Transcript Metabolic Syndrome - Culprits - Josephine Carlos

METABOLIC SYNDROME:
CURRENT CONCEPTS
Josephine Carlos-Raboca, MD, FPCP, FPSEM
Chief, Section of Endocrinology, Diabetes and Metabolism
OUTLINE
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Definition of Metabolic Syndrome
Clinical Significance of Metabolic Syndrome
What Causes Metabolic Syndrome
Link up between Obesity, Insulin Resistance and
Metabolic Syndrome
Principles in Management of Metabolic
Syndrome
Metabolic Syndrome
A constellation of major risk factors, life-habit risk
factors:
 Abdominal obesity
 Atherogenic dyslipidemia
− Elevated TG
− Small, dense LDL particles
− Low HDL-C
 Elevated blood pressure
 Insulin resistance
 Prothrombotic and proinflammatory states
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486-2497.
WHO definition of ‘Metabolic
Syndrome’
AT LEAST ONE OF:
• glucose intolerance
• IGT
• type 2 diabetes
• insulin resistance*
* Insulin resistance defined under
hyperinsulinemic, euglycemic
conditions as glucose uptake below
the lowest quartile for the background
population under investigation
+
AT LEAST TWO OF:
• impaired glucose regulation or diabetes
• insulin resistance*
•  arterial pressure
 140/90 mmHg
•  plasma triglycerides
 1.7 mmol/l or 150 mg/dl and/or
 HDL cholesterol
< 0.9 mmol/l or 35 mg/dl for men;
< 1.0 mmol/l or 39 mg/dl for women
• central obesity
waist:hip ratio > 0.90 for men, > 0.85 for
women; and/or BMI > 30 kg/m2
• microalbuminuria
urinary albumin excretion rate  20 g/min
or albumin to creatinine ratio  30 mg/g
World Health Organization. Definition, diagnosis and classification of diabetes mellitus and its complications.
Part I: Diagnosis and classification of diabetes mellitus. WHO Department of Noncommunicable Disease Surveillance; 1999.
2005 Revised ATP III Clinical Screening Criteria
to Identify Metabolic Syndrome (AHA and NHLBI)
Measure (any 3 of 5 constitute
diagnosis of metabolic syndrome)
Categorical cutpoints
Elevated waist circumference
≥102 cm in men
≥88 cm in women
Elevated triglycerides
≥150 mg/dl (1.7 mmol/l) or on drug
treatment for elevated triglycerides
Reduced HDL-cholesterol
<40 mg/dl (0.9 mmol/l) in men
<50 mg/dl (1.1 mmol/l) in women
Or on drug treatment for reduced HDLC
Elevated blood pressure
≥130 mmHg systolic blood pressure or
≥85 mmHg diastolic blood pressure
or on antihypertensive drug treatment in
a patient with a history of hypertension
Elevated fasting glucose
≥100 mg/dl or on drug treatment for
elevated glucose
Diagnosis of The Metabolic
Syndrome
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IDF CRITERIA (2005)
Central obesity (defined as waist circumference 94 cm
for Europid men and 80 cm for Europid women, with
ethnicity specific values for other groups)
Plus any two of the following four factors
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TG 150 mg/dl (1.7 mmol/l), or specific treatment for this lipid
abnormality
HDL <40 mg/l (1.03 mmol/l) in males and <50 mg/l (1.29
mmol/l) in females, or specific treatment for this lipid abnormality
Systolic BP 130 or diastolic BP 85 mmHg, or treatment of
previously diagnosed hypertension
Fasting plasma glucose 100 mg/dl (5.6 mmol/l), or previously
diagnosed type 2 diabetes. If above 5.6 mmol/l or 100 mg/dl,
OGTT is strongly recommended but is not necessary to define
presence of the syndrome
Diagnosis of The Metabolic
Syndrome
IDF CRITERIA (2005)
Ethnic-specific cut-points for waist circumference
Country/Ethnic group
