BYDr.Liniyanti D.Oswari, MNS, MSc.

To understand the lipid & lipoprotein metabolism in the body.Recognize the significance of dyslipidemia in Atherosclerosis on CVD & CHD, including the role of HDL-C as a protective risk factor for CVD &CHDRecognize the relationship dyslipidemia with central obesity & Insulin resistanceExamine recent clinical trials of dyslipidemia as it relates to the prevention and treatment of CVD & CHD

Clusters of lipids associated with proteins that serve as transport vehicles for lipids in the lymph and blood

ChylomicronsVLDL Very low density lipoproteinIDL Intermediate density lipoproteinLDL Low density lipoproteinHDL High density lipoprotein

Distinguished by size and densityEach contains different kinds and amounts of lipids and proteinsThe more lipid, the lower the densityThe more protein, the higher the density

ClassSize (nm)LipidsMajor ApoproteinsChylomicra100-500Dietary TGB-48,C-II,EVLDL30-80Endogenous TGB-100,C-II,EIDL25-50CEs & TGsB-100, ELDL18-28CEsB-100HDL5-15CEsA,C-II,ELp (a)25-30CEsB-100 & glycoproteins

LipidChylomicronVLDLIDLLDLHDLCholesterol922354719Triglyceride82522093Phospholipid718202328

Made by intestinal cells Most of lipid is triglycerideLittle proteinApoA-I, ApoA-II, ApoB-48, ApoCDeliver fatty acids via lipoprotein lipase

Chylomicron remnantsLipoprotein particle that remains after a chylomicron has lost most of its fatty acidsTaken up by liverContents reused or recycled

LiverSynthesizes & metabolizes lipidsCentral command center for relation of lipid metabolismMakes additional lipoproteins Transports exogeneous ( dietary ) triglycerides90 - 95 % by weight is triglycerides(dominant)Absent from fasting plasmaRemoved from the plasma within 6 hours by the liverInadequate clearance produces a creamy layer on the plasma

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Vessel wall CholestAAFAP,glycerol

LiverFecal bile acids and neutral sterolsExogenousExtrahepatic tissuesEndogenousDietarycholesterol (~300700 mg/day)IntestineAdapted from Champe PC, Harvey RA. Biochemistry. 2nd ed. Philadelphia: Lippincott Raven, 1994; Glew RH. In Textbook of Biochemistry with Clinical Correlations. 5th ed. New York: Wiley-Liss, 2002:728-777; Ginsberg HN, Goldberg IJ. In Harrisons Principles of Internal Medicine. 14th ed. New York: McGraw-Hill, 1998:2138-2149; Shepherd J Eur Heart J Suppl 2001;3(suppl E):E2-E5; Hopfer U. In Textbook of Biochemistry with Clinical Correlations. 5th ed. New York: Wiley-Liss, 2002:1082-1150.Biliary cholesterol (~1000 mg/day)~700 mg/daySynthesis (~800 mg/day)

Cholesterol is obtained from endogenous and exogenous sources. Endogenous cholesterol is synthesized in all tissues, but primarily the liver, intestine, adrenal cortex, and reproductive tissues, including the placenta. Exogenous cholesterol is absorbed by the intestine from dietary and biliary sources and transported to the liver.1,2 In individuals eating a relatively low-cholesterol diet, the liver produces about 800 mg of cholesterol per day to replace bile salts and cholesterol lost in the feces.2 Depending on diet, people typically consume 300 to 700 mg of cholesterol daily.3,4 Approximately 1000 mg of cholesterol is secreted by the liver into the bile. Thus, approximately 1300 to 1700 mg of cholesterol per day passes through the intestines,4 of which about 700 mg per day is absorbed.5 Because plasma cholesterol levels are maintained within a relatively narrow range in healthy individuals, a reduction in the amount of dietary cholesterol leads to increased synthesis in the liver and intestine.2

ResinsPlant stanolsNPC1L1 (Ezetimibe)Inhibitors

Cholesterol that is absorbed from the intestinal lumen comes from two sources: dietary cholesterol and biliary cholesterol (which is by far the greater of the two in quantity).Cholesterol is emulsified by bile acids and packaged in lipid micelles.These lipid micelles are transported to the brush border of jejunal enterocytes.At the brush border of the enterocyte, the cholesterol is released from the lipid micelle and then enters the enterocyte.

*Exogeneous PathwayTransport of dietary lipids, mostly the chylomicrons transportation of triglycerides to the liver

Endogeneous PathwayTransportation of lipids from the liver to the tissues ( VLDL & LDL )

Effects of hormonesInsulinRemember, insulin always decreases plasma glucoseInactivates lipase decreases lipolysis and the catabolism of triglycerides to fatty acids / glucoseStimulates lipogenesis ( fatty acid conversion to triglycerides )Insulin helps make fatIn diabetes mellitus, insulin deficiency promotes the release of fatty acids and their conversion to triglycerides by the liver

Made by liverTransports endogeneous triglycerides from liver to tissues50 - 65 % by weight is triglyceridesExcess dietary carbohydrates are converted to triglycerides by the liver

Delivers fatty acids to cellsMore dense than chylomicronsA bit more protein (8%):ApoB-100, ApoC, ApoE

1- Assembly and secretion2- Hydrolysis by LPL3- Direct uptake by hepatocyte4- Flux of pathway into LDL

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Lipoprotein that results from loss of fatty acids from VLDLMajor lipid is cholesterol estersProteins similar to VLDL but greater percentage (15%) ApoB-100, ApoC, ApoETaken up by liver or remain in circulationConverted to low-density lipoproteins (LDL)

