1

THE METABOLIC SYNDROME (LRD STAGE-3)

PRECLINICAL STAGE OF THE CVDs
(LRD Stage 0-4, GULOH-CISAR, DRUG THERAPY, TIME BOMB DISEASE)

2007
(31)
Askandar Tjokroprawiro
Diabetes and Nutrition Centre - Dr. Soetomo Teaching Hospital
Airlangga University School of Medicine, Surabaya

Simposium Sumpah Dokter FK-UNS Periode-161

Holistic Approach of the Metabolic Syndrome
Surakarta, 9 September 2007
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 2
The Metabolic Syndrome : from CMR to CVDs
(Summarized : Tjokroprawiro 2005-2007)

Cardiometabolic Risk = CMR Syndrome-X (Reaven-1988) Cardiovascular Disease = CVD

Deadly Quartet IRS or the MetS The MetS

(Kaplan-1989) (Zimmet-1989) (WHO-1998)

Metabolic Syndrome-X (Reaven-1999) Metabolic Syndrome (EGIR-1999)

Metabolic Syndrome (ATP III-2001)

Dysmetabolic Syndrome Insulin Resistance Syndrome

S

(AACE-2002, ACE-2002)

Metabolic Syndrome (AHA/NHLBI/ADA-2004)

The MetS (IDF-April 2005) The MetS (AHA/NHLBI-July 2005) The MetS (ADA/EASD-September 2005)
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 3
Global Projections for the Diabetes Epidemic : 2003-2025
IDF, Diabetes Atlas, Second Edition 2003, Provided : 2006-2007

48.4
58.62
21% 43.0
23.0 75.8
36.2 76%
57%
19.2
39.4
105%
7.1
14.2 39.3
15.0
26.2 81.6
110%
84% 107%

ALL T2DMS WORLD 70% - 90% of Cases

High Risk of CVD
> 2003 = 194 Million
> 2025 = 333 Million
72% in Developing World

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Type 2 Diabetes in the Top 10 Countries
(IDF, Diabetes Atlas, Second Edition 2003, Provided : 2006-2007)

1 * Affects 5% to 7% of the World's Population

35
* Global Prevalence of DM will be double between
30
No. of Cases (Millions)

between 19952025, and will reach 333 Millions

25 2
ASIA (WHO, 1998) : 1997 (58 Mill.), and 2025 (136 Millions)
20
3
15

10 4
5 6 7 8
5 9 10

0
INDIA CHINA USA PKTAN JAPAN INA MEXI EGYPT BRAZIL ITALY

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Clinical Identification
Metabolic Syndrome Insulin Resistance Syndrome
(Summarized : Tjokroprawiro 2005 - 2007)

WHO (1998)
Hyperinsulinemia and/or IFG, IGT, T2DM
METABOLIC SYNDROME
PLUS
AT LEAST 2 OF THE FOLLOWING 3 :
1 ABDOMINAL OBESITY : - BMI > 30 kg/m2; INA > 25 kg/m2
- WHR > 0.90 for men, > 0.85 for women
2 DYSLIPIDEMIA : - Serum Triglyceride > 150 mg/dl or
- HDL-Cholesterol < 35 mg/dl
3 HYPERTENSION : - Blood Pressure > 140/90 mm/Hg or
on Hypertensive Medication

*) New Criterion of FPG in Normals : < 100 mg/dl (ADA-2004)

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Clinical Identification
Metabolic Syndrome Insulin Resistance Syndrome
(Summarized : Tjokroprawiro 2005 - 2007)

ATP (2001)
METABOLIC SYNDROME
At least 3 of the Following 5 (cm, mg/dl, mmHg) : (diabetes is not excluded)
1 Abdominal Obesity (Waist Circumference) Men* : > 102 Women** : > 88
Predisposition Patients : *94 **80
INA : Men > 90 Women > 80
2 Serum Triglyceride > 150
3 Serum HDL-Cholesterol Men : < 40 Women : < 50
4 Blood Pressure > 130 / > 85
5 Fasting Glucose > 100*)
*) New Criterion of FPG in Normals : < 100 mg/dl (ADA-2004)
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The IDF Definition for the MetS-2005
(Berlin, 14 April 2005, Summarized : Tjokroprawiro 2005 -2007)

Central Obesity (WC for Europids : Men > 94 cm; Women > 80 cm
(INA : Men > 90 cm; Women > 80 cm)

