OBESITAS

DISLIPIDEMI
SINDROMA METABOLIK
Dr. M a h a t m a SpPD
SMF Penyakit Dalam F.K. UMS
SURAKARTA
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 OBESITY HYPERTENSION, 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)
Dietary
Fat
INTESTINES
Bile Acids
+
Cholesterol
LPL
2
1
LIVER
Endogenous
Cholesterol
LDL
Apo, B-100
7
11
10
EXTRAHEPATIC
TISSUES
NASCENT HDL
HDL
3
LCAT HTGL
CETP
HDL
2
LDL
Apo E, B-100
LPL
6
VLDL
Apo E, C-II,
B-100
Endogenous
Pathway
REMNANTS
Apo E, B-48
CHYLOMICRONS
Apo E, C-II, B-48
Exogenous
Pathway
3
4
8 9
5
Lipemia is normal , however dyslipidemia 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
lipoprotein
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Triglyceride-rich lipoproteins:
size, structure and composition
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HDL metabolism and reverse cholesterol transport
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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/m
2
> 25 kg/m
2

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
SlametS 12
Kegemukan (Obesitas)
Android
Gemuk tidak sehat
Ginekoid
Gemuk sehat
SlametS 13
Diabetes
Hipertensi
Sindrom Metabolik
Jantung
koroner
Trigliserid
Kolesterol HDL
Penurunan Berat Badan 5-10%

SlametS 14
Mengapa Orang Jadi Gemuk?
SlametS 15
EVOLUSI MANUSIA
25 tahun
50 tahun
Banyak gerak
Makanan yang
diproses
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
Cushings 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
LDLR
LRP
VLDL
LPL
Fatty Acids
HSL Triglycerides
Adipocyte
SR-B1
CETP
IDL
LDL
HL
Small
dense
LDL
Artery
Wall
HDL ABC1
Cholesterol
LPL
Oxidation
Matrix
Ca
++
Inflammation
Smooth
muscle
cells
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
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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 shock
protein (HSP-60) via CD14, (4) by PAF and cytokines released from macrophages in an autocrine loop.(Mehrabian 2003)
LPS
SR-A1
MC
CD36
+
+
+
+
Oxygen
radicals
MCP-1
M-CSF
Cytokines
+
HSP-60
Proteo-
glycans

MM-LDL

LysoPC

Native LDL

Mac-1, LFA-1
ICAM-1

VLA-4
VCAM-1
Mo
PSGL-1
Mo
P,E-selectins
von Willebrand
Foam cell
CD40
CD40L
CD14
TLR4

Mo
Cell mediated oxidation

Oxidized LDL

SMC
EC
T
Mo

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Media
Lipid
oxidation
oxLDL uptake
by SRA
Matrix
MM-LDL
ROS
M-CSF
GM-CSF
Intima
Macrophage
GM-CSF
5LO
5LO
Cell
Cytokine
induction
proliferation
Monocytes
5LO
LTA
4
Native
LDL
MCP-1
LTB
4
Chemotaxis
BLTR
Lumen
TNF-o
IL-1|
Procoagulants
adhesion
NF-kB, cytokines
NC
DC
IL-1|/TNFo
ROS

TC
EC
Platelets
MC
Advanced
plaque
SMC cell proliferation
5LO
SMC
Progression to advanced atherosclerotic lesions (3
rd
step)
5LO (5 Lipoxyoxygenase) and (LTB
4
) (leukotriene B4) plays very important role in
the 1
st
, 2
nd
and 3
rd
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
Stimulates
endothelial NO
production
Enhances reverse
cholesterol 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/m
2

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 garam
empedu 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 and
esterification 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 the
significance of this effect on lipoprotein physiology is unclear.
Meyers EMCNA 33 (2004):561)
TG
ADIPOCYTE
HSL

