DIABETES MELLITUSEpidemiologi dan Permasalahannya

Dr. SUHAEMI, SpPD, FINASIM

Diabetes Mellitus

Suatu Sindroma kelainan metabolik, ditandai adanya hiperglikemia, akibat

defek sekresi insulin, defek kerja insulin, atau kombinasi keduanya.

Definition, Diagnosis and Classification of Diabetes Mellitus and its Complications. Department of Noncommunicable Disease Surveillance, World Health Organization, Geneva 1999.

Definition of Type 2 Diabetes

Type 2 diabetes is characterised by:

• chronic hyperglycaemia with disturbances of carbohydrate, fat and protein metabolism

• defects in insulin secretion (-cell dysfunction) and insulin action (insulin resistance)

Diabetes care 2004

Diabetes Care 2004 27:1047-53

¡Viva la Vida con Salud!

Diabetes in the World

millions

India

31.731.7

China

20.820.8

USA

17.717.7

Indonesia

8.48.4

Japan

6.86.8

YearYear20002000

Reference: Wild S, Roglic G, Green A, Sicree R, King H. Global prevalence of diabetes. Diabetes Care. 2004; 27(5): 1047-1053.

¡Viva la Vida con Salud!

Diabetes in the World

millions

India

79.479.4

China

42.342.3

USA

30.330.3

Indonesia

21.321.3

Japan

8.98.9

YearYear20102010

Reference: Wild S, Roglic G, Green A, Sicree R, King H. Global prevalence of diabetes. Diabetes Care. 2004; 27(5): 1047-1053.

Fast Food and Obesity

• 200% fast-food visits 1977-1995• 30% of US children (4-19 yrs) consume fast

food daily

Fast Food and Obesity

• Fast-foods fat and energy – Big Mac + medium fries = 83% daily fat intake

• Adversely affects dietary quality• Less fiber, fruits, vegetables and milk• Mega-meals

Mega – Meals

Super Size

• Each 12 oz soda has 10 tsp sugar (150 cal)

• One can of soda/day child’s risk obesity 60%

• Most popular Canadian drink– > 110 L/ person/yr

• 1942-1998: – US production increased 9X

Diabetes Today: An Epidemic

Relative risks associated with obesityGreatly increased (>3) Moderately increased (2-3) Slightly increased (1-2)

DM tipe 2 CHD CANCER breast cancer (in post menopausal women), endometrial, colon

Gallbladder disease HypertensionHypertension Reproductive hormone abnormalities

Dyslipidaemia OsteoarthritisOsteoarthritis Polycystic ovary syndrome

Insulin Resistance

Breathlessness

Sleep apnoea

Hyperuricaemia and Hyperuricaemia and goutgout

Table 4.1 WHO TRS 894 Obesity: Preventing and Managing the Global Epidemic

Impaired fertility

Low back painAnaesthesia complicationsFetal defects in maternal obesity

ChylomicronRemnants

VLDL

IDL

LDL

HDL2

HDL3

Lp(a)Endothelial cellsEndothelial cells

Inflammation

Macrophage

Calcium

Intimal thickening

Lp-pla2Lp-pla2

Endothelial function

Traffic patterns in the blood

Glucose

TriglyceridesLDL Receptor

Liver

ProteinsHomocysteineHs-CRPApo-AApo-B

Hb A1C

Resistensi Insulin

DiabetesDiabetesTipe 2Tipe 2

DeFronzo et al. Diabetes Care 1992;15:318-68DeFronzo et al. Diabetes Care 1992;15:318-68

Diabetes MelitusDiabetes Melitus

Definisi :Definisi :

- gangguan metabolisme gangguan metabolisme

- kenaikan kadar glukosa darah kroniskenaikan kadar glukosa darah kronis

- disebabkan oleh adanya gangguan produksi insulin akibat disebabkan oleh adanya gangguan produksi insulin akibat kerusakan kerusakan

sel beta pankreas dan atau kerja insulin.sel beta pankreas dan atau kerja insulin.

Kerusakan selKerusakan selBeta pankreasBeta pankreas

Evolusi diabetes

NormalFase

KompensasiDiabetes

DeFronzo R.A. et al., Diabetes Care (1998)

Resistensi Insulin & Defisiensi Insulin:

2 mekanisme yang saling berhubungan

Pada saat diagnosis ditegakkan, sudah ada defek pada kedua-nya

ResistensiInsulin

ResistensiInsulin

Glukosa darah Puasa

SekresiInsulin

SekresiInsulin

History of DM

Diabetes Greek for “passing water like a siphon”

Mellitus Latin for “sweetened with honey”

“Ebers Papyrus” (Egyptian, 1500 B.C.)first depiction of diabetes mellitus - urination of excess amounts - manipulation of diet therapy

• Sudah dikenal sejak zaman Ebers Papyrus 1550 SM• Willis : mencatat ada rasa manis pada urine• IBNU SINA : Gangren Diabetic• Matthew Dobson : Rasa manis karena gula• 1815 : Chevreul (ahli Kimia) membuktikan bahwa gula

dalam urine adalah glukosa• 1921 : Frederic Grant Banting, Charles Best berhasil

mengekstraksi insulin pertama kali dari pankreas anjing• 11 Jan 1922 : Leonardo Thompson, remaja merupakan

pasien pertama yang mendapat insulin di RS Toronto Kanada

• 1979 : Goedde menghasilkan human insulin dengan rekayasa genetik

Faktor Resiko untuk Terjadinya DM

• Kelompok Usia > 45 tahun• Gemuk : BB > 120% BBI (IMT > 27 kg/m2)• Hypertensi• Riwayat Keluarga DM• Riwayat melahirkan bayi > 4 kg.• Riwayat DM pada waktu hamil (DM Gestasi)• Dislipidemia : HDL < 35 mg/dl, Trigliserida > 250

mg/dl• Pernah mengalami gangguan toleransi glukosa

Etiologi

• Herediter, diperlukan faktor lain yang disebut faktor risiko atau faktor pencetus

