyNeuropathy

Vascular ComplicationsVascular Complications

MicroangiopathyMicroangiopathy

C V DS N HP A D

C V DS N HP A D

NephropathyRetinopathy

Neuropathy

NephropathyRetinopathy

Neuropathy

DiabetesDiabetes

MacroangiopathyMacroangiopathy

EAGLE FLIES ALONE, MHT

PPGPPGFPGFPG

69Adapted from Type 2 Diabetes BASICS. Minneapolis, Minn: International Diabetes Center; 2000.

Years -10 -5 0 5 10 15 20 25

350300250200150100

50

Insulinlevel

Insulin resistance

-cell failure

250

200

150

100

50

0

Rel

ativ

e -

cell

func

tion

(%)

Fastingglucose

Post-mealglucose

Glu

cose

(m

g/dl

) DIAGNOSIS

Clinicalfeatures

Obesity IGT Diabetes Uncontrolled hyperglycaemia

Prediabetes Type 2 diabetes

Macrovascular complicationsMicrovascular complications

Saat terdiagnosis Diabetes Mellituskomplikasi telah terjadi

When Macrovascular & Microvascular Complication in T2DM?

MORBIDITAS&

MORTALITAS

• Kebutaan 30% DM (Retinopati)

• Komplikasi P. Darah perifer

40 x non-DM

Amputasi tungkai 10% DM

• Kematian 2-5 x non-DM

• Penyakit Jantung

• Gagal Ginjal Kronik

• Penyakit Serebro Vaskular

• Life Expectacy (5 - 10 th)

Hipertensi pada diabetes

• 2/3 penderita diabetes menderita hipertensi

• Diabetes + hipertensi meningkatkan risiko:

risiko penyakit jantung, stroke, gangguan mata dan gangguan ginjal

              

             

72

Reaching glucose goals is important to reduce complications

1Gray RP & Yudkin JS. Cardiovascular disease in diabetes mellitus. In Textbook of Diabetes 2nd Edition, 1997. Blackwell Sciences.

2Kannel WB, et al. Am Heart J 1990; 120:672–676.

Overall, 75% of people with type 2 diabetes will die

from cardiovascular disease1,2

DasarDasarCardioprotectiveCardioprotective

GlucoseAGEs

Glycolysis Autoxidation Glycation SorbitolPathway

Generation of reactive oxygen species

ROS

Ca signalling Protein kinase C NFkB

Reactive intermediatesMitochondrial resp. chain GSH reduction

Reactive intermediates

RAGE

Vascular disease

NAD(P)HOxidase

?

Pro-oxidant effects of glucoseleading to increased CV risks

MortalitasKardiovaskuler

Disfungsi

endotel

Aterogenesis

Glukosa

Post Prandial

Hiperglikemi

Hipertrigliseridemi

Korelasi

PJK

Mikroangiopati

Penebalan MB BasalisP. Darah Kapiler

Perubahan Viskositas darah

& fungsi trombosit

GangguanHemodinamic

ProduksiProstasiklin

ProduksiAktivatorFibrinolisis

ProduksiThromboxane A2

• Viskositas• Mikrotrombus• Penyempitan vaskuler

Perjalanan nefropati diabetik

Awal DM

Makroalbuminuri/ gross protein Kreatinin

ESRD

• GFR • Albuminuria reversible• Ginjal membesar• Hyperfiltration

• Penebalan membrana basalis • Ekspansi mesangium• Hyperperfusion

• Hiperfiltrasi • Mikroalbuminuria • Hipertensi

0 2 5 Waktu (tahun) 15 20 25

ACE Inhibitor

GFR ml/mnt 150

Serum creat mg/dl 0,8

120

1

60

> 2,0

< 10

> 5

Perubahan fungsi

Incipiens Nephropathy

Perubahan struktur Overt nephropathy

P e n y a k i t P a l i n g M a h a l

ERECTILE DYSFUNCTION

Kita lahir & besar bersama.Tapi mengapa kamu matiduluan ?

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

Disfungsi Makrofag

Penurunan kemampuan Intracelluler Killing PMN, MN

Perlekatan

Intracellular Killing

Eksositosis

Fagositosis

Kemotaksis

H2O2, spesies oksigen aktif

Be a Good Doctor’s with Active Learning and Share Knowledge Each OtherThink Globally but Act Locally (WHO Statement)