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Metabolic syndrome

By Dr Amr Abdelmonem,MD.Assistant professor of cardiothoracic anesthesia ,surgical intensive care and clinical nutrition in faculty of medicine, Cairo universityMember of North American Association For The Study Of Obesity

What is metabolic syndrome?

• Metabolic syndrome is a collection of health risks that increase the chance of developing heart disease, stroke, and diabetes.

• The condition is also known by other names including Syndrome X, insulin resistance syndrome, and dysmetabolic syndrome.

What are these health risks?ATP III Guidelines WHO Guidelines

Abdominal Obesity 

Waist Circumference Waist/Hip Ratio Men > 40 inches (102 CM)  >0.90 Women > 35 inches (88 CM)  >0.85

Other Variables Triglycerides 150 mg/dL 150 mg/dLHDL-Cholesterol Men < 40 mg/dL <35 mg/dL Women < 50 mg/dL <39 mg/dLBlood Pressure 130/ 85 mm Hg >140/>90 mm HgFasting Glucose 110 mg/dL 110 mg/dLWHO guidelines also include microalbuminuria (>20 µg/min or albumin:creatinine ratio >30 mg/g).

The Pathogenesis of metabolic syndrome

Environmental lifestyle-related factors:

When we eat ,our bodies break down the food into its basic components ( protein- carbohydrates- fat), and absorbs them into blood stream rise in blood sugar pancreas will release insulin moves sugar into cells either burned for energy or stored away as fat in fat cells or glycogen in liver and muscles

Years of dietery abuse in susceptible patients malfunctioning of insulin sensors hyperinsulinemia

Continued dietery abuse insulin sensors to sluggish insulin resistance

Markers of insulin resistance :

Hypertriglyceridemia

HDL

Hypertension

Hyperinsulinemia (>15µu/ml) Marc C,et al. Obes Res.2005;13:703

Abdominal obesity

Hyperglycemia

Marjo etal , proven liver fat accumulation as an important marker Obes Res 2002; 10: 859

It is now clear that an individual could be

insulin-resistant from one of two main reasons

1. he/she could be genetically resistant (like Reaven’s group) or

2. Could acquire the resistance by becoming obese

Obesity

Lets walk through the fat metabolism pathway and follow the flow of fat molecules:

Fat travels in the form of triglycerides at cells ezymatic breakdowen fatty acids enter the cells mitochondria breakdowen fat in order to enter mitochondria ,fats need carnitine

insulin inhibits Fat- carnitine shuttle system fats move back into blood

Glucagon accelerates this shuttle system

Muscle ,liver, kidney, lung, heart and other cells break down fat

Two enzyme systems on the surface of fat cells regulated by insulin and glucagon

Insulin stimulates lipoprotein lipase that transports fatty acid into fat cells

Glucagon stimulates hormone sensitive lipase that releases the fat from fat cells into the blood

Although we cannot control lipoprotein lipase directly, we can control It indirectly by cotrolling the metabolic hormones ,insulin and glucagon

Fat cells merely store the fat molecules !

DYSLIPIDEMIA

Where does cholesterol come from?

80 % comes from the body itself , every cell in the body is capable of making its own cholesterol , most don’t and rely instead on that made in the liver and skin.

Cholesterol and triglycerides are insoluble in blood

Lipoproteins are envelops that enclose cholesterol and triglycerides Making them soluble in blood,so that they can be transported to tissues

Sequence of events in the life of lipoproteins

Liver Makes and release VLDL

TRIGLYCERIDES WITH CHOLESTEROL

TRI AND CHOLES MATUREVLDL

TriglyceridesReleased to bloodAnd tissues

CholesterolBulk +tri LDL

HDL

Scavenges cholesterlFrom tissues carriesThrough bloodHands it off to

VLDL

More triglycerides release

Removed by liver

CholesteroLrich

LDL

Released to tissuesDeposited in coronary arteries

When the level of cholesterol inside the cells falls LDL receptors Attach to the surfaces of the hepatic cells invaginate LDL cholesterol By endocytosis

Obese patients with insulin resistance have LDL receptors dysfunction

Cholesterol synthesis inside the cells depends on an enzyme named3- hydroxy-3 methyl-glutaryl-coenzyme A reductase

Couple of hormones affect the activity of the rate limiting enzymeHMG-CoA reductase

INSULIN AND GLUCAGON

Hypertension

Data from NHANES III show that the (age – adjusted prevalence) Of high blood pressure increases progressively with higher levels Of BMI in men and women

High blood pressure is defined as

SBP 140 mm Hg or MBP 90 mm Hg or currently taking antihypertensives

What is the etiology that connects obesity and hypertension?