• Virus– Pada DM tipe 1 dijumpai HLA gen yang rentan terhadap

infeksi virus tertentu.– Virus yang selalu menimbulkan insulitis adalah : Coxackie,

Mumps, Rubella, Cytomegalovirus, Herpes, dll.• Obesitas

– Kadar Insulin cukup tetapi tidak efektif (Resistensi Insulin )• Memakai obat-obatan yang menyebabkan Kadar

Gula Darah meningkat

Not specifiedNot specifiedOthersOthers

TuberculosisTuberculosis

Accident / suicideAccident / suicideGangreneGangrene

Renal insufficiencyRenal insufficiency

Diabetic comaDiabetic coma

InfectionsInfections

TumorsTumorsStrokeStroke

Myocardial Myocardial infarctioninfarction

00 1010 2020 3030 4040

% deaths in diabetics% deaths in diabetics3.43.4

11.411.4

0.90.9

2.12.1

2.72.7

2.92.9

3.13.16.76.7

10102222

34.734.7

Panzram G. Diabetologia 1987; 30: 120-31Panzram G. Diabetologia 1987; 30: 120-31

Causes of Mortality in Diabetic Patients

Pankreas

• Terletak dibelakang lambung• Berat : 200 – 250 gram• Bentuk : Kerucut terbaring• Bagian yang lebar : Kepala (Caput)• Bagian yang kecil : Ekor (Cauda)• Terdapat kumpulan sel disebut pulau-pulau Langerhans yang

berisi sel Beta dan mengeluarkan hormon Insulin.• Disamping sel Beta terdapat sel Alfa yang mengeluarkan

Glukagon yang bekerja berlawanan dengan insulin yaitu meningkatkan kadar gula darah. Juga ada sel Delta yang mengeluarkan Somatostatin

INSULIN

Definisi :Definisi :

Insulin adalah hormon yang Insulin adalah hormon yang dikeluarkan oleh sel beta dikeluarkan oleh sel beta pankreas yang berperanan pankreas yang berperanan dalam mengatur kadar dalam mengatur kadar glukosa darahglukosa darah

Insulin diibaratkan sbg anak Insulin diibaratkan sbg anak kunci yang membuka pintu kunci yang membuka pintu masuknya glukosa ke masuknya glukosa ke dalam sel dalam sel

KERJA FISIOLOGIS INSULIN& PENGLEPASAN INSULIN

Insulin dibentuk dari pro insulin distimulasi dg pe glukosa darah menghasilkan insulin & C-peptide yg akan masuk ke dlm aliran darah & akan me kan kadar glukosa darah

Insulin membantu meningkatkan sintesa protein, meningkatkan penyimpanan lemak, menstimulasi mesuknya glukosa ke dlm sel utk sumber energi dan membantu penyimpanan glikogen dlm lemak dan hati

Insulin : endogen & eksogen

Fasting

K+

Glu t-2

+

-cell

Normal glycemia

Ca2+

Insulin

proinsulin

In the unstimulated b-cell, KATP channels are open and the outward movement of K+ ions holds the membrane potential at a negative level.

-- - -

Resting Resting -cell-cell

Postprandial

ATP

Glucose

G-6-P

GK

PKPyruvate

K+

Insulin

Depolarization

Glu t-2

+++-

--

+ +- - -

+

cell

Glycemia

Krebs cycle

Ca2+

The flux of K+ is regulated by intracellular ATP.

A surge in blood glucose leads to increased production of ATP.

Stimulated Stimulated -cell-cell

InsulinInsulin

Tenaga

Glukosa darah Pintu masuk sel

Insulin

Insulin

Insulin

Glukosa dibakar

pembawa glukosa

NORMAL

Insulin InsulinPintu terbuka

InsulinInsulin

Tenaga

Glukosa darah Pintu masuk sel

Tak ada yang dibakar

Pembawa glukosa

DIABETES

Pintu tertutup

Glukosa darah

F A S E 1 F A S E - 2

F A S E - 1 F A S E - 2

Individu normal

Penderita DM tipe-2

Insulin

plasma

waktu

Insulin

plasma

(Tumpul) (Lebih tinggi dan lama)

(Delayed Insulin secretion)Waktu

3-5 mnt 50-60 menit

60 ng/ml

Insulin secretion

time

Type 2 diabetic

Non-diabetic

IV Glucose stimulus

Loss of the early peak of insulin secretion

Why does the -cell Fail?

Chronic hyperglycemia

Oversecretion of insulin to compensate for insulin resistance1,2

High circulating free fatty acids

Glucotoxicity2

Pancreas

Lipotoxicity3

-celldysfunction

1Boden G & Shulman GI. Eur J Clin Invest 2002; 32:14–23.2Kaiser N, et al. J Pediatr Endocrinol Metab 2003; 16:5–22.

3Finegood DT & Topp B. Diabetes Obes Metab 2001; 3 (Suppl. 1):S20–S27.