Plus Any 2 of the Following 4 Factors (mg/dl, mmHg)

1 TG > 150, or Specific Treatment for this Lipid Abnormality

2 HDL-C < 40 (Males) and < 50 (Females), or

Specific Treatment for this Lipid Abnormality

3 Blood Pressure > 130/85, or Treatment of Previously Dx Hypertension

4 Fasting Plasma Glucose > 100, or Previously Dx T2DM

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AHA/NHLBI (July 2005)
Criteria for Diagnosis of the MetS
DIAGNOSIS OF THE METS CATEGORICAL CUTPOINTS
ANY 3 OF FOLLOWING 5 FACTORS
> 102 cm in Men
1 ELEVATED WC > 88 cm in Women
> 150 mg/dl or on Drug Treatment
2 ELEVATED TG
for Elevated Triglycerides
< 40 mg/dl in Men
3 REDUCED HDL-C < 50 mg/dl in Women or
on Drug Treatment for Reduce HDL-C
> 130 mmHg SBP or
> 85 mmHg DBP or
4 ELEVATED BP on Antihypertensive Drug Treatment in
a Patients with a History of Hypertension
> 100 mg/dl or
5 ELEVATED FBG
on Drug Treatment for Elevated Glucose
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 "The Widened Metabolic Syndrome : The Widened MetS 9
A Cluster of 10 Metabolic-Cardiovascular Risk Components
(Abdominal Obesity is the Key Player)
(Summarized : Tjokroprawiro 2002-2007)

Fatty Acid Deposition 10 Visceral Fat Insulin Resistance

Liver Steatosis = NASH "The Black Goat" * 2 Hyperinsulinemia IGT-IFG T2DM *
1 Atherogenic Dyslipidemia
Adrenal Incidentaloma 3
ACTH, Cortisol 9 1 Increased Fasting FFA *
2 Elevated Apolipoprotein B
( Salivary Cortisol) 3 Elevated Remnant Lipoproteinemia
4 Elevated Fasting Triglyceride
Hyperuricemia 8 5 Elevated Post Prandial TG
ABDOMINAL 6 "Normal" LDL
7 Increased LDL
Vascular Abnormalities 7 OBESITY 8 Increased Small-dense LDL :
LDL
< 1.2
Apo B
- Urinary Albumin Excretion GABRA-6 ? 9 Reduced HDL-C Increased "Small HDL"
(ACR >30 g/mg creatinine) 10 Increased Cholesterol/HDL-C Ratio
- Endothelial Dysfunction
4 Raised Blood Pressure
Prothrombotic State 6 LVH, CHF *
Prolonged QT Syndrome
PAI-1 (Esp. Omental Fat)
Factor VII
* Apn ADMA
Fibrinogen 5 Proinflammatory State
vWF ADIPONECTIN-RAISERS CRP , TNF, IL - 1, *
Adhesion Molecules GLIM, GLITAZONES, GLITAZARS IL - 6, Fibrinogen

1 , 2 , 3 , 4 , 5 , 6 are the 6-Major Components* of the Metabolic Syndrome

(AHA/NHLBI/ADA-2004 : Grundy et al 2004)
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Novel Extension of Metabolic Syndrome on
the Basis of Resistance to the Novel Actions of Insulin
(Dandona et al 2005, Provided : Tjokroprawiro 2006-2007)

10 Platelet 1 2 Tonic Vasoconstriction

Hyperaggregability Insulin - Abnormal Vascular Reactivity
Resistance - Vascular Flow Reserve
NO, PGI2
NO bioavailability, ADMA

9 ROS Generation
Oxidative Stress 3 Cardio-protection
NADPH Oxidase
Mitochondrial Superoxide NOVEL FEATURES Larger Infarcts
Tendency to CHF
OF
THE METS
8 Chronic Pro-inflammatory State
4 Pro-apoptosis State
IB, NF, MIF, CRP, TNF- Infarct Size