Synthesized in the liverApproximately 50 % by weight cholesterolMost atherogenic lipoprotein Bad Cholesterol Delivers cholesterol from liver to cellsCell membranesHormone productionProtein (21%) ApoB-100Binds to specific LDL receptorLDL receptorsMembrane-bound proteins that bind LDL, causing them to be taken up & dismantled

Increase LDLSFAsTrans fatty acidsHigh cholesterol intakeLifestyle factorsGenetics

Decrease LDLHigh PUFA diet-3 fatty acidsDietary fiberLifestyle factorsGenetics

Insulin resistance increased NEFA and glucose flux to liverInsulin resistance and decreased apo-B degradationInsulin resistance and decreased LPLIR impairs LDLR Increased VLDLFCHLDM IIMetabolic syndrome

Direct AssociationLonger residence time in plasma than normal sized LDL due to decreased recognition by receptors in liverEnhanced interaction with scavenger receptor promoting foam cell formationMore susceptible to oxidation due to decreased antioxidants in the coreEnter and attach more easily to arterial wall Endothelial cell dysfunctionIndirect AssociationInverse relationship with HDLMarker for atherogenic TG remnant accumulationInsulin resistance

Good cholesterol; major lipid is phospholipidLipoprotein made by liver & intestine that circulates in the blood to collect excess cholesterol from cellsLowest lipid-to-protein ratio

Composition30% PHOSPHOLIPIDS20% CHOLESTEROL Protein (50%) ApoA, ApoC, ApoE

Reverse cholesterol transportSalvage excess cholesterol from cellsTransported back to liver

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HMG-CoA reductase-reduces HMG-CoA to mevalonic acid in the rate-limiting step of cholesterol biosynthesis (mainly liver and intestine)Lipoprotein Lipase- digests TG core of CMC and VLDL

Hepatic Lipase-conversion of IDL to LDLCETP-transfers cholesteryl esters from HDL to other lipoproteins in exchange for TGLCAT(lecithin cholesterol acyl transferase) conversion of cholesterol to cholesterol estersApolipoprotein A-major protein of HDL activating many reactionsApo-B-major protein of VLDL, IDL, and LDL

Apo-CII and Apo E obtained from HDL by CMC and VLDL for activation of LPL and receptor recognition respectively

Why Does HDL-C Protect?HDL-C

What raises HDL?Uncertain if low carbohydrate diets offer protectionHigh MUFA intakeLifestyle factors ( Exercise)

Genetic factors influence HDL

Reverse cholesterol transport

Maintenance of endothelial function

Protection against thrombosisWith Apo A-I inhibits generation of calcium-induced procoagulant activity on erythrocytes by stabilizing cell membrane

Low blood viscosity via permitting red cell deformability

Anti-oxidant properties-may be related to enzymes called paraoxonase

Elevated triglyceridesPost-prandial lipemiaSmall dense LDL (type B) Elevated LDLLow HDL cholesterolElevated Total CholesterolNature Medicine 2002

Fat CellsTGApo BVLDLLiverIRInsulinFFACE (CETP) TG(lipoproteinorhepatic lipase)KidneyApo A-1VLDL LDLCE(CETP)TG HDLSDLDL(hepatic lipase)

IncreasedApo BTriglyceridesVLDLLDL and Small Dense LDLDecreasedHDLApo A-I

VLDL1 gives rise to small dense LDLIncrease TG/Chol content through CETPIncrease delipidation by hepatic lipase

HDL-3, larger with apo A, C-II, & C-IIIHDL-2, largest, with additional apo E.Best negative correlate CADOther functions attributed to HDL: inhibits monocyte chemotaxis, LDL oxidation Tulenko 2002 J Nuclear Cardiology 9:638

CETPinhibitorsLow HDL-cholesterolIncreased catabolism of small dense HDLLow HDL cholesterol by both content and # particles

High triglyceridesPost-prandial lipemiaSmall dense LDL (type B)Low HDL cholesterolABCA-1CETPNiacinStatinFibrate

Total Cholesterol : HDL + LDL + Triglycerides/5

LDL : Total Cholesterol (HDL + Triglycerides/5)

HDL : Total Cholesterol (LDL +Triglycerides/5)

VLDL : Triglycerides/ 5

Familial Hypercholesterolemia High LDL-C (Type IIA)Polygenic Familial HypercholesterolemiaFamilial Combined Hyperlipidemia High LDL-C and/or high TG levelsFamilial Dyslipidemias High TG and low HDLFamilial Dysbetalipoproteinemia (Type III)

*IDL, intermediate-density lipoproteinLDL, low-density lipoproteinVLDL, very-low-density lipoproteinFredrickson-Levy-Lees ClassificationDiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy: A Pathophysiologic Approach, 7th Edition: http://www.accesspharmacy.com

TypeLipoprotein ElevationIChylomicronsIIaLDLIIbLDL + VLDLIIIIDL (LDL1)IVVLDLVVLDL + Chylomicrons

*DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy: A Pathophysiologic Approach, 7th Edition: http://www.accesspharmacy.com

Lipid PhenotypePlasma Lipid Levels [mmol/L (mg/dL)] Lipoprotein ElevatedPhenotypeClinical SignsIsolated hypercholesterolemiaFamilial hypercholesterolemiaHeterozygotes TC = 713 (275500)LDLIIaUsually develop xanthomas in adulthood and vascular disease at 3050 yearsHomozygotes TