F A T

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OBESITASDISLIPIDEMI

SINDROMA METABOLIKDr. M a h a t m a SpPD

SMF Penyakit Dalam F.K. UMS

SURAKARTA

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INTRODUCTION

• OBESITY NOT A NEW FENOMENA

– THE VENOUS OF WILLENDORF (25OOO YEARS AGO)

• PREVALENCE OF OBESITY INCREASE

– Di Amerika 20%(1991)40%(2001) (CARO 2002)

– Di koja, Jkt 4,2%(1982) 10,9%(1992)48,6%(2001)(SOEGONDO 2003)

– Di Sembiran 19,8%(2002), Sangsit 21,1%(2003), Denpasar

56,1%(2003)(obesitas sentral) (ARYANA 2002;SUASTIKA 2003)

• CENTRAL OBESITYHYPERTENSION, DM, DYSLIPIDEMIA,

HYPERINSULINEMIA, SOME RISK FACTORS CHD (METABOLIC

SYNDROME)

– DYSMETABOLIC CARDIOVASKULAR SYNDROM (McFarlane 2001)

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Digestion and metabolism of dietary fat

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Diagrammatic representation of lipoprotein metabolism. (Oberman, 1992)

DietaryFat

INTESTINES

Bile Acids

+Cholesterol

LPL

2

1

LIVER

EndogenousCholesterol

LDLApo, B-100

7

11

10

EXTRAHEPATICTISSUES

NASCENT HDL

HDL3

LCAT HTGL

CETP

HDL2

LDLApo E, B-100

LPL

6

VLDLApo E, C-II,

B-100

EndogenousPathway

REMNANTSApo E, B-48

CHYLOMICRONSApo E, C-II, B-48

ExogenousPathway

3

4

8 9

5

Lipemia is normal , however dysl ip idemia is abnormal . We need lipid for

normal body metabolism . There are several kinds of lipids. Lipids are

hydrophobic therefore its must be tranferred in a hydrophilic form as

l ipoprote in

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Triglyceride-rich lipoproteins:

size, structure and composition

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High-Density Lipoprotein

-2% -3%

Cardiovascular

risk

1 mg/dl (0.026 mmol/l)

HDL cholesterol

HDL, apo A-I

and

Apo A-II rich

lipoprotein

Apo A-I

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LDL metabolism and reverse cholesterol transport

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Obesity is caused by imbalance of high

Food intake and or low energy expenditure

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Eropa Asia

IMT > 30 kg/m2 > 25 kg/m2

Waist Circumference

♀ > 90

♂ > 102

♀ > 80 cm

♂ > 90 cm

Obesitas

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PATOGENESIS OBESITAS

Faktor genetik

Parental fatness

7 gen penyebab : - Leptin receptor

- Melanocortin receptor – 4

- Alpha-melanocyte stimulating hormone

- Prohormone convertase – 1

- Leptin

- Bardert-Biedl

- Dunnigan partial lypodystrophy

Faktor lingkungan : - Nutrisional - Medikasi

- Aktifitas fisik - Sosial ekonomi

- Trauma

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SlametS 12

Kegemukan (Obesitas)

Android

Gemuk tidak sehat

Ginekoid

Gemuk “sehat”

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SlametS 13

Diabetes Hipertensi

Sindrom Metabolik

Jantung

koroner

Trigliserid Kolesterol HDL

Penurunan Berat Badan 5-10%

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SlametS 14

Mengapa Orang Jadi Gemuk?

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SlametS 15

EVOLUSI MANUSIA

25 tahun 50 tahun

Banyak gerak

Makanan yangdiproses

Hidup santai

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“Overweight and Obesity widespread, serious

But treatable”

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Low Calorie Balance Diets

( LCD )

Awal program : kalori 600 – 1000 kcal/hari

- Asupan lemak

- Asupan KH

Kalori : 1200 – 1600 kcal/hari

Protein : 1 g/Kg BB aktual KH : sisanya

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Very Low Calorie Diets

( LCD )