100

80

60

40

20

0

Years from Diagnosis

Beta

-Cel

l Fun

ction

(%)

Beta-Cell Function in the UKPDS

-12 -10 -8 -6 -4 -2 0 2 4 6

Diagnosis

KERJA FISIOLOGIK INSULIN• MEMASUKKAN GLUKOSA DARI DALAM DARAH KE:

– Hati: • Glukosa di robah jadi glikogen (Glikogenesis)• Glikogen hati menjadi cadangan gula dalam tubuh

– Otot: • Glukosa di robah jadi Glikogen (Glikogenesis)• Glikogen otot dibakar menjadi sumber kalori.

– Adiposa: • Glucosa dirobah (?) jadi trigliserida• Mencegah pemecahan lemak (Antilipolisis)

– Mengaktifkan Lipoprotein Lipase di sel sel endotel P.darah – Jaringan lain: Meningkatkan sintesa protein dari A.Amino

• INSULIN MENURUNKAN KADAR GLUKOSA DARAH

SlametS 37

100

75

50

25

0

100

75

50

25

0

UKPDS :Natural Deterioration of -Cell FunctionUKPDS :Natural Deterioration of -Cell Function

Years from DiagnosisYears from DiagnosisLebovitz H. Diabetes Review 1999;7:139-53

Be

ta C

ell

Fun

ctio

n (%

)B

eta

Ce

ll F

unct

ion

(%)

-12 –10 -6 -2 0 2 6 10 14 -12 –10 -6 -2 0 2 6 10 14

Th/Expectation

Facts

ResistensiInsulin

DiabetesTipe-2

Disfungsi Sel Beta

InsulinInsulinResistanceResistance

Hyperglycaemia

Hyperglycaemia

InsulinInsulinConcentrationConcentration

Insulin Action

Insulin Action

EuglycaemiaEuglycaemia

-cell Failure-cell Failure

NormalNormal IGT IGT ± Obesity± Obesity Diagnosis Diagnosis oofftype 2 diabetestype 2 diabetes

Progression oProgression offtype 2 diabetestype 2 diabetes

DEFEK GANDA PADA DIABETES TIPE-2PENANGAN SASARAN YANG JELAS

DeFronzo et al. Diabetes Care 1992;15:318-68DeFronzo et al. Diabetes Care 1992;15:318-68

Insulin release in vitro in response to glucose stimulation

1st phase

2nd phase

0 5 100

minutes

Basal

Normal

Type 2 DM

Insulin Release: Normal & Type 2 DM

Polonsky et al., 1988b

Insulin Secretion Profiles in Type 2 Diabetic Patients and Healthy Persons

Type 2 diabetesHealthy

Insu

lin s

ecre

t ion

(pm

o l/m

in)

100

200

300

400

500

600

700

800

Time6 a.m. 10 a.m. 2 p.m. 6 p.m. 6 a.m.10 p.m. 2 a.m.

SlametS 41

Hyperglycemia

Glucose autoxidationGlucose autoxidation Sorbitol pathwayrSorbitol pathwayrAGE formationAGE formation

Oxidative Sress Oxidative Sress Antoxidants Antoxidants

Lipid peroxidation Leukocyte adhesion Foam cell formation

TNF

Lipid peroxidation Leukocyte adhesion Foam cell formation

TNF

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

Stehouwer CDA et al. 2004

Effect of Hyperglycemia

Effect of Hyperglycemia

Oxidative stressOxidative stress

Sorbitol pathwaySorbitol pathway

DAG-PKCpathwayDAG-PKCpathway

Hexosaminepathway

Hexosaminepathway

AGEpathway

AGEpathway

Increase of :• Extracellular

matrix• Collagen• Fibronectin

Increase of :• Extracellular

matrix• Collagen• Fibronectin

Increase of pro- coagulant proteins

• von Willebrandt factor • tissue factor

Increase of pro- coagulant proteins

• von Willebrandt factor • tissue factor

Decrease of proliferation, migration, and fibrinolytic potential

Decrease of proliferation, migration, and fibrinolytic potential

Increase of apoptosisIncrease of apoptosis

Vascular complicationsVascular complications

RESISTENSI INSULIN INSULIN DALAM JUMLAH YANG NOR MAL TIDAK DAPAT BEKERJA SECARA OPTIMAL DI JARINGAN SASARAN NYASEPERTI DI OTOT, HATI DAN ADIPOSA.

Sel sel β pancreas mengkompensasi keadaan inidengan meningkatkan produksi insulin dan menyebabkan HIPERINSULINEMIA

Insulin Resistance

Evolution of Type 2 DiabetesWhen do the Complications Begin ?

NGT IGT IFG DM Early Late

Normal Prediabetes Clinical Diabetes

Insulin resistance Insulin resistance Insulin resistance

GlucotoxicityLipotoxicity

• Macrovascular complications : present at different stages in the evolution of DM, often before DM is establish

• Insulin resistance, glucotoxicity and lipotoxicity : arise during prediabetic phase

Birth Death

Hyperglycemia (Type 2 DM)Hyperglycemia (Type 2 DM)

Increase LipolysisDecrease

Lipogenesis

Increase LipolysisDecrease

Lipogenesis

Adipose tissue(Obesity)

Adipose tissue(Obesity)