Europids
South Asians
Chinese
Japanese
Male
Female
Male
Female
Male
Female
Male
Female
Waist circumference (as
measure of central obesity)
94 cm
80 cm
90 cm
80 cm
90 cm
80 cm
85 cm
90 cm
Diagnosis of The Metabolic
Syndrome
IDF CRITERIA (2005)
Ethnic-specific cut-points for waist circumference
Country/Ethnic
group
Ethnic South and
Central Americans
Sub-Saharan
Africans
Eastern
Mediterranean and
Middle East (Arab)
populations
Waist circumference (as measure of
central obesity)
Use South Asian recommendations until
more specific data are available
Use European data until more specific
data are available
Use European data until more specific
data are available
A Major Health Issue Worldwide
Prevalence of the metabolic syndrome
(ATP III)
*Obesity criteria adjusted to waist circumference appropriate
for an Indian population
 Clinical
Significance of Metabolic
Syndrome
Metabolic syndrome predicts future CHD
and DM
Metabolic Syndrome
High LDL-C
T2DM
Coronary Heart Disease
Metabolic Syndrome and Risk of
CV Events
Whatever The
Definition, The
Metabolic Syndrome
Increases 1.5 to 2fold The Risk of CV
Events
Dekker JM, et al. (Hoorn study). Circulation 2005;112:666-673.
CHD Death or Non-fatal MI
3.7 Fold Increase CHD Risk with 4-5
Features of the Metabolic Syndrome
Sattar et a Circ 2003;108:414-419l
Diabetes and Metabolic Syndrome Worsen Long-term
Prognosis in Patients with Acute Myocardial Infarction
G Levantesi G, et al. (GISSI-Prevenzione). J Am Coll Cardiol 2005;46:277-283.
Onset of new DM
24.5 Fold Increase Risk of New Onset
Diabetes with 4-5 Features of the Metabolic
Syndrome
Sattar et a Circ 2003;108:414-419l
Other Associated Disorders
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Obstructive Sleep Apnea
Fatty Liver (Non Alcoholic Steatorrheic
Hepatitis)
Arthritis
Polycystic Ovarian Syndrome
Malignancy
 What
is the root cause of
Metabolic Syndrome?
Insulin Resistance?
Obesity?
Inflammation?
The Metabolic Syndrome: a network
of atherogenic factors
Genetic factors
Environmental
Factors
(Obesity,
Physical
Inactivity)
Hyperglycemia/IGT
Dyslipidemia
Insulin
Resistance
Hypertension
Endothelial dysfunction/
Microalbuminuria
Hypofibrinolysis
Inflammation
Atherosclerosis
McFarlane S, et al. J Clin Endocrinol Metab 2001; 86:713–718.
Link
between Insulin
Resistance and Metabolic
Syndrome
Insulin resistance – a reduced response
of target tissues to circulating insulin
Carbohydrate
Endothelial
dysfunction
Glucose (G)
Defective
insulin secretion
Excessive fatty
acid release
I
Insulin (I)
Excess glucose
production
I
Reduced glucose
uptake
Resistance to the action of insulin
Indicators of Insulin Resistance
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HOMA
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Hyperinsulinemia
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Triglyceride/HDL >4
Insulin Resistance Syndrome
Central obesity
Endothelial
dysfunction/
microalbuminuria
Dyslipidemia
Hyperglycemia
Insulin
resistance
Hypofibrinolysis
Hypertension
Inflammation
Cardiovascular disease
Festa A et al. Circulation 2000; 102:42–47;
Reaven GM et al. Annu Rev Med 1993; 44:121–131.
Prevalence of HOMA-estimated
insulin resistance (%)
Prevalence of insulin resistance
correlates with increasing number of
100
metabolic disorders
80
60
40
20
0
0
1
2
3
4
Number of metabolic disorders
n = 888
Metabolic disorders: glucose intolerance, dyslipidemia, hyperuricemia and/or
hypertension. P < 0.001 for differences between all categories.
Bonora E, et al. Diabetes 1998; 47:1643.
Link between Obesity and Metabolic
Syndrome
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Fat accumulation leads to systemic oxidative
stress
Increase ROS (eg H2O2)
-increase NADPH oxidase activity and
decreased antioxidant enzymes – leads to
dysregulated adipocytokine production
- insulin resistance
- increase MCP -1 – HPN and atherosclerosis
Insulin resistant adipocytes secrete multiple
signaling molecules linked with inflammation &
insulin resistance
Free fatty acids 
TNF a 
Leptin 
Resistin 
Adiponectin 
Angiotensin II 
PAI-1
Adipokines Mediates IR and
Inflammation
Adiponectin,  TNFa,  Leptin, PAI-1,  IL-6, Angiotensinogen
 Insulin Sensitivity
 Vascular Infllammation
Insulin Resistance
Endothelial Dysfunction
How Does Abdominal Obesity
Cause Insulin Resistance
Reduced
Physical
Activity
Genetic
factors
Excessive
food intake
Inflammation insulin
receptor
 IL-6
Substrate
 TNF-a (IRS-1 & IRS-2)
 various
cytokines
adiponectin 
 leptin
 blood FFA
Insulin Resistance of Abdominal Adipose Tissue
and Atherogenic Dyslipidaemia
Liver
FFA
Insulin
Resistant
Abdominal
Adipocytes
CE
 TG
 Apo B
VLDL (CETP)
TG
CE
(CETP)
TG
(HL)
HD2
HDL3
Apo A-1
Kidney
LDL
LDL small, Dense
( HL)
LDL
Visceral Fat Associates with
Atherogenic Dyslipidaemia
Adapted from Pouliot MC, et al. Diabetes 1992;41:826-834.
Low HDL-C Predicts CHD Risk
Low HDL-C is an independent predictor of CHD risk
even when LDL-C is low
Castelli WP. Can J Cardiol. 1998;4 (suppl A):5A-10A.
Patients with Elevated Triglycerides are at Increased
Risk for CHD
High TG associates with higher relative risk for CHD in
the Framingham Heart Study
Castelli WP. Can J Cardiol. 1998;4 (suppl A):5A-10A.
Small, Dense, LDL Particles were an Independent
Risk Factor for CAD in Quebec Cardiovascular Study
St Pierre, et al. Circulation. 2001:104:2295.
Obesity Is An Inflammatory
Stimulus
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Metabolic syndrome is a proinflammatory,
proatherogenic condition
Many adipose tissue products can cause insulin
resistance and inflammation:
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Cytokines (e.g., TNF-a, IL-6)
Chemokines
Growth factors
Procoagulants (e.g., PAI-1)
Free fatty acids
Resistin
Adiponectin
Nitric oxide synthase
Atherosclerosis Is An
Inflammatory Disease
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Initial step of atherosclerosis: leukocyte recruitment by the
dysfunctional endothelium, facilitated by chemo-attractants
and adhesion molecules (VCAM-1, ICAM-1)
In the intima, maturation of the mononuclear phagocyte
towards the foam cell (capture of modified lipoproteins)
Activated foam cells
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express the procoagulant tissue factor
generate reactive oxygen species and pro-inflammatory cytokines
(CRP, IL-6)
can also be the source of enzymes that alter the metabolism of the
extracellular matrix
Death of the mononuclear phagocyte by either oncosis or
apoptosis leads to formation of the lipid core of the
atherosclerotic plaque
Atherosclerosis Is An
Inflammatory Disease
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The endothelium and smooth muscle vascular
cells can themselves elaborate pro-inflammatory
cytokines.
In the initial phase of inflammation, elaboration
of
pro-inflammatory cytokines and the cross talk
between leukocytes and intrinsic vascular wall
cells play a key role in the initiation of the
progression phase.
Atherosclerosis Is An
Inflammatory Disease
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Alterations in the metabolism of the extracellular
matrix under the plaque
arterial remodelling
Suppression of new collagen synthesis by smooth
muscle cells
 Overproduction of collagen-degrading proteinases
that attack the collagen within the fibrous cap
 Inflammatory
mediators tightly control the
biosynthesis of tissue factor (a procoagulant)
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Weakening of the fibrous cap
a disrupted atheroma
thrombosis of
C-Reactive Protein and
Metabolic Syndrome
Ridker et al. Circulation. 2003;107:391.
High CRP Levels Predict CVD in Patients with
and without Metabolic Disorders
Malik S, et al. (NHANES 1999-2000). Diabetes Care. 2005;28:690-93.
Adiponectin Levels are Significantly
Lower in Hypertensive Subjects
Iwashima Y, et al. Hypertension 2004;43:1318-1323.
Excess FFA are linked to both Insulin
Resistance and Inflammation
FFA
FA CoA
DAG
P --Ser—IRS1
Insulin Resistance
IkB
NFkB
ROS
PKC
Inflammation
Inoguchi et al. Diabetes 2000;49:1939-45.
Yu et al. Diabetologia 2001;44:614-20; Lu et al. Circ.Res. 1996;79:611-8.
Elevated circulating FFA is a central factor in
the development of type 2 diabetes
Insulin resistance
Decreased glucose uptake
into muscle and adipose
tissue and raised hepatic
glucose output
High insulin demand and
insulin resistance in
pancreas
Increased
lipolysis
Elevated circulating FFA
Hyperglycemia
-cell dysfunction
Arner P. Diabetes Obes Met
2001;3 (Suppl.1); S11–S19.
Obesity, Type 2 Diabetes, and
Metabolic Syndrome: 3 Interrelated Epidemics
Overweight/Obesity: a worldwide epidemic
 >1 billion adults worldwide were:
- Overweight in 2002 1
- BMI>25 kg/m2
 At least 300 million are
clinically obese 2
- BMI>30 kg/m2
1- World Health Organization. Global strategy on diet, physical activity and health, 2003.
Available at: http://www.who.int/hpr/NPH/docs/gs_obesity.pdf. Accessed November 11, 2003.
2- International Obesity Task Force. Available at: http://www.iotf.org. Accessed November 13, 2003.
The Metabolic Syndrome Is
A Metabolic Time Bomb
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With the elevated risk of
diabetes and
cardiovascular disease
from the metabolic
syndrome, there is an
urgent need for
strategies to defuse this
metabolic time bomb
Management of
Metabolic Syndrome
What to do About the Metabolic
Syndrome?
A. Intervening in the Metabolic Syndrome:
Cardiovascular Risk Assessment
Metabolic Syndrome
Traditional Risk Factors
B. Lifestyle Modification
C. Drug Treatment
First Step: Assessment of Global
Cardiovascular Risk
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Risk engines incorporate the major cardiovascular
risk factors into a summary 10-year CHD risk score
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Framingham: age, sex, smoking, total cholesterol,
HDL-C, systolic blood pressure or treated hypertension
PROCAM: age, smoking, LDL-C, HDL-C, triglycerides,
SBP, fasting blood glucose, diabetes, treated
hypertension, family history of CHD
UKPDS risk engine: estimation of cardiovascular risk in
patients with type 2 diabetes and no previous MI
Therapeutic Objectives
To reduce underlying causes:
Overweight and obesity
 Physical inactivity
To treat associated lipid and non-lipid risk factors:
 Hypertension
 Prothrombotic state
 Atherogenic dyslipidaemia
 Insulin Resistance or Glucose Intolerance
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Lifestyle Therapies: First-Line Interventions
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to Reduce Metabolic Risk Factors
The major lifestyle interventions include:
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Weight loss in overweight or obese subjects
Increased physical activity
Modification of an atherogenic diet
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These changes will produce a reduction in all
of the metabolic risk factors simultaneously
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In the long run, the greatest benefit for those
with the metabolic syndrome will be derived
from effective lifestyle intervention
Weight Reduction or
Maintenance
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Weight reduction through caloric restriction:
Caloric intake should be reduced by 500-1000
calories per day to produce a weight loss of 0.5-1.0
kg per week
 The goal is to reduce bodyweight by about 7-10%
over 6-12 months
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Weight maintenance can be achieved through
long-term lifestyle changes
Dietary Changes
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Caloric restriction must be combined with a set
of dietary principles:
Saturated fat: 7% of total calories
 Reduced trans fat
 Dietary cholesterol: <200 mg daily
 Total fat: 25-35% of total calories
 Reduced consumption of simple sugars
 Increased intakes of fruits, vegetables, and whole
grains
The relative amounts of carbohydrate and
unsaturated fats is more controversial
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Physical Activity
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Regular and sustained physical activity will improve
all risk factors of the metabolic syndrome
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Combination of weight loss and exercise reduces
the incidence of type 2 diabetes in patients with
glucose intolerance
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Current guidelines recommend 30-60 min
moderate-intensity exercise daily (e.g., brisk walking)
Third Step: Using Drug Therapy to Modify
CV
Risk Factors in High-Risk Patients
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Therapeutic lifestyle changes will reduce the
severity of all components of the metabolic
syndrome
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However, drug therapy may be necessary in
people at particularly high risk or if a given risk
factor is severely abnormal
Therapy of Metabolic Risk Factors
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Atherogenic dyslipidaemia
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Elevated BP
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Primary target:  LDL-C levels to ATP III goal levels
Secondary target: TG >200 mg/dl,  non-HDL-C to ATP
goals
Tertiary targets: HDL-C <40 (men) or <50( women) – after
attaining non-HDL-C goal, raise HDL-C to extent possible
 BP to at least achieve BP <140/90 mmHg
(or <130/80 mmHg if diabetes)
Elevated glucose – for IGF, delay progression to type 2
DM; for diabetes, HbA1C <7.0 %
Prothrombotic state: reduce thrombotic and fibrinolytic
risk factors
Drug Treatment
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Weight Reduction
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Dyslipidiemia
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Statins, Fibrates, Nicotinic Acid,Ezetimibe
Diabetes Mellitus
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Orlistat
Sibutramine
Insulin Enhancers –SU,Meglitinides,Incretins
Insulin Sensitizers – Biguanides, TZD
Metabolic Syndrome ?
PPARs , Romonabant
From Basic Science to Treatment
PPARS: Modulators of the Metabolic
Syndrome
PPARs
=
Regulators of energy homeostasis,
lipid and glucose metabolism and
inflammation
Modulators of the metabolic syndrome
and its cardiovascular complications
Control of Gene Expression by PPARs
PPAR agonists
(fatty acids, fibrates, glitazones, glitazars)
PPAR
PPAR
RXR
p65 p50
Fos
Jun
STAT1 STAT3
PPAR RXR
AGGTCA (N) 1, 2 AGGTCA Target
gene
GGGGACTTTCCC TGAGTCA
PPRE
Trans- activation
Lipid homeostasis
Glucose homeostasis
NF-kB-RE TRE
CTGGGA
ISGF-RE
Trans-repression
Anti-inflammatory
properties
Glucose Metabolism PPARs Regulate Lipid
and Glucose
PPAR Agonists Interrupt the
Inflammatory Cycle
PPAR Agonists May Block Inflammatory
Atherogenesis at Several Steps
PPARa/g
CONCLUSION
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Metabolic Syndrome is a clustering of
cardiovascular risk factors
Metabolic Syndrome is a global epidemic
Insulin Resistance is the core of Metabolic
Syndrome modified by obesity, inflammation,
genetics and environmental factors
Management of
MS include lifestyle
modifcation and drug treatment of the
individual components