FFA
NICOTINIC
ACID
-


TG
Cholesterol
PL
B100
VLDL
DGAT2
DG
Acyl
CoA
Acetyl
CoA
HEPATOCYTE
Cholesterol
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-o (ppar-o)
- 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
PPARo
PPAR
Mechanism of action of fibrates on lipoprotein metabolism.
Glitazones
Nucleus
AGGTCA N AGGTCA
PPRE
Target 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 di
usus halus. (NPC1L1).
Timbunan kol. di hepar +.
Klirens kol. plasma |.
Utk + kol-total, kol-LDL dan Apo-B pd
hiperkolesterolemia primer.
Efektif sbg mono terapi maupun kombinasi dg
statin.
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Enterohepatic recirculation of ezetimibe and its glucuronide. On first pass, ezetimibe inhibits cholesterol absorption in the
brush border of the small intestinal enterocytes. The drug is then partially transformed by the enterocytes into its main
metabolite, 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 glucuronide
is 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 agent
in 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
1
st
: Statin, Resin, Ezetimibe
2
nd
: Nicotinic Acid
3
rd
: Combination
Drugs of Choice
1
st
: Nicotinic Acid
(TG 150-400)
Fibrate / fenofibrate
(TG >400)
2
nd
: Statin, Fish Oil
3
rd
: Combination
1
st
: Nicotinic Acid
2
nd
: Fibrate, Statin
3
rd
: Combination
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Cholesterol balance in man
VLDL
Chylomicron transport
50% intestinal
Cholesterol absorbed
IDL
Faecal sterols
50% cholesterol
excreted
LDL
Dietary
Cholesterol
300 mg/day
25%
Biliary
Cholesterol
75%
Extrahepatic
Organs
Cholesterol
Synthesis
900 mg/day
Cholesterol
Synthesis
Transport
via HDL & LDL
Plant stanols Ezetimibe Resins Statins
Cholesterol lowering drugs
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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
Nicotinic acid
(NA)
Elevated TG, low
HDL, elevated TG
VLDL hepatic
synthesis
Cutaneous flushing, elevated
glucose and UA, and LFT
Fibric acid
derivatives
Elevated TG, and
remnants
LPL, VLDL
synthesis
Dyspepsia, myalgia, gallstones,
OT/PT

Fish oil
Severely elevated
TG
VLDL and
chylomicron
production

Dyspepsia, fish odor, diarrhoea
Specific
Cholesterol
absorption
inhibitors
(SCAI)


Elevated LDL

Intestinal cholesterol
absorbtion


Elevated transaminase
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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/hari
5 30 gr/hari

100 mg/ 2 x sehari ditingkatkan
sampai 1,5 3 gr/hari
250 mg 2 x sehari
1000 2000 mg 1 x sehari

40 80 mg malam hari
5 40 mg malam hari
5 40 mg malam hari
5 40 mg malam hari
10 80 mg malam hari
10 40 mg malam hari
Tabel 7. Obat Hipolipidemik
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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)
100 mg 3 x sehari atau
300 mg sekali sehari
600 mg 2 x sehari atau
900 mg sekali sehari

500 mg 2 x sehari


10 mg sekali sehari
Lanjutan
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Pathogenesis ? Even suggested pathogenesis is useful for prevention program.
a. Genetic abnormality b. Fetal malnutrition c.Visceral obesity
CVD
Insulin Resistance
Syndrome
Retinopathy
Nephropathy
Neuropathy
Hypertension
Stroke
PCOS
NAFLD
Food intake
excess
Genetic
background
Physic
inacting
Adipo Genesis Overweight
Obesity
Insulin Resistance
Hyperinsulinemia
Inadequate
Insulin Response
Compensatory
Hyperinsulinemia
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
SlametS
Chronic
hyperglycemia
High circulating
free fatty acids
Pancreas
Amyloid
deposit
Glucotoxicity
2
Lipotoxicity
3
HGP
Uptake
Lipolysis
TNF o
patofisiologi
Insulin resistance
Hyperinsulinemia
to compensate for insulin
resistance
1,2
Insulin deficiency
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The Metabolic Syndrome
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FFA
Lipid
FFA

Leptin
Adiponectin

Visfatin

Resistin

Adipsin (ASP)

Angiotensinogen/AT-II

Cytokines
(TNF-o, IL-6)
Adipose
Tissue
Prostaglandin NO PAI-1
Adipokines Secreted by Adipose Tissue
DM-BR- 2004
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Factors FFA, TNFo and PAI -1 can affect peripheral tissues
Autocrine
Paracrine
Endocrine
Leptin
?TNF
?IL-6
Sex steroids
Glucocorticoids
?Angiotensin
?PAI-1
?Adiponectin
?AdipoQ
PAI-1
TGF-
TF
Adipsin/ASP
?TNF- /IL-6/Leptin
Renin-Angiotensin
system
Steroid hormones
Adipose tissue