7 Pro-Thrombotic State 6 Anti-Fibrinolytic State 5 Atherosclerosis

TF PAI-1 CHD, Stroke

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 11
MAP of FAT Cell : 60 HORMONES AND BIOLOGIC SUBSTANCES
(Summarized : Tjokroprawiro 1997-2007)
FIAF 30 31 Lactate, Lysophospholipid, Adenosine, Glutamine
32 Monobutyrin
Aquaporins 29 33 Galectin-12
34 ESM-1
PC-1 28 35 Apelin
NO 27 36 FATPI
37 aP2
ApoE,LPL,ICAL,CETP,PLTP 26 38 UCP, P450, ZAG
39 Complement System Products Necrosis
RBP 25 40 Macrophage CSF
41 Macrophage Inflammatory Protein 1 Apoptosis
Metallothionein 24 1 Estrogen Proliferative Effect
Aromatase 23 2 Ob Protein (LEPTIN) 1 Renal Renin (AII)
Hypertension
11 HSD-1 22 Agouti Related
3
Protein (AgRP)
Hyperuricemia
ACTH, Cortisol 21
FAT CELL VCAM-1
2 NPY, AGRP Body Weight
Eicosanoids,
20 Inhibits Bone Formation
PGE2, PGI2 3
TGF, VEGF,
4 TNF (Central Relay)
19 5 4
IGF-1, IGF BP
6 IL-1, IL-6
MIF 18
IRS-1
FFAs 17 Ob Protein (LEPTIN)
IRTK
Insulin Cell
Perilipsins 16 Resistance STAT-3
AII
7 LPL & FFA
Lipotransin 15 TG
HSL, DGAT 14 ASP, Adipsin, Factors : B, C3 HDL GLUT-4 Insulin
LDL3 Expression Secretion
VISFATIN 13 8 Adhesive Proteins
Fribrinogen
Adiponectin 12 PAI-1
9 PAI-1
(Esp. Omental Fat)
Resistin 11
10 TF
F VII IGT - T2DM
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Obesity - induced Inflammatory Changes in Adipose Tissue
(Wellen et al 2003, Provided : Tjokroprawiro 2005-2007)

Normal Apn Mild Low Apn Low Apn-High ADMA

Apn, ADMA
ADIPOCYTE
WEIGHT GAIN WEIGHT GAIN
IR Apn

JNK
NFB
TNF-
Leptin
VEGF
Endothelial IL-6
Cell IL-1
Angiogenesis
TNF-
Physical stress/oxidative
MCP-1 damage to endothelium?

PREADIPOCYTE FFA MCP-1

Macrophage
Recruitment

MACROPHAGE MACROPHAGE
Apn = ADIPONECTIN RECRUITMENT
ADMA = Asymetric DiMethyl Arginine ADMA

Normal Adipocyte Early Adipocyte Dysfunction Advanced Adipocyte Dysfunction

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ADMA : Asymetric DiMethyl Arginine
An Endogenous, Competitive Inhibitor of NOS
(Sydow et al 2003, Levine et al 2006, Summarized: Tjokroprawiro 2007)

PROTEIN BOUND OBESITY

ARGININE TNF The MetS

METFORMIN OXIDATIVE STRESS

GLITAZONES PMRT Inflammation NADPH OXIDASE

ADMA DDAH O2

NOS III
Mediated Nitric Oxide
Formation
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ADMA NO ATHEROSCLEROSIS
(Summarized : Tjokroprawiro 2007)

L-Citrulline
ICAM, VICAM, ox LDL, O2
ARGININE NO Platelet Aggregation
Vasodilation, SMC Proliferation

L-NMMA, L-NAME NOS

Co-Factors, BH4 (Tetrahydrobiopterin)
Statins, Apn
NADPH, Calmodulin + Ca2+
Testosteron

DDAH ADMA ENDOTHELIAL DYSFUNCTION

TNF OXIDATIVE STRESS US-TRIO Wins Price-1998 (US$ 1.6 Mill.)

OBESITY THE METS Furchgott (82), Murad (62), Ignarro (57)
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Formation and Elimination of ADMA
(Maas 2005, Provided : Tjokroprawiro 2007)

Protein L-Arginine SAM L-METHIONINE

PRMT 1 CH3-Donors

CH3
SAH HOMOCYSTEINE

Metformin 2 Oxidative Stress Farnesoid x Rec. Agonist

DDAH1 Gene Expression
Glitazones
DDAH Dimethylamine
ADMA Citrulline
3
4
TRANSPORTER
5 PLASMA ADMA

6
Urine (< 20%) KIDNEY
7
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ATHEROSCLEROSIS
1
CHRONIC RENAL FAILURE 12 2 OBESITY