Formula pabrik

Sering sebabkan gangguan metabolisme

Perlu pengawasan di RS

Utk persiapan operasi

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Berbagai macam obat

Penurun Berat Badan

1. Bekerja di saluran cerna ( penghambat ensim

lipase pankreas ) : orlistat

2. Bekerja menekan pusat nafsu makan di otak :

Lewat jalur serotoninergik : fenfluramine & dexfenfluramine

Lewat jalur noradrenergik : phentermine

lewat jalur serotoninergik & jalur noradrenergik : sibutramine

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Complication• Cancer

• Cardiovascular

• Diabetes Mellitus

• Gallstones

• Hiperlipidemia

• Obstructive Sleep Apneu

• Obesity Hypoventilation Syndrome

• Osteoarthritis

• Polycystic Ovarian Syndrome

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DISLIPIDEMIA

Kelainan metabolisme lipid, ditandai

dengan peningkatan serta penurunan

fraksi lipid plasma.

TRIAD LIPID

Kol-total/ kol-LDL Trigliserid (TG)

Kol-HDL.

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KLASIFIKASI DISLIPIDEMIA

• DISLIPIDEMIA PRIMER

- kelainan pada ensim atau apoprotein

- bersifat genetik

• DISLIPIDEMIA SEKUNDER

- akibat penyakit: DM, Peny.ginjal, Tiroid- akibat obat: diuretika, penyekat beta,

kontrasepsi oral, kortikosteroid.

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Secondary Dyslipidemia

• Pathological states – Diabetes

– Hypothyroidism

– Cushing’s syndrome

– Nephrotic syndrome

– Chronic renal failure

– Monoclonal gammapathy

– Obstructive liver disease

• Lifestyle habits – Obesity

– Alcohol

– Stress

• Drugs that raise LDL-C and/or

lower HDL-C

– Oral estrogens

– Progestins

– Anabolic steroids

– Corticosteroids

– Retinoids, such as isotretinoin

– Sertraline hydrochloride

– Human immunodeficiency virus (HIV) – protease inhibitors

– Non-selective -adrenergic

antagonists

– Cyclosporine

– Thiazide diuretics

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Pathophysiology of diabetic dyslipidemia. (1) FFA due to insulin lack, (2) VLDL is major cause (3)TG metabolized by

LDL, (4) particles by HL, (5) all have access to sub endothelial space, (6) RCT is operative when cholesterol is transferred to HDL

via ABC-1 (7) transferred further to VLDL through CETP, (8) cleared by receptors LDL-R / LRP (LDL-receptor related protein)

, (9) HDL direct via SR-B1(Semenkovich, 2003)

Liver

Lipid + MTP+ ApoB

LDLRLRP

VLDL

LPL

Fatty Acids

HSL Triglycerides

Adipocyte

SR-B1

CETP

IDLLDL

HL

SmalldenseLDL

ArteryWall

HDL ABC1

Cholesterol

• LPL

• Oxidation

• Matrix

• Ca++

• Inflammation

• Smooth

musclecells

1

2

3

8 7

9

6

4

5

In diabetics cholesterol / LDL level may not sufficient to identify risk

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Modifiable risk factors

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Atherogenicity of small dense LDL

Mo

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Foam cell formation in the intima. LDL can pass into / out intima. If excess it is trapped in the matrix by proteoglycans

binding. At antioxidants lack, lipids and LDL proteins are oxydized by oxidating products from cells in the vessel wall. LDL

proteins are also glycated. Extensive uptake of m-LDL via scavenger receptors (CD36 and SR-A) macrophages are turned into

foam cells. This process is accelerated by (1) MCSF, (2) LPS via receptor CD14 with toll-like receptor 4 (TLR4), (3) by heat shockprotein (HSP-60) via CD14, (4) by PAF and cytokines released from macrophages in an autocrine loop.(Mehrabian 2003)

LPSSR-A1

M

CD36+

+

++

Oxygen

radicals

MCP-1M-CSF

Cytokines

+ HSP-60Proteo-glycans

MM-LDL LysoPC

Native LDL

Mac-1, LFA-1

ICAM-1

VLA-4VCAM-1

Mo

PSGL-1

Mo

P,E-selectins

von Willebrand

Foam cell

CD40CD40L

CD14TLR4

Mo

Cell mediated oxidation

Oxidized LDL

SMC

EC

T

Mo

Progression to advanced atherosclerotic lesions (3rd step)