Hyperinsulinemia and Insulin resistance

Mechanism

1. Increased sodium retention

2. Increased sympathetic nervous system activity

3. Alteration in the mechanics of blood vessels

Recently

Type II Diabetes mellitus

•The cells become resistant to insulin that even large amounts cant adequately move the sugar into cells

•Resistin is a protein secreted by fat cells as a signal from adipose tissue linking obesity to insulin resistance and type II diabetes Liese et al, Eur J Nutr.2001;40:282

•Increased White blood cell count is correlated with insulin resistance in diabetic obese females

Pannacciulli et al,Obes Res.2003;11:1232

Coronary artery disease

• Observational studies have shown that overweight,obesity, and VAT are directly related to cardiovascular risk factors

( cholesterol , LDL, triglycerides, hypertension, fibrinogen,hyperinsulinemia , HDL, plasminogen activator inhibitor )

RECENTLYComplement 3 and acute phase proteins is the immunological link between central obesity and CHD

The term "Syndrome X" refers to a heart condition where chest pain and electrocardiographic changes that suggest ischemic heart disease are present, but where there are no angiographic findings of coronary disease.

Obesity and cardiac dysrhythmias(prolonged Q-T interval)

• Q-T interval is usually measured in lead II , and is corrected for heart rate .

• Q-Tc= measured Q-T square root of R-R interval• Prolonged Q-T interval reflects prolonged

repolarization of the ventricle• Proposed mechanism is increased SNS activity• Recent study had found that Prolonged Q-T

interval is associated with abnormal WHR ,higher levels of FFA and hyperinsulinemia in obese women .

• Wight loss leads to normalization of Q-Tc with attenuation of hyperinsulinemia

Esposito et al,Obes Res.2003;11:653-659

Oxidant Stress

Imbalance

Between

Formation Of Reactive oxygen/nitrogen species (ROS/RNS)

And Antioxidants

Pathologic stress Induces monocytes to release mediators

(TNF and interleukins 1-6-8) Activates PMNs

Release ROS(superoxide (O2·-), hydrogen

peroxide, hypochlorite, nitric oxide (NO), hydroxyl radical

Induce tissue injury by:1. damaging DNA2. Cross linking cellular proteins3. Peroxidation of membrane lipids • Diminishing membrane fluidity• Increasing membrane permeability

Oxidant Stress and Obesity

•Adipocytes and preadipocytes have been identified as sources of inflammatory cytokines:

including TNF , interleukin (IL)1-ß, and IL-6.

•Stimuli capable of inducing cytokine release from adipocytes may include:

lipopolysaccharides, intracellular triglycerides, and catecholamines

http://www.obesityresearch.org/cgi/content/full/10/9/964/F2

We could predict that:

•The accumulation of intracellular triglycerides or tissue adiposity promotes increased oxidant stress

•Therefore reduction of total body fat through diet and/or exercise may be an effective means of reducing systemic inflammation and oxidant stress.

Consistent with this prediction

Reductions in plasma markers of oxidant stress and in ROS generation by isolated leukocytes have been observed after 4 weeks of energy restriction and weight loss.

Dandona et al. J Clin Endocrinol Metab,2001; 86:355-363

Good news

Physical activity •Decreases adipose derived inflammatory mediators •Activates signaling pathways that lead to increased synthesis of intracellular antioxidants and antioxidant enzymes and decreased ROS production Miyazaki et al, Eur Appl Physiol.2001; 84:1-6 Pischon et al, Obes Res.2003;11:1055

A novel pathway to the manifestations of metabolic syndrome(2004)