HYPERTENSION 11 3 DIABETES MELLITUS

PREECLAMPSIA 10
ADMA 4 SMOKING (?)
Summarized :
Tjokroprawiro 2007

HYPERHOMOCYSTEINEMIA 9 5 HYPERCHOLESTEROLEMIA

LIVER FAILURE 8 6 ERECTILE DYSFUNCTION

7
CONGESTIVE HEART FAILURE

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 STAGING OF LIFESTYLE RELATED DISEASE 17

(Clinical Experiences : Tjokroprawiro 2005-2007)

STAGE 0 STAGE 1 STAGE 2 STAGE 3 STAGE 4

Westernized Obesity Preclinical : the MetS Clinical : CAD
Healthy Lifestyle
Unhealthy Lifestyle (Abdominal Obesity) IFG, IGT, Pedr.-Obese T2DM, Pedr.-T2DM, Stroke

Waist Circumference = WC
NOS o > 90 cm o SUMETSU
+ > 80 cm
(2002) (2005)

4 Fasting Glucose 1 Triglyceride

> 100 mg/dl > 150 mg/dl

SDU MECARSU
(1996) (2007)

2 HDL-Chol
3 Blood Pressure o < 40 mg/dl
> 130/85 mmHg o
+ < 50 mg/dl

Stage 3 or the MetS will be "TIME-BOMB DISEASE in Indonesia ?

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 Hypertriglyceridemic-Waist
HTG-W SYNDROME
WC > 90 cm; HTG > 180 mg/dl
HTG = Hypertriglyceridemia
W = Waist
II Atherogenic Dyslipidemia
HTG-W
10 Reduced HDL-C Increased "Small HDL"
I Insulin Resistance Hypertriglyceridemic-Waist
18
Hyperinsulinemia
Prediabetes = IGT, IFG + 80% Metabolic Syndrome
T2DM
1 Atherogenic Dyslipidemia
2 IGT-IFG
1 Increased Fasting FFA 3 Impaired : - Inflammatory
2 Elevated Apolipoprotein B - Fibrinolysis
3 Elevated Remnant Lipoproteinemia - Thrombosis.
4 Elevated Fasting Triglyceride
5 Elevated Post Prandial TG
6 "Normal" LDL
7 Increased LDL
8 Increased Small-dense LDL :
LDL
< 1.2
Apo B
9 Increased Cholesterol/HDL-C Ratio

Coronary Atherosclerosis
Proinflammatory State Unstable Plaque
III Prothrombotic State
1 PAI-1 6 Fibrinogen
Apn ADMA 2 TNF 7 FVII Increased Risk
3 CRP 8 vWF Acute Coronary Syndrome
Desprs, 2003, 4 IL-6 9 Adhesion Mol.
Provided : Tjokroprawiro 2005,2006 5 IL-I 10 Adiponectin
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The 23 Metabolic Disorders in Abdominal Obesity
(Summarized : Tjokroprawiro 2006-2007)

ADMA 23 IR 2 Apn
VAT
ROS 22 3 ApoB
1
Fasting FFA 21 4 Remnant LP

Adhesion Mol. 20 5 Fasting TG

vWF 19 6 Post Prandial TG
FVII 18 Abdominal 7 "Normal" LDL

Fibrinogen 17
Obesity 8 LDL

IL-I 16 9 Small Dense LDL

IL-6 15 10 Chol/HDL-C Ratio

CRP 14 11 HDL-C and sd HDL

TNF 13 12 PAI-1
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Practical Tool for Insulin Resistance and -Cell Function

(Mathews et al 1985, Falutz et al 2002, Clinical Experiences : Tjokroprawiro 2002-2007)

HOMA-R : Fasting Insulin (U/ml) x FPG (mmol/l) (N: < 4.0)

Insulin Resistance 22.5

HOMA-B 20 x Fasting Insulin (U/ml) (N: 70150%)

-Cell Function
:
FPG (mmol/l) 3.5

HOMA-R and HOMA-B : 1 Rationale Treatment

Useful in Daily Practice 2 Follow-up of Treatment

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Prevalence of IR in Selected Metabolic Disorders
(Bonora 1998, Designed : Tjokroprawiro 2006-2007)

Hyper-Chol
1

The MetS 8 2 Hypertension

Sequential
Prevalences of IR
Low HDL-C 7 in 3 Uric Acid
Metabolic
Disorders

Hyper TG 6 4 IGT

5
T2DM
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 22
Map of Oral Antidiabetic Drugs in Daily Practice
(Summarized : Tjokroprawiro1996-2007)

I Insulin Secretagogues : - Sulphonylureas (Gen I, II, III : GLIMEPIRIDE )

- Non-Sulphonylureas (Metaglinides : Nateglinide, Repaglinide)
II Insulin Sensitizers :
1 Thiazolidinediones (TZDs) : Glitazones Class ( Rosiglitazone , Pioglitazone)
2 Non-TZDs : Avandamet : Prefixed ROS-MET
a Glitazar Class (Muraglitazar, Ragaglitazar, Tesaglitazar) : MRT
b Non-Glitazar Class (Metaglidasen : Non Edema and Non Weight Gain)
3 Biguanide : - Metformin , Metformin XRa (Glucophage XR)
- 3-Guanidinopropionic-Acid
III Intestinal Enzyme Inhibitors : 1 -Glucosidase Inhibitor : Acarbose
2 -Amylase Inhibitor : Tendamistase
IV Fixed Dose Combination Types : Glucovance, Avandamet , Avandaryl , Amaryl-M
V Other Specific Types : DPP-IV Inhibitors (Vildagliptin, Sitagliptin, Saxagliptin),
Amylin Analogues (Pramlintide, Etc)
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THIAZOLIDINEDIONES = GLITAZONES CLASS
(PPAR - AGONISTS)
Insulin Sensitizer - Specific Ligands for PPAR
(Summarized : Tjokroprawiro 2000-2007)

1 Ciglitazone
2 Englitazone 4 Rosiglitazone=ROS:FDA May 1999
3 Troglitazone (R/ Rezuline)
5 Pioglitazone = PIO : FDA July 1999
Tocopherol Side-Chain
Oxidative Stress in Liver
6 Darglitazone
Liver Damage
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INSULIN SENSITIVITY IN TYPE 2 DM

(Summarized : Tjokroprawiro 2006-2007)

Insulin Sensitivity Insulin Sensitivity

Decreased by : Increased by :
1 TNF PPARs - Agonist
2 RESISTIN 1 TNF
3 FFA :
2 Resistin
Intramyocellular Lipid : IMCL
3 FFA
Hexosamine Pathway
Membrane Fluidity Change 4 Adiponectin
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 25
3 PPAR Isotypes : , , /
(Barish et al 2006, Levine et al 2006, Summarized : 2007)

MECHANISM OF ACTION

-ADIPOCYTE / -HEPATOCYTE
GLITAZONES FIBRATES

1 Artery 2 Heart 3 Muscle 4 Adipose Tissue 5 Liver 6 Macrophage

PPAR : a Dagger in the Heart of the MetS

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 Therapeutic Targets of PPAR in the MetS 26

(Barish et al 2006, Mitchell et al 2006, Provided : 2007)

1 ARTERY 4 ADIPOSE TISSUE

Obesity, FA Ox,
HDL
Thermogenesis

2 HEART PPAR 5 LIVER

Contractility
HGP
FA Ox

3 MUSCLE 6 MACROPHAGE
FA Ox
Anti-Inflammatory
Thermogenesis

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Mechanism of Action of Fibrates () and TZDs ()
(Staels 2000)

FIBRATES () TZDs ()
HEPATOCYTE ADIPOCYTE
+ +
Inactive PPAR Inactive PPAR
Apo C-III
Active PPAR Transcription LPL
PPRE Transcription
Active PPAR
AAAAA PPRE
Apo C-III mRNA
AAAAA LPL mRNA

Apo C-III Protein LPL Activity

TG-Rich Particles
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Mechanism of Action of TZD()s in ADIPOCYTE
(Bailey 2003, Modified : Tjokroprawiro 2003, 2005, 2006)

PPAR AGONISTs (TZDs) RETINOIC ACID

Nucleus Lipogenesis
PPAR RXR Adipocyte Differentiation
Repressor Repressor RNA Polymerase
Co-Activators
Lipoprotein Lipase
Acyl-CoA Synthase
DNA
PPRE
mRNA
Glucose
Enzymes GLUT-4 Uptake
Rough
Endoplasmic Transport
Reticulum FATP, aP2 Fatty Acids
Proteins Uptake

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 29
What is Cardiometabolic Risk (CMR)
Based on the Concept of Risk Continuum
(Summarized : Tjokroprawiro 2007)