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Media

Lipidoxidation

oxLDL uptakeby SRA

Matrix

MM-LDLROS

M-CSF GM-CSF

Intima Macrophage

GM-CSF

5LO

5LOCell

Cytokineinduction

proliferation

Monocytes

5LO

LTA4

NativeLDL

MCP-1

LTB4

Chemotaxis BLTR

Lumen

TNF- IL-1 Procoagulants

adhesionNF-B, cytokines

NC

DC IL-1 /TNF ROS

TC

EC

Platelets

MC

Advancedplaque

SMC cell proliferation5LO

SMC

Progression to advanced atherosclerotic lesions (3 step)

5LO (5 –Lipoxyoxygenase) and (LTB4) (leukotriene B4) plays very important role in

the 1st

, 2nd

and 3rd

step of atherogenesis besides LDL oxidation and oxidized LDL(Mehrabian, 2003)

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Biological effect of C-reactive

protein on vascular cells

Adhesion molecules (VCAM-1 and E-selection)

Chemokines (MCP-1)

Expression of eNOS

Release of prostacyclin

Expression of plasminogen activator inhibitor-1

Expression of angiotensin type 1 receptor

LDL uptake by macrophages Endothelium-independent relaxation of smooth

muscle cells

Generation of ROS

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CRP, inflammation, and endothelial activation

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Potential mechanisms by which HDLs oppose atherothrombosis.(Barter. EMCNA (2004):398)

Inhibits oxidation

of LDLs

Inhibits

tissue factor

Inhibits endothelial

adhesion molecules

Stimulatesendothelial NO

production

Enhances reversecholesterol transport

Opposes atherothrombosis

HDL

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PENATALAKSANAAN DISLIPIDEMIA

Target : menormalkan fraksi lipid sesuai

faktor risiko PJK yang ada.

• Non-farmakologik :

- Life style obesitas- Terapi nutrisi

- Batasi minuman beralkohol

- Hindari merokok

• Farmakologik :

- Non farmakologik + obat hipolipidemik

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Kolesterol Total

< 200 yg diinginkan

200 – 239 batas tinggi 240 tinggi

Kolesterol LDL

< 100 optimal

100 – 129 di atas optimal

130 – 159 batas tinggi 160 – 189 tinggi

190 sangat tinggi

Kolesterol HDL

< 40 rendah

> 60 tinggi

Trigliserida

< 150 normal

150 – 199 batas tinggi

200 – 499 tinggi

500 sangat tinggi

Target Lipid

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Makanan Asupan yg dianjurkan

Total lemak

Lemak saturasi

Lemak PUFA

Lemak MUFA

Karbohidrat

Serat

Protein

Kolesterol

25 – 30% dari total kalori

< 7% dari total kalori

Sampai 10% dari total kalori

Sampai 10% dari total kalori

60% total kalori (terutama karbohidrat kompleks)

10 gr/ kkal perhari

Sekitar 15% dari total kalori

200 mg/ hari

Total kalori Cukup utk mempertahankan IMT 18,5 – 25 kg/m2

Pengaturan makanan utk hiperkolesterolemia

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OBAT HIPOLIPIDEMIK ORAL

1. Penghambat HMG-CoA reduktase(statin)

2. Sequestran asam empedu (resin)3. Asam fibrat

4. Asam nikotinat (niacin)

5. Penghambat absorbsi kolesterol(ezetimibe)

6. Probucol

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Penghambat HMG-CoA reduktase

• Menurunkan produksi kolesterol hepar

• Mengaktifasi Sterol Regulatory Binding

Protein (SREBP)--- ekspresi reseptor

LDL .

• Katabolisme LDL meningkat

• Uptake VLDL & IDL oleh reseptor LDL , TG plasma .

• Kombinasi dgn NIACIN atau FIBRAT-----

miopati atau gangguan fungsi hepar.

• Pd hiperkolesterolemia berat, kombinasi dg RESIN.

• Efek pleiotropik ---- cegah aterosklerosis.

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Sequestran asam empedu (resin)

• Efektif kol-LDL

• Mengikat as.empedu di usus ---- ekskresi garamempedu feces .

• Memotong siklus enterohepatik

Asam nikotinat (niacin)

• Hambat mobilisasi as.lemak bebas jar. perifer ke

hepar.