ElevatedPlasma

FFA

ElevatedPlasma

FFAElevated

TNF-Elevated

TNF-

Insulin secretionInsulin secretion Insulin resistanceInsulin resistance

HyperinsulinemiaHyperinsulinemia

Amyloid deposit

Islet -cell degranulation;Reduced insulin content

Islet -cell degranulation;Reduced insulin content

Reduced plasma insulin

Reduced plasma insulin

Increased hepatic glucose output

Increased hepatic glucose output

+

-

Gluconeogenesis

decreased glucose uptake

decreased glucose uptake

Glucose toxicity

Lipotoxicity

04/22/23 Dr Risa Anwar -Glucophage Page 48

SEBELUM metformin

SESUDAH metformin

insulin

glukosaglucosetransporter

Efek pada RESITENSI INSULIN

Action of Insulin on the CellMetabolism

Glucose Transporters

• GLUT – 1 : Endothelium• GLUT – 2 : Liver, B-cells of Pancreas• GLUT – 3 : Neurons• GLUT – 4 : Muscle, Adipose Tissue• GLUT – 5 : Intestine

promoterCoding 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

PPAR

PPRE

Insulinreceptor

Insulin

RXR

Glucose

Insulin Action

PPAR

promoter Coding reg

+RXR

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

PPRE

Insulin

Insulin ResistanceGlucose

mRNA

Synthesis GLUT 4

X

X

transcription

Insulinreceptor

Translocation

Muscle Cells

4:004:00

2525

5050

8:008:00 12:0012:00 16:0016:00 20:00 20:00 24:0024:00 4:004:00

BreakfastBreakfast LunchLunch DinnerDinner

Plas

ma

insu

lin (

Plas

ma

insu

lin (µ

U/m

l) U

/ml)

TimeTime8:008:00

Physiological Serum Insulin Secretion Profile

InsulinKGD pp

KGD p.

I III IV V

GTGDM

Perjalanan Klinis D.M Tipe-2

II

DiabeticretinopathyLeading causeof blindnessin working-ageadults1

DiabeticnephropathyLeading cause of end-stage renal disease2

Cardiovasculardisease

Stroke1.2- to 1.8-fold increase in stroke3

DiabeticneuropathyLeading cause of non-traumatic lower extremity amputations5

75% diabetic patients die from CV events4

Type 2 Diabetes is NOT a mild disease

1Fong DS, et al. Diabetes Care. 2003; 26 (Suppl. 1): S99–S102. 2Molitch ME, et al. Diabetes Care. 2003; 26 (Suppl. 1): S94–8. 3Kannel WB, et al. Am Heart J. 1990; 120: 672–6. 4Gray RP & Yudkin JS. In Textbook of Diabetes 1997.

5Mayfield JA, et al. Diabetes Care. 2003; 26 (Suppl. 1): S78–S79.

Microvascular Macrovascular

Type 2 Diabetes: A Complex Metabolic Disorder

DyslipidaemiaDyslipidaemia

ImpairedImpairedinsulininsulin

secretionsecretion

MacrovascularMacrovascularcomplicationscomplications

CentralCentralobesityobesity

InsulinInsulinresistanceresistance

MicrovascularMicrovascularcomplicationscomplications

HypertensionHypertension

“INSULINRESISTANCESYNDROME”

Adapted from Beckman JA et al. JAMA. 2002; 287: 2570- 81

InsulinMetforminSulfonylureasThiazolidinediones

AspirinClopidogrel

ACE inhibitorsARBsBeta blockersCalcium-channel blockersDiuretics

StatinsFibratesNicotinic Acid Atherosclerosis

Dyslipidaemia Hypertension

HyperglycemiaInsulin

resistanceObesity

OrlistatSibutramineRimonabant

Anti-atherosclerosis Therapy in T2DM and the Metabolic Syndrome

Platelet activation

and aggregation

liver

pancreas

liver

Regulation of Blood Sugar

blood sugar level(90mg/100ml)

insulin

body cells takeup sugar from blood

liver storessugar

reducesappetite

glucagon

pancreas

liver releasessugar

triggershunger

high

low

FeedbackEndocrine System Control

Glucose regulation

Bila insulin tidak ada sama sekali (DM tipe 1) atau :Insulin tidak cukup atau efisiensi kerjanya rendah (DM tipe 2)

PEMASUKAN GLUKOSA KE HATI, OTOT, ADIPOSA

AKAN TERGANGGUHIPERGLIKEMIA

GLUKOSURIA

GLIKOGENOLISIS &GLUKONEOGENESIS

TIDAK DIHAMBAT

GANGGUAN SINT.PROTEIN LIPOLISIS TAK DIHAMBAT

POLIURI POLIDIPSILEMAS /MUDAH LELAH

BERAT MAKIN MENURUN

Klinis Diabetes Melitus :

Polifagia : sel mengalami starvasi karena cadangan KH,Lemak, Protein berkurang ( tdk ada pengisian depot yg biasanya dilakukan oleh Insulin )

Polidipsia : glukosuria (diuresis osmotik) → dehidrasi intraselular dan stimulasi pusat haus di hipotalamus) kompensasi: penderita banyak minum

Poliuria : glukosuria (diuresis osmotik) → penderita banyak kencing

Penurunan BB : cairan tubuh berkurang karena diuresis osmotik, protein dan lemak berkurang karena dipecah sbg sumber energi.

Lelah : Metabolisme tdk berjalan sebagaimana mestinya.