GLOBAL CARDIOMETABOLIC RISK

Overall Risk of Developing

T2DM and/or CVD (MI and Stroke)

CLUSTER OF MODIFIABLE RISK FACTORS / MARKERS

EMERGING RISK FACTORS
CLASSICAL FACTORS
(Closely Related to Abdominal Obesity)
1 Smoking 3 Hypertension 5 Low HDL 7 Insulin Resistance
2 High LDL 4 Elevated Blood Glucose 6 High TG 8 High Inflammatory Markers
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Global Cardiometabolic Risk (CMR)
(Vasudevan AR et al 2005, Gelfand EV et al 2006, Provided : 2007)

ADA-2006 ADA-2006

Smoking

High High TG
Blood High
Pressure LDL-C
Type 2 Intra-
Insulin abdominal CVD
Diabetes Low
Resistance Adiposity HDL-C
Elevated
Inflammatory
Blood
Markers
Glucose

HDL-CO FIGAR
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 Basic Strategies for Prevention and Treatment 31

IR Prediabetes The MetS T2DM CVD

(ACE Position Statement - 2002, Summarized : Tjokroprawiro 2004-2007)

A Reducing WC B Treating CMR

1 TLCs : GULOH-CISAR
- Weight Loss 5-10%
- Aerobic Exercise
2 Pharmacological Treatment
- Metformin : Can be Prescribed for
- Acarbose Children > 10 yrs
- Glitazones : Rosiglitazone Pioglitazone
- Avandamet : Prefixed ROS + MET
- Sibutramine Orlistat
- Rimonabant (Phase-III)
- Glitazars : Mura-, Raga-, Tesaglitazar
- Metaglidasen
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1 TLCs : GULOH-CISAR
- MNT = Medical Nutritional Therapy
- Regular Exercise
2 Recommended Treatment Goals
(mg/dl, mmHg) : WC, BMI, H, D, L
* WC < 90 o ; WC < 80 o ; BMI < 25
+
* BP < 130/85; < 130/80 for DM
* FPG < 100; 2h-PG < 140
* LDL < 100, TG < 150 o
* HDL > 40 ( o ), HDL > 50 ( + )
CMR : Cardiometabolic Risk
 32
Obesity Pandemic : The Time-Bomb Disease in the FUTURE ?
(Clinical Experiences : Tjokroprawiro 1995-2007)

Stage - 0 Stage - 1 Stage - 2

"Healthy Lifestyle" "Westernized Lifestyle" Obesity
(Abdominal Obesity)

INTENSIVE
INTENSIVE "Well Programmed"
1 HEALTH EDUCATION 1 HEALTH EDUCATION 1 HEALTH EDUCATION
2 TLC : GULOH-CISAR 2 TLC : GULOH-CISAR 2 TLC : GULOH-CISAR

LEVEL OF INTERVENTION A and B

A FAMILY and B COMMUNITY PHARMACOTHERAPY
Continued
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Obesity Pandemic : The Time-Bomb Disease in FUTURE ?
(Clinical Experiences : Tjokroprawiro 1995-2007)

Stage - 3 Stage - 4
Preclinical Diseases Clinical Diseases
the MetS, Pre-DM, Adolescent Pre-DM CAD, T2DM, Adolescent-T2DM, Stroke
Intensive - Well Programmed Intensive - Well Programmed
TLC : GULOH-CISAR TLC : GULOH-CISAR

DRUG INTERVENTIONS : 6 MAJOR COMPONENTS :

1 Metformin 1 Abdominal Obesity
2 Acarbose 2 Insulin Resistance (IFG, IGT)
3 Glitazones : ROS and PIO 3 Atherogenic Dyslipidemia
4 Avandamet (Prefixed ROS & MET) 4 Raised Blood Pressure
5 Sibutramine - Orlistat
6 5 Proinflammatory State : Fibrinogen, CRP, etc
Rimonabant
7 Glitazars : MRT (Mu-Ra-Te) 6 Prothrombotic State:Fibrinogen,FVII,PAI-1,FXIIIa
8 Metaglidasen
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 TEN PRACTICAL GUIDELINES FOR HEALTHY LIFE 34

GULOH-CISAR = SYNDROME-10
(Tjokroprawiro 1995-2007)

1 G Limit Sugar Consumption 6 C Stop Smoking

+300 kcal/day or 3 km walk
2 U Restrict Purine Intake : JAS-BUKET 7 I Daily Regular Exercise :
+Sit up 50-100 x/day
3 L Consume Low Fat Diet : TEK-KUK-CS2 8 S TAKE MINIMALLY 6-HOUR SLEEP/DAY
4 O Prevent Obesity (Target : BMI < 25) 9 A Stop Alcohol
5 H Measure BP Regularly 10 R Regular Check-Up
(Less than 3 g Sodium/day) Esp. > 40 Years Old : 3, 6 or 12 Months
G = Glucose U = Uric Acid L = Lipids O = Obesity H = Hypertension
C = Cigarette I = Inactivity S = Stress A = Alcohol R = Regular Check Up

JAS-BUKET : Jerohan, Alkohol, Sarden - Burung Dara, Unggas, Kaldu, Emping, Tape
(Bowels, Alcohol, Sardines - Pigeon, Fowls, Meat-Broth, Beaten Nut, Fermented Cassava)

TEK-KUK-CS2 : Telor, Keju - Kepiting, Udang, Kerang - Cumi, Susu, Santen

(Egg, Cheese - Crab, Shrimp, Mussel - Squid, Milk, Coconut - Juice)

"MABUK" (Rich in Chromium) : Mrica, Apel, Brokoli, Udang, Kacang-kacangan; good for DM

Recommended Food Supplements G

: reen Bean, Onions, Green Tea, Pepper, ARGININE, TKW-PJKA-BK
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 35
Beneficial Effects of Weight Loss
(Ryan 2005, Provided : Tjokroprawiro 2007)

CVD Risk CVD Risk

Lipid
Diabetes
Improvements
Prevention BP
2 3
Improvement in
Insulin
1 4 Thrombotic Profile
WEIGHT
LOSS
8 5
Fat Mass Sleep Apnea
Endocrinopathy Osteoarthritis
Improvement 6
7
Oxidative Cancer Risk
Pro-inflammatory Stress
Cytokines
Cancer Risk
CVD Risk
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ROSIGLITAZONE with 13 MECAR EFFECTS
(Viberti 2003, Provided : Tjokroprawiro 2006-2007)

IR
1
ADMA 13
2 Apn
MMP-9 12
3 HDL
BP 11
ROSIGLITAZONE
SMC Migration 10
with 4 LDL but sd LDL
Proliferation MECAR EFFECTS

CRP 9 5 Microalbuminuria

PAI-1 8 6 ROS
7
VAT

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METFORMIN WITH 23 MECAR EFFECTS
(Summarized : Tjokroprawiro 1994-2007)

INSULIN RESISTANCE
ADIPONECTIN 22 1 23 ADMA
SMC Fibroblast 21 2 Glucose Absorption
Hyperinsulinemia 20 3 FBS
Capillary Perm. 19 4 2h PP
Periph. A Blood Flow 18 5 Glycogenesis
METFORMIN
Fibrinolysis 17 with 6 Ins. Receptor Binding
Erythrocyte Deform. 16 MECAR EFFECTS 7 GUT : GLUT-5 Exp.
Platelet Aggregation 15 8 Post-Receptor Effect
Carbonyl Stress 14 9 GLP-1
HDL-Chol 13 10 Gluco- & Lipo-toxicity

TG 12 11 Tot-Chol, LDL-Chol
METFORMIN
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 AVANDAMET WITH 22 MECAR EFFECTS 38

(Viberti 2003, Del Prato et al 2005, Provided : Tjokroprawiro 2006-2007)

-Cell Function 21 IR 2 Insulin Sensitivity

1
ROS 20 3 HDL

MMP-9 19 4 TNF

LDL but SDLDL 18 5 PAI-1

SMC Migr.-Prolif 17 AVANDAMET 6 CRP
with
VAT 16 MECAR EFFECTS 7 Fibrinogen

NASH 15 8 FXIIIa

CD40L 14 9 FVII

ACR 13 10 vWF

ADMA 12 22 11 ADIPONECTIN
FFAs
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 39
ADIPONECTIN with 2 MAIN EFFECTS
Ouchi et al 2000-2001, Yamauchi et al 2001-2003, Arita et al 2002,
Kobayashi et al 2004, Summarized : Tjokroprawiro 2007