• Sintesis TG & VLDL di hepar

• Hambat konversi VLDL menjadi IDL

• Meningkatkan GLUKOSA & asam urat plasma

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Mechanisms of action of NA Nicotinic acid inhibits hepatic TG synthesis at the level of FA synthesis andesterification of DG. NA also blocks apoAI-containing HDL holoparticle uptake at the liver without altering

transport of cholesterol from HDL to the liver by SRB1. Finally, NA acutely inhibits adipocyte lipolysis, but thesignificance of this effect on lipoprotein physiology is unclear.

Meyers EMCNA 33 (2004):561)

TG

ADIPOCYTE

HSL

FFA

NICOTINIC

ACID

*

TG

Cholesterol

PL

B100

VLDL

DGAT2DG

Acyl

CoA

Acetyl

CoA

HEPATOCYTECholesterol

HDL

HDL

PERIPHERAL

TISSUES

Cholesterol

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Fibrat (derivat asam fibrat)

- Sangat tepat untuk hipertrigliseridemia. - Dapat untuk hiperlipidemia kombinasi

- Dapat dikombinasi dengan RESIN & NIACIN, kom

binasi dengan statin dapat timbul miopati, Gemfi-

brosil jangan dikombinasi dengan statin.

- Bekerja pada peroxisome proliferator-activated re

ceptor- (ppar-)

- Jarang: transaminase hepar naik, batu empedu,kreatin kinase otot naik, libido turun.

- Efek potensiasi dg Obat Hipoglikemik Oral dan an-

ti-koagulan oral.

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PPAR

PPAR PPAR

Mechanism of action of fibrates on lipoprotein metabolism.

Glitazones

Nucleus

AGGTCA N AGGTCA

PPRETarget Genes Regulating 5

Lipoprotein Metabolism

FIBRATES

Eicosanoids

gemfibrozil, fenofibrates

Peroxisome Proliferator-Activated Receptor- a transcription factor

(Peroxysome Proliferator Responsive Elements)

- Activated PPAR

- Retinoid R

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Penghambat absorbsi kolesterol(ezetimibe)

• Hambat kol. makanan & kol. Cairan empedu diusus halus. (NPC1L1).

• Timbunan kol. di hepar.

• Klirens kol. plasma .

• Utk kol-total, kol-LDL dan Apo-B pdhiperkolesterolemia primer.

• Efektif sbg mono terapi maupun kombinasi dgstatin.

Ezetimibe

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Enterohepatic recirculation of ezetimibe and its glucuronide. On first pass, ezetimibe inhibits cholesterol absorption in thebrush border of the small intestinal enterocytes. The drug is then partially transformed by the enterocytes into its mainmetabolite, ezetimibe glucuronide. Further metabolism takes place in the liver and the active glucuronide metabolite is

excreted back in the intestine through the bile duct. Inhibition of cholesterol absorption is prolonged and the glucuronideis reabsorbed and recirculated through the bile duct. (Simord, Can J Clin Pharmacol 2003, etc)

Ezetimibe

glucuronide

Ezetimibe

Bile duct

Ezetimibe

glucuronide

Ezetimibe

Inhibition

of cholesterol

absorption

Ezetimibe Ezetimibe

glucuronide

Portal

vein

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The role of nicotinic acid in the treatment of the metabolic syndrome. Nicotinic acid is an effective agentin the attainment of both primary and secondary goals set by the NCEP. (Meyers. EMCNA 33 (2004):570)

LDL-C (or non-HDL-C)

per NCEP calculations

TG < 150 mg/dl

HDL-C > 40 (men)

> 50 (women)

Primary Lipid Goal

Secondary Lipid Goals

1st : Statin, Resin, Ezetimibe

2nd : Nicotinic Acid

3

rd

: Combination

Drugs of Choice

1st : Nicotinic Acid

(TG 150-400)

Fibrate / fenofibrate

(TG >400)2nd : Statin, Fish Oil

3rd : Combination

1st : Nicotinic Acid

2nd

: Fibrate, Statin3rd : Combination

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Cholesterol balance in man

VLDL

Chylomicron transport

50% intestinal

Cholesterol absorbed

IDL

Faecal sterols

50% cholesterol

excreted

LDL DietaryCholesterol

300 mg/day

25%

BiliaryCholesterol

75%

ExtrahepaticOrgans

CholesterolSynthesis

900 mg/day CholesterolSynthesis

Transport

via HDL & LDL

Plant stanolsEzetimibe ResinsStatins

Cholesterol lowering drugs

S f th j d d f th t t t f h li id i

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Summary of the major drugs used for the treatment of hyperlipidemias(Rader 2004)