KLASSIFIKASI DIABETES MELLITUS

1. DM tipe-1 (Autoimun dan Idiopatik)2. DM tipe-2

– Gemuk : Resistensi Insulin > Disfungsi sel ß

– Tak gemuk : Disfungsi sel ß > Resistensi Insulin

3. DM tipe lain : MODY; Peny.Eksokrin pancreas,Cushing S dll

4. DM Gestasi (Kalau hamil DM, tak hamil DM nya sembuh).

Pathogenesis of Type II DMEnvironmentEnvironment

Obesity ???Obesity ???ß cell defectß cell defect

GeneticGenetic

ß cell ß cell

exhaustionexhaustion Type II DMType II DM

Insulin resistanceInsulin resistance

Relative Insulin Def.Relative Insulin Def.

IDDMIDDM

Abnormal SecretionAbnormal Secretion

G

L

U

C

O

S

E

Intestine

Absorbed

Blood Glucose

ß cell pancreasGlucose Insulin

(+)

Glycogen

Non Sugar

(-)

Glucose

Glycogen

(+)

Adipose Tissue

Antilipolysis

Trigliserida

NORMAL /PHYSIOLOGIC CARBOHYDRATE METABOLISM

H A T I O T O T

Insulin

L.P.L+

Asam Lemak

NORMAL /PHYSIOLOGIC CARBOHYDRATE METABOLISM

GLUCOSE

Intestine

Blood Glucose ↑

AbsorbedAdipose TissueAntilipolysisTrigliserida

ß cell pancreas

Non Sugar

Glycogen

Glucose

Glycogen

H A T I O T O T

Insulin

Insulin

Asam LemakLPL

(+)(-)

(+)

Glucose

+

Liver glucose output responds to multiple hormonal signals

Antonio Vidal-Puig & Stephen O'rahilly (2001) Nature 413, 125 – 126.

GEJALA KLASIK DM

• 4 P

• 1. POLI DIPSIA• 2. POLIFAGIA• 3. POLI URIA• 3. PENURUNAN BERAT BADAN

Kriteria Diagnosa DM• Gejala Klasik DM + Kadar Gula Darah Sewaktu > 200

mg/dl • Gejala Klasik DM + Kadar Gula Darah Puasa > 126

mg/dl • Kadar Gula Darah 2 jam TTGO > 200 mg/dl

• Puasa diartikan tidak mendapat kalori tambahan sedikitnya 8 jam TTGO dengan standar WHO, menggunakan beban glukosa yang setara dengan 75 gram glukosa anhidrous yang dilarutkan dalam air

OGTT 1

TEST TOLERANSI GLUKOSA ORAL (T.T.G.O)

1. Makan minum seperti biasa 3 hari sebelum pemeriksaan2. Kegiatan jasmani dilakukan seperti biasa3. Berpuasa 10-12 jam sebelum pemeriksaan4. Pagi diperiksa KGD puasa5. Minum larutan 75 gr glukosa dalam 250cc air (5 menit)6. Pasien menunggu selama 2 jam dan tidak merokok7. Diperiksa KGD 2 jam sesudah minum larutan glukosa

• TGT – KGD puasa normal. KGD 2 jam paska pembebanan – 75 gram glukosa antara 140-200 mg%

• GDPT– KGD Puasa 110-126 mg%,KGD 2 j PG Normal.

GEJALA KLINIS DIABETES MELLITUS TIPE-2

GEJALA KHAS GEJALA TIDAK KHAS Poliuria KesemutanPolidipsia Gatal di daerah genitalPolifagia Keputihan BB turun cepat Infeksi sukar sembuh

Bisul hilang timbul. Penglihatan kabur

Cepat lelahMudah mengantuk

Complications of Diabetes Mellitus

• Chronic Complications of Diabetes Mellitus– Microvascular

• Retinopathy (nonproliferative/proliferative)

• Nephropathy • Neuropathy• Sensory and motor (mono-

and polyneuropathy)• Autonomic

– Macrovascular• Coronary artery disease• Peripheral vascular disease• Cerebrovascular disease

• Acute Complications of Diabetes Mellitus– Hyperglycemia crisis

• Diabetic ketoacidosis• Hyperglycemia

hyperosmolar State • Lactic acidosis

– Hypoglycemia

GAMBARAN KLINIS DM TIPE-1 DAN DM TIPE-2

• GEJALA DM tipe-1 DM tipe-2– Poliuria dan Polidipsia ++ + – Lemas dan mudah lelah ++ +– Kuat makan tapi tambah kurus ++ -– Penglihatan sering berulang kabur + ++– Gatal /radang kemaluan + ++– Neuropati periferal (kebas/kesemutan) + ++– Selalu ngompol malam (Enuresis Noct) ++ -– Sama sekali tanpa gejala - ++

KARAKTERISTIK DM TIPE 1DAN DM TIPE 2

• DM TIPE 1 – Mudah terjadi ketoasidosis– Pengobatan harus dgn insulin– Onsetnya akut– Biasanya kurus /Umur muda– Terkait dgn HLA-DR3 & DR4– ICA; GADA; & IAA selalu (+)– Riwayat keluarga (+) pd 10%– 30-50% kembar identik terkena

• DM TIPE 2– Jarang ketoasidosis (HONK bisa)– Tidak mesti diberi insulin– Onsetlambat (pelan-pelan)– Gemuk atau tak gemuk / > 45 thn– Tak ada kaitan dengan HLA– Tak ada autoantibodi– Riwayat keluarga (+) pada 30% – ± 100% kembar identik terkena