I Insulin Sensitizing Actions Antiatherosclerotic Actions

II Antiatherosclerotic Actions
1 Strongly the Expression of
1 TISSUE TG CONTENT Adhesion Molecules :
ICAM-1, VCAM-1, E-selectin; also
TNF-induced NFB Activation
2 UPREGULATE INSULIN SIGNALING
2 Macrophage : SRA-1, Uptake
of Ox-LDL, Foam Cell
3 ACTIVATE PPAR 3 Cell Proliferation, Migration
4 Endothelial Cell Apoptosis
4 ACTIVATE AMPK via AMPK Activation by HMW
multiform of Adiponectin
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AVANDAMETTM with MECAR PROPERTIES

Fixed Dose Combination of ROS and MET

(Summarized : Tjokroprawiro 2006-2007)

ROSIGLITAZONE : 13 METFORMIN : 23
1 At the Level of the Peripheral Tissue 1 At the Level of the Liver

2 To a Lesser Extent, 2 To a Lesser Extent,

Hepatic Glucose Production at Peripheral Tissue
23 Benefits: VAT , IR , Adiponectin , ADMA , FFAs, TNF,
HDL, PAI-1, Fibrinogen, CRP, MMP-9, CD40L, vWF,
NASH, AER, FVII, FXIIIa, SMC Migration and Proliferation,
LDL but sd LDL, ROS,, -Cell Function , Insulin Sensitivity
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AVANDAMET : a Novel "Two-in-One" Drug
(Summarized : Tjokroprawiro 2006-2007)
QUADRUPLE PROPERTIES WITH MECAR EFFECTS
Prefixed Dose ROSIGLITAZONE-METFORMIN Combination

1 INSULIN 2 PRESERVES 3 ANTI 4 ANTI

SENSITIZER -CELL FUNCTION INFLAMMATORY ATHEROSCLEROSIS

FOR METABOLIC CARDIOVASCULAR CARE

BENEFITS FOR PTS WITH CMR FACTORS

New Strategies for the Cardio-Metabolic Syndrome
CHD IR Pre DM the MetS T2DM
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Worldwide Obesity Trends : Globesity
(Summarized : Tjokroprawiro 2007)

WHO Report 1998 Obesity : Preventing and Managing the Global Epidemic
(Classified Obesity as a Growing Epidemic)

NO IMMEDIATE ACTION OBESITY RELATED DISEASE

LRD and ORD : SDU (17) NOS (x6), SUMETSU (x3), MECARSU (x1)

STAGE 0 STAGE 1 STAGE 2 STAGE 3 STAGE 4

Healthy Unhealthy Obesity Preclinical Clinical
Lifestyle Lifestyle (Abdominal) (Pre DM, MetS) (T2DM, CVDs, Etc)

GLOBESITY : TIME-BOMB DISEASE in the FUTURE ?

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HEALTHCARE
ECONOMIC REPRO-
HEART
BURDEN DUCTION
DISEASE
PROBLEM
12 1 2
PSICO- TYPE 2
SOCIAL DIABETES
11 3

OSTEO-
10 GLOBESITY 4 STROKE
ARTHRITIS
Time Bomb Disease?
Tjokroprawiro: 2007
9 5
CERTAIN LIVER
CANCER DISEASE
8 7 6
CELL
GOUT BLADDER
RESPIRATORY DISEASE
PROBLEM

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WORLD OBESITY TRENDS GLOBESITY DIABESITY
(Summarized : Tjokroprawiro 2005-2007)

STAGE 0 STAGE 1 STAGE 2 STAGE 3 STAGE 4

Westernized Obesity Preclinical : the MetS Clinical : CAD
Healthy Lifestyle
Unhealthy Lifestyle (Abdominal Obesity) IFG, IGT, Pedr.-Obese T2DM, Pedr.-T2DM, Stroke

Waist Circumference = WC
PEDIATRIC o > 90 cm o PEDIATRIC
+ > 80 cm
OBESE T2DM

4 Fasting Glucose 1 Triglyceride

> 100 mg/dl > 150 mg/dl

ATP-III 2001 - Criteria GULOH CISAR IDF 2005 - Criteria

2 HDL-Chol
3 Blood Pressure o < 40 mg/dl
> 130/85 mmHg o
+ < 50 mg/dl

Stage 3 or the MetS will be "TIME-BOMB DISEASE in Indonesia ?

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HOLLAND
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KEUKENHOF HOLLAND
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Choose the Right One !!