AUGUST 3-7
TH
2006 INTERNATIONAL SYMPOSIUM SHOCK AND CRITICAL CARE
PROTEIN YANG DISEKRESI ADIPOSIT
1. ESTROGEN
2. LEPTIN
3. AGOUTI RELATED PROTEIN
4. TNF
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-
22. VEGF
23. IGF-1
24. PGE2
25. PGI1
26. GLUCOCORTICOID
27. 11HSD
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)
Adiponectin and Clinical Consequences
Type 2 diabetes and
glycemic disorders

Dyslipidemia
Low HDL
Small, dense LDL
Hypertriglyceridemia

Hypertension

Endothelial dysfunction/
inflammation (hsCRP)

Impaired thrombolysis
| PAI-1
Visceral
Obesity
A
t
h
e
r
o
s
c
l
e
r
o
s
i
s


Dasar
Cardioprotective
overview
ANTI INSULIN RESISTANCE ANTIATHEROSCLEROSIS
TISSUE TG CONTENT
UPREGULATE INSULIN
SIGNALING
ACTIVATE PPAR
ACTIVATE AMPK
1
2
3
4


THE Expression of Adhesion Mol. :
ICAM-1, VCAM-1, E-selectin, also
TNF-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 :
ROLES OF

ADIPONECTIN
V IV III
ANTI OXIDANT

OXIDATIVE STRESS
ANTI INFLAMMATION

INFLAMMATORY MARKERS
APOPTOSIS

BRAIN, HEART, - 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
SINDROMA METABOLIK
NCEP-ATP III WHO
IGT/DM/IFG
3 dari 5 2 dari 4
BMI > 30 Kg/m2
Mikral urin > 20 g/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

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Definitions of the metabolic syndrome Definitions of the metabolic syndrome
( (Bloomgarden Bloomgarden 2004, 1st 2004, 1st Conggress Conggress on Insulin Resistance Syndrome) on Insulin Resistance Syndrome)
FPG >6,1 mmol/l
(exc.DM)
FBG 110-125 or
2hpc 140-200
> 110 mg/dl Blood glucose
>140/90 mmHg or
treated for Hyp.
>130/85 mmHg > 140/90 mmHg >130/8 5mmHg Blood pressure
< 1.0 mmol/l <40 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/dl Triglycerides
> 94 cm
> 80 cm
>102 cm
> 88 cm
Waist CF male
female
>90 in men
>85 in women
WHR male
female
> 20 g / m Uirinary alb exc
2 of 4 And 2 of 4 At 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) WHO ATP 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
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
Hepatic
Glucose
production
FFA ?
Visceral
Adipose tissue ?
| Insulin
sensitivity
METFORMIN
| Insulin
sensitivity
| Muscle
glucose uptake
+ Glucose
()
(+)
(=)
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
Effects of metformin on non-conventional factors
(Grant PJ, 2003).
Risk marker Effect
PlAI-1
Factor VII
Fibrinogen

Factor XIII
Fibrin
C-reactive protein
Platelets


Blood flow
Marker reduction
Reduction
Equivocal , some studies report reduction, others
no effect
Reduces A and B subunit
Alters structure / function
Reduction
Reduction platelet growth factor 4 and
thromboglobulin, stabilises platelet and antioxidant
effect
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
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















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Definisi
Dx
D r u g Komplikasi
Obesity
Akumulasi
jaringan lemak
berlebihan, baik
besar maupun
jumlahnya


I M T
W C
Orlistat
Sibutramine





Dislipidemi

Kelainan
metabolisme
lipid


TG
CH
LDL
HDL

Statin
Niacin
Ezetimibe
Nicoitinic




Aterosklerosis accelareted
C H D
S N H
Metabolic
Syndrome

Kumpulan
gejala yang
disebabkan oleh
karena obesitas
sentral ---- ------
Insulin resisten

W C
Ht
DM
TG
CH
LDL
HDL
Alb
AU
Metformin
Glitazone



Dislipidemia
C H D, SNH
Hipertensi
Diabetes Mellitus
NAFLD
PCOS
Hperuricemia
Microalbuminuria

S U M M A R Y
Cancer
Cardiovascular
Diabetes Mellitus
Gallstones
Hiperlipidemia
Obstructive Sleep Apneu
Obesity Hypoventilation Syndrome
Osteoarthritis
Polycystic Ovarian Syndrome
5/21/2013