Kriteria Pemantauan Diabetes Mellitus

BAIK LUMAYAN BURUKKGD puasa 80-109 110-139 > 140KGD 2 jam pp 110-159 160-199 > 200HbA1c* 4 - 5.9% 6 – 8% > 8%Kolesterol total* < 200 200-239 > 240Kolest. LDL (PJK-)* < 130 130-159 > 160Kolest.LDL (PJK+)* < 100 100-129 > 130Trigliserida (PJK-)* < 200 200-249 > 250 Trigliserida (PJK+)* < 150 150-199 > 200

* = diperiksa tiap 3 hingga 6 bulan

Glycated Hemoglobin (HbA1c) 1

PADA TIAP KUNJUNGAN HARUS DIPANTAU

• KGD Sewaktu • Tekanan darah (diukur dalam keadaan duduk)

• Indeks Massa Tubuh = BB (kg) / TB (M)2

PEMERIKSAAN BAIK LUMAYAN BURUKTD sistolik (mmHg) < 130 130-150 >150TD diastolik < 80 80-85 >85IMT Pria (Kg/M2) 20-24.9 25- 27 < 20 atau >27 IMT wanita (Kg/M2) 18.5-22.9 23- 25 < 18.5 atau >25

ACUTE COMPLICATION OF DIABETES

• Diabetic ketoacidosis (DKA)

• Hyperosmolar nonketotic (HONK)

• Hypoglycemia

Hyperglycemia

• Drowsy• Flushed• Thirsty

Diabetic Emergencies Accordingto Blood Glucose Level

Signs of Diabetic Coma• Kussmaul respirations• Dehydration• “Fruity” breath odor• Rapid, weak pulse• Normal or slightly low blood pressure• Varying degrees of unresponsiveness

Hypoglycemia

• Weak, sweaty• Confused/irritable/

disoriented

HypoglycemiaSymptoms of hypoglycemiaSymptoms of hypoglycemia

Neurogenic (autonomic)Neurogenic (autonomic) NeuroglycopeniaNeuroglycopenia

TremblingTrembling

PalpitationsPalpitations

SweatingSweating

AnxietyAnxiety

HungerHunger

NauseaNausea

TinglingTingling

Difficulty concentratingDifficulty concentrating

ConfusionConfusion

WeaknessWeakness

DrowsinessDrowsiness

Vision changesVision changes

Difficulty speakingDifficulty speaking

HeadacheHeadache

DizzinessDizziness

tirednesstiredness

Drugs associated with Hypoglycemia

• ACE inhibitors• Alcohol• Antimalarials• Beta-blockers (non-cardioselective)• Disopyramide• Fluoroquinolones (e.g. gatifloxacin)• Quinidine• Salicylates (high doses only)

Baseline Vital Signs

• Hypoglycemia– Respirations = normal to rapid– Pulse = normal to rapid– Skin = pale and clammy– Blood pressure = low

• Hyperglycemia– Respirations = deep and rapid– Pulse = normal to fast– Skin = warm and dry– Blood pressure = normal

Tujuan Pengelolaan Diabetes Mellitus

• Menghilangkan gejala• Mempertahankan rasa sehat• Memperbaiki kualitas hidup• Mencegah komplikasi (akut dan kronis)• Mengurangi laju komplikasi yang sudah ada• Menurunkan jumlah kematian

Edukasi

Tujuan:

Pencegahan Primer Pencegahan Sekunder

Pencegahan Tertier

Diabetes Mellitus

• Complications of chronic hyperglycemia– Macrovascular complications

• Cardiovascular disease (heart attack)• Cerebrovascular disease (strokes)

– Microvascular• Blindness (retinal proliferation, macular degeneration)• Amputations• Diabetic neuropathy (diffuse, generalized, or focal)• Erectile dysfunction

Microvascular Complications

Hyperglycemia

Pericyteloss

Hyperperfusion Capillary/Endothelial

damage

Loss ofautoregulation

Capillaryocclusion

Vasoactivefactors Loss of tight

junction

Retinal ischemia

New vessels -Low resistance

- No pericyte/autoregulation

Growth factors

Macularoedema

Pathophysiology of diabetic retinopathy

94

Diabetic retinopathy

Two types of diabetic retinopathy:

• Nonproliferative diabetic retinopathy (NPDR)– Early stage diabetic retinopathy

• Proliferative diabetic retinopathy (PDR)– Later stage diabetic retinopathy

Treatment – Eye Disease

• Cataract removal• Laser surgery for

retinopathy

96

Nonproliferative diabetic retinopathy (NPDR)

• Also called background diabetic retinopathy.

• Earliest stage of diabetic retinopathy.

• Damaged blood vessels in the retina leak extra fluid and small amounts of blood into the eye.

• Cholesterol or other fat deposits from blood, called hard exudates, may leak into retina.

Top: Healthy retina

Bottom: Retina with NPDR, containing hard exudates

Diabetic nephropathy

Pathophysiology of diabetic nephropathyHyperglycemia

Renal vasodilatation Increased

intraglomerular capillary pressure

Protein glycation

Increased glomular filtration rate

Hypertension

Increased protein excretion

Microalbuminuria or macroalbuminuria

Nephropathy

Glomurular damage

Treatment - Nephropathy

• ACE inhibitors• MNT – protein

restriction

Diabetic neuropathy

Mechanism of nerve damage in diabetes

METABOLIC VASCULAR

glucose

sorbitol

H2O

nerve oedema

myoinositol

NOproduction

AGEformation

vasoconstriction

Arterial narrowing

Vesselocclusion

Slow nerveconduction

Impairingaxonal transport

Altered membrane potensial

Burning, feeling like the feet are on fire Freezing, like the feet are on ice, although they feel warm to touch

Stabbing, like sharp knives Lancinating, like electric shocks

Autonomic Neuropathy

Case 4

“How do you know if the ulcer is infected then?” Assessing foot ulcers for the presence of infection is vital. All open wounds are likely to get colonised with microorganisms, such as Staphylococcus aureus, and not necessarily infected. Therefore, the presence of infection needs to be defined clinically rather than microbiologically.