Drugs Major

indications

Mechanism Common side effects

Statins Elevated LDL

↓ cholesterol

synthesis, LDL

hepatic receptor ↑

VLDL production ↓

Myalgia, arthralgia, dyspepsia,

transient transaminase elevation

Bile acid

sequestrant

(BAS)

Elevated LDL

↑ bile excretion ↑LDL

receptors

Bloating, constipation, elevated

TG

Nicot in ic acid

(NA)

Elevated TG, low

HDL, elevated TG

↓ VLDL hepatic

synthesis

Cutaneous flushing, elevated

glucose and UA, and LFT

Fibr ic acid

derivat ives

Elevated TG, and

remnants

↑ LPL, ↓ VLDL

synthesis

Dyspepsia, myalgia, gallstones,

OT/PT ↑

Fish oi l

Severely elevated

TG

↓ VLDL and

chylomicron

production

Dyspepsia, fish odor, diarrhoea

Specif ic

Cholestero l

absorpt ion

inhib i tors

( SCAI)

Elevated LDL

↓Intestinal cholesterol

absorbtion Elevated transaminase

Tabel 7. Obat Hipolipidemik

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Obat Dosis

Gol. Resin Pengikat Asam Empedu

- Kolestiramin- Kolestipol

Gol. Asam Nikotinat

- Asam Nikotinat

- Acipimox

- Niacin ER

Gol. Statin

- Fluvastatin

- Lovastatin

- Pravastatin

- Simvastatin

- Atorvastatin

- Rosuvastatin

4 – 24 gr/hari5 – 30 gr/hari

100 mg/ 2 x sehari ditingkatkan

sampai 1,5 – 3 gr/hari

250 mg 2 x sehari1000 – 2000 mg 1 x sehari

40 – 80 mg malam hari


5 – 40 mg malam hari5 – 40 mg malam hari



p p

Lanjutan

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Obat Dosis

Gol. Asam fibrat

Bezafibrat

Fenofibrat

Gemfibrozil

Golongan lain

Probukol

Penghambat absorbsi lemak

Ezetimibe

200 mg 3 x sehari atau

400 mg sekali sehari (retard)


300 mg sekali sehari


900 mg sekali sehari

500 mg 2 x sehari

10 mg sekali sehari

Lanjutan

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P th i ? E t d th i i f l f ti

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Pathogenesis ? Even suggested pathogenesis is useful for prevention program.

a. Genetic abnormality b. Fetal malnutrition c.Visceral obesity

CVD

Insulin ResistanceSyndrome

RetinopathyNephropathyNeuropathy

HypertensionStrokePCOSNAFLD

Food intake

excess

Genetic

background

Physicinacting

Adipo Genesis Overweight

Obesity

Insulin Resistance

Hyperinsulinemia

“Inadequate”Insulin Response

CompensatoryHyperinsulinemia

Pancreatic-cell stress &damage

Type 2 Diabetes

Differentiation between the Insulin Resistance Syndrome and type 2 diabetes.Modified from ACE (2003) & Tenenbaum (2003) (Djokomoeljanto, 2004)

*ACE position statement (2003)

*

DM-BR- 2004

patofisiologi

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SlametS

Chronic

hyperglycemia

High circulating

free fatty acidsPancreas

Amyloid

deposit

Glucotox ic i ty 2 Lipotox ic i ty 3

HGP

Uptake

Lipolysis

TNF

p g

Insulin resistance

Hyper insul inemia to compensate for insulin

resistance1,2

Insulin deficiency

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The Metabolic Syndrome

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FFA LipidFFA

Leptin

Adiponectin

Visfatin

Resistin

Adipsin (ASP)

Angiotensinogen/AT-II

Cytokines

(TNF-, IL-6)

AdiposeTissue

Prostaglandin NO PAI-1

Adipokines Secreted by Adipose TissueDM-BR- 2004

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5/21/2013Factors FFA, TNF and PAI -1 can affect per ipheral tissues