An infected ulcer

Signs suggesting infection include;

1. purulent secretions

2. presence of friable tissue

3. undermined edges4. foul odour

Page 105 of 67

Assessment Infected Ulcers

Autonomic Neuropathy• DM-related autonomic neuropathy can involve multiple

systems, including the cardiovascular, gastrointestinal, genitourinary, sudomotor, and metabolic systems.

• Autonomic neuropathies affecting the cardiovascular system cause a resting tachycardia and orthostatic hypotension.

• Gastroparesis and bladderemptying abnormalities are often caused by the autonomic neuropathy seen in DM (discussed below).

• Hyperhidrosis of the upper extremities and anhidrosis of the lower extremities result from sympathetic nervous system dysfunction.

• Anhidrosis of the feet can promote dry skin with cracking, which increases the risk of foot ulcers.

• Autonomic neuropathy may reduce counterregulatory hormone release, leading to an inability to sense hypoglycemia appropriately ((hypoglycemia unawareness)

Macrovascular complications

Atherothrombosis Has Multiple Manifestations

Adapted from: Drouet L. Cerebrovasc Dis 2002;13(suppl 1):1–6

Transient ischemic attack

Angina:• Stable• Unstable

Ischemic stroke

Myocardial infarction

Peripheral arterial disease:• Intermittent claudication• Rest pain• Gangrene• Necrosis

Diabetes and Macrovascular Disease

Libby and Plutsky. Circulation. 2002.

100 100

7575

5050

2525

0 0

-12 -10 -6 -2 0 2 6 10 14-12 -10 -6 -2 0 2 6 10 14

Fungsi selFungsi selBeta (%)Beta (%)

Tahun Sejak DiagnosisTahun Sejak Diagnosis

TGTHiperglikemiPostprandial Fase I

DM tipe 2Fase II

DM tipe 2

Fase IIIFase IIIDM tipe 2DM tipe 2

Hubungan kegagalan terapi dg Stadium pada DM Tipe 2 dan Fungsi Sel Beta Pankreas

Matching Pharmacology to Pathophysiology

Hyperglycemia

Biguanides(TZD)

TZD(Biguanides)

Alpha-glucosidaseinhibitors

SulfonylureasMeglitinidesNateglinide

Glucose influx

↓ Peripheralglucose uptake

↓ Insulinsecretion

Hepaticglucoseoutput

Sejarah Insulin• 1921 Insulin ditemukan

oleh Banting dan Best

• 1922 Leonard Thompson adalah pasien pertama yang mendapat suntikan insulin

• 1923 Novo Nordisk mulai produksi Insulin Hewan (Sapi dan Babi)

• 1973 Insulin Hewan Monokomponen

• 1987 Insulin Human• 1990 Insulin Analog

INDIKASI PENGGUNAAN INSULIN

1.1. DM tipe 1DM tipe 1

2.2. Penurunan berat badan yg cepatPenurunan berat badan yg cepat

3.3. Hiperglikemia yg berat disertai dg ketosisHiperglikemia yg berat disertai dg ketosis

4.4. Ketoasidosis diabetikKetoasidosis diabetik

5.5. Hiperglikemia hiperosmolar non ketotikHiperglikemia hiperosmolar non ketotik

6.6. Hiperglikemia dg asidosis laktatHiperglikemia dg asidosis laktat

7.7. Gagal dg kombinasi OHO dosis hampir maxGagal dg kombinasi OHO dosis hampir max

8.8. Stress beratStress berat

9.9. Kehamilan dg DM atau DM GestasionalKehamilan dg DM atau DM Gestasional

10.10. Gangguan fs. ginjal atau hati yg beratGangguan fs. ginjal atau hati yg berat

11.11. Kontraindikasi dan atau alergi thp OHOKontraindikasi dan atau alergi thp OHO

KEGUNAAN METABOLIK TERAPI INSULIN

• Menurunkan kadar GD puasa & pp• Supresi produksi glukosa oleh hati• Stimulasi utilisasi glukosa perifer oksidasi gluk / penyimpanan di otot• Perbaiki komposisi lipoprotein abnormal• Mengurangi glucose toxicity• Perbaiki kemampuan sekresi endogen• Mengurangi glycosilated end products

KAPAN INSULIN DIPERLUKAN?

Data UKPDS :Data UKPDS : 50% DMT2 perlu insulin setelah 6 50% DMT2 perlu insulin setelah 6

tahuntahun Fungsi B-cell yg rendah pd saat Fungsi B-cell yg rendah pd saat

diagnosis diagnosis risiko kegagalan OHO risiko kegagalan OHO lebih tinggilebih tinggi

Marre M. Int J Obesity (2002) ; 26 (Suppl 3) : S25-S30Marre M. Int J Obesity (2002) ; 26 (Suppl 3) : S25-S30

Modern "Aggressive" Rx of Type 2 DM from Time of Diagnosis

• HbA1c > 10 % – or

• FPG >260 mg/dl– or

• Symptomatic– or

• Ketotic

IMMEDIATE INSULIN

Modern "Aggressive" Rx 4

• HbA1c not < 7% by 6 months Start

Insulin

DM Treatment Steps (OLD THEORY)

1

2

3

4

5

Combination oforal medicines

Oral plus insulin

Insulin

One oral medicine

Diet &exercise

+

++

A chainA chainGly IIe Val Gl

uGln

Cys Cys Thr

Ser

Ile Cys Ser

Leu Tyr Glu

Leu Glu

Asn Tyr Cys Asn

11 55 1100

1155

2211

SS SS

11 55 1010 1515 2020

2525

3300

B chainB chain SS

SS SS

SS

Phe

Val Asn Gln His LeuCys Gly Ser His Leu

Val Glu Ala Leu Tyr

Leu

Val

Cys Gly Glu Arg GlyPhe

PheTyrThr

LysPro

The

Phe

HUMAN INSULIN HUMAN INSULIN

Human insulinA chain 21 amino acidsB chain 30 amino acids

JENIS INSULIN• Natural (animal) insulin : ekstraksi dari

pankreas hewan• Semisynthetic human insulin : insulin dari

hewan yg dimodifikasi secara enzimatik• Biosynthetic human insulin : dibuat

dengan DNA rekombinan menggunakan ragi atau bakteri

• Insulin analog : biosynthetic human insulin yg direkayasa dgn mempertukarkan posisi asam amino atau menambahkan satu atau lebih asam amino/asam lemak pada rantai molekul insulin

Tipe insulin berdasarkan puncak dan jangka waktu kerjanya :

1. Insulin kerja sangat cepat : NovoRapid, Humalog, Apidra

2. Insulin kerja pendek : Actrapid , Humulin R 3. Insulin kerja sedang : Insulatard, Humulin N

4. Insulin campur : Mixtard, Humulin 30/70, NovoMix 30, Humalog 25

5. Insulin kerja panjang : Levemir, Lantus

Adanya anggapan :Adanya anggapan : Sekali dimulai, tidak pernah bisa berhenti Sekali dimulai, tidak pernah bisa berhenti Akan membatasi aktivitas sehari-hariAkan membatasi aktivitas sehari-hari Memulai terapi Insulin berarti: Memulai terapi Insulin berarti:

Saya telah gagalSaya telah gagalDM-nya sudah menjadi serius DM-nya sudah menjadi serius

Suntikan insulin akan sangat sakit/nyeriSuntikan insulin akan sangat sakit/nyeri Suntikan insulin menyebabkan kebutaanSuntikan insulin menyebabkan kebutaan Frank’s storyFrank’s story: “Jika anda tidak bekerja keras, : “Jika anda tidak bekerja keras,

anda akan saya suntik insulin lho” anda akan saya suntik insulin lho”

Kendala Terapi InsulinKendala Terapi Insulin

Prinsip Terapi

• Insulin Basal menurunkan gula darah puasa

• Insulin Bolus menurunkan gula darah post prandial (setelah makan)

• Insulin Premixed menurunkan GD puasa dan GD 2 jam PP

Macam-macam Rejimen Insulin

• Basal Bolus 4 suntikan per hari (3 bolus dan 1 basal)

• Satu kali suntikan insulin basal pada malam hari ditambah dengan obat oral

• Premixed Insulin, sekali sampai 3 kali sehari, sebelum makan.

• Premixed dikombinasi dengan short acting

4 Suntikan per Hari 3 Short + 1 Intermediate/Long Acting

(Basal Bolus)

6 7 8 9 10 11 12 1 2 3 4 5 6 7 8 9 10 11 12 1 2 3 4 5

Breakfast Lunch Evening Meal Sleep

time

Insu

lin

in b

lood

Dua kali Suntikan Premixed Insulin Per Hari

6 7 8 9 10 11 12 1 2 3 4 5 6 7 8 9 10 11 12 1 2 3 4 5

Breakfast Lunch Evening Meal Sleep

Insu

lin

in b

lood

time

45 -60 31 -45

61 -75 16 -30

75 -90 1 -15

Tempat Penyuntikan Insulin Subkutan : Searah Jarum Jam

Efek Samping Insulin

• Hipoglikemia (kadar glukosa darah terlalu rendah)

• Peningkatan berat badan• Reaksi Alergi (kemerahan, gatal-gatal di tempat

penyuntikkan)• Lipodistrofi

Diabetes Diabetes

dan Peran dan Peran InsulinInsulin Dalam Penanganannya Dalam Penanganannya

Dr. SUHAEMI, SpPD, FINASIM

Leonard Thompson

1922 – 1923

Meninggal tahun 1935

Perkembangan Terakhir Injeksi Insulin

Trans-dermal insulin delivery

Oral insulin delivery

Buccal insulin deliveryPulmonary insulin delivery

Non-Injectable InsulinNon-Injectable Insulin

Insulin Delivery Devices 3

Inhaled Insulin

• Exubera

Inhaled Insulin

1-1-08

voluntary discontinuation

4-6-08

Cancer Warning

Other Injectable Drugs 1

• Exenatide (Byetta)– insulin secretagogue– peptide– gila monster saliva– use with other drugs– no hypoglycemia– bid

Other Injectable Drugs 1

• Pramlintide (Symlin)– analogue of hormone

amylin– polypetide– slows gastric emptying– induces satiety– opposes glucagon

reduces posprandial BG

– give with mealsused with insulin

Glycated Hemoglobin (HbA1c) 2

SMBG

• Value in Type 2 DM not established

• Useful for titrating insulin