Autocrine

ParacrineEndocrine

Leptin

?TNFα

?IL-6

Sex steroids

Glucocorticoids

?Angiotensin

?PAI-1

?Adiponectin

?AdipoQ

PAI-1

TGF-β

TF

Adipsin/ASP

?TNF-α /IL-6/Leptin

Renin-Angiotensin

system

Steroid hormones

Adipose tissue

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AUGUST 3-7TH 2006 INTERNATIONAL SYMPOSIUM SHOCK AND CRITICAL CARE

PROTEIN YANG DISEKRESI ADIPOSIT

1. ESTROGEN

2. LEPTIN

3. AGOUTI RELATED PROTEIN

4. TNF α

5. IL1B

6. IL-6

7. ANGITENSINOGEN

8. ASP

9. ADIPSIN

10. FACTORS B,C3

11. ADHESIVE PROTEIN

12. PAI-1

13. TF

14. RESISTIN

15. ADIPONECTIN

16. VISFATIN

17. HSL

18. LIPOTRANSIN

19. PERILIPINS

20. FFAs

21. TGF-β

22. VEGF

23. IGF-1

24. PGE2

25. PGI1

26. GLUCOCORTICOID

27. 11βHSD

28. AROMATASE

29. METALLOTHIONIEN

30. MIF

31. RBP

32. APO-E

33. ICAL

34. LPL

35. CETP

36. PLTP

37. NO

38. PC-1

39. AQUAPORINS

40. FIAF

41. LACTATE

42. MONOBUTYRIN

43. GALACTIN-12

44. ESM-1

45. APELIN

(TJOKROPRAWIRO 2003)

Dasar Cardioprotective

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Adiponectin and Clinical Consequences

Type 2 diabetes andglycemic disorders

Dyslipidemia – Low HDL – Small, dense LDL

– Hypertriglyceridemia

Hypertension

Endothelial dysfunction/inflammation (hsCRP)

Impaired thrombolysis PAI-1

VisceralObesity

A t h er o s c l er o s i s

Cardioprotective

overview

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ANTI INSULIN RESISTANCE ANTIATHEROSCLEROSIS

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ANTI INSULIN RESISTANCE ANTIATHEROSCLEROSIS

↓ TISSUE TG CONTENT

UPREGULATE INSULINSIGNALING

ACTIVATE PPARœ

ACTIVATE AMPK

1

2

3

4

•↓ THE Expression of Adhesion Mol. :

ICAM-1, VCAM-1, E-selectin, also

↓ TNFœ-induced NFkB Activation

•↓ Endothelial Cell Apoptosis via

AMPK Activation by HMW multiform

Of Adiponectin

1 ENDOTHELIUM

↓ Cell Proliferation

↓ Migration

↓ SRA- 1

↓ Uptake of Ox-LDL,↓ Foam Cell

2 MACROPHAGE

3 SMC :

⑤ ROLES OF

ADIPONECTIN

V IV III

ANTI OXIDANT

↓ OXIDATIVE STRESS

ANTI INFLAMMATION

↓ INFLAMMATORY MARKERS

↓ APOPTOSIS

BRAIN, HEART, β - CELL

Ouchi et al 2000-2001, Yamauchi et al 2001-2003, Arita et al 2002

Kobayashi et al 2004, IIIustrated : Tjokroprawiro 2007-2011

FIGURE – 2 ADIPONECTIN WITH ITS CARDIOPROTECTIVE PROPERTIES

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SINDROMA METABOLIK

NCEP-ATP III WHOIGT/DM/IFG

3 dari 5 2 dari 4

BMI > 30 Kg/m2

Mikral urin > 20 µg/ml

WHR ♂ > 0.90

♀ > 0.85

WCF ♂ > 102 cm (> 90 cm )

♀ > 88 cm (> 80 cm)

Trigliserid ≥ 150 mg/dl > 150 mg/dl Kol-HDL ♂ < 40 mg/dl < 35 mg/dl

♀ < 50 mg/dl < 39 mg/dl

Tensi ≥ 130/85 mmHg ≥ 140/90 mmHg

Gluk.puasa ≥ 110 mg/dl ≥ 6.1 mMol/L

D fi iti f th t b li dD fi iti f th t b li d

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5/21/2013

Definitions of the metabolic syndromeDefinitions of the metabolic syndrome((BloomgardenBloomgarden 2004, 1st2004, 1st ConggressConggress on Insulin Resistance Syndrome)on Insulin Resistance Syndrome)

FPG 6,1 mmol/l

(exc.DM)

FBG 110-125 or

2hpc 140-200

110 mg/dlBlood glucose

140/90 mmHg or treated for Hyp.

130/85 mmHg140/90 mmHg130/8 5mmHgBlood pressure

1.0 mmol/l40 mg/dl

50 mg/dl

35 mg/dl

39 mg/dl

40 mg/dl

50 mg/dl

HDL chol male

female

2.0 mmol/l or 150 mg/dl or 150 mg/dl or 150 mg/dlTriglycerides

94 cm

80 cm

>102 cm

> 88 cm

Waist CF male

female

90 in men

85 in women

WHR male

female

> 20 g / mUirinary alb exc

2 of 4And 2 of 4At least 3 of 5

Fasting hyperin-sulinemia( highest

quartile) and

One of **IGT/HOMA-IR,IFG/DM and

2 of 4 below

EGIR (IRS)AACE (IRS)WHOATP III

** CVD, hypertension, PCOS, NAFLD, family history of T2DM / hypertension / CVD, history of

gestational diabetes, non Caucasian, sedentary lifestyle, BMI>125 or WC>40 male, >35 female,

age>40yrs

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Model showing the potential contribution of the related loss of visceral adipose tissue to the beneficial

effects of metformin on the features of the metabolic syndrome FFA : free fatty acids

HepaticGlucoseproduction

FFA ?

Visceral Adipose tissue ?

Insulinsensitivity

METFORMIN

Insulin

sensitivity Muscleglucose uptake

Glucose

( —)

(+)

(=)

M tf i

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Vascular benefits of metformin

AGE : advanced glycation end-products

Reduced cardiovascular risk

Metformin

Improved

Insulin sensitivity

Fibrinolysis

Nutritive capillary flow

Haemorrheology

Postischaemic flow

Reduced

Hypertriglyceridaemia

AGE formation

Cross-linked fibrin

Neovascularisation

Oxidative stress

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

Risk marker EffectPlAI-1

Factor VII

Fibrinogen

Facto r XIII Fibrin

C-reactive pro tein

Platelets

Blood f low

Marker reduction

Reduct ion

Equivocal , some studies report reduction, others

no effect

Reduces A and B su bun i t Alters structure / function

Reduct ion

Reduction platelet growth factor 4 and

thromboglobulin, stabilises platelet and antioxidant

effectMetformin increases hemodynam ic respo nses to L-

arg in ine. Lowers levels o f asymptom atic

dimethylarg in ine, impro ves post ischem ic blood

f low and improves bloo d f low in b oth sekeletal

mu scle and adipose t issue

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Reciprocal effect of increased activity of the Randle

cycle and treatment with metformin on glucose / lipid

metabolism in T2DM (Del Prato 1995)

Item Increased Randle

cycle activity

Metformin

Treatment

Lipid oxidation

Glucose tolerance

Glucose disposal

Glucose oxidation

Insulin sensitivity

Hepatic glucose production

↑

↓

↓

↓

↓

↑

↓

↑

↑

↑

↑

↓

Definisi Dx D K lik i

S U M M A R Y

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Definisi Dx D r u g Komplikasi

Obesity

Akumulasi

jaringan lemak

berlebihan, baikbesar maupun

jumlahnya

I M TW C

OrlistatSibutramine

Dislipidemi Kelainanmetabolisme

lipid

TG

CH

LDL

HDL

Statin

Niacin

Ezetimibe

Nicoitinic

Aterosklerosis accelareted

C H D

S N H

Metabolic

Syndrome

Kumpulangejala yang

disebabkan oleh

karena obesitas

sentral ---- ------

Insulin resisten

W C

HtDM

TG

CH

LDL

HDL

Alb

Metformin

Glitazone

Dislipidemia

C H D, SNHHipertensi

Diabetes Mellitus

NAFLD

PCOS

Hperuricemia

Microalbuminuria

Cancer

Cardiovascular

Diabetes Mellitus

GallstonesHiperlipidemia

Obstructive Sleep Apneu

Obesity Hypoventilation Syndrome

Osteoarthritis

Polycystic Ovarian Syndrome

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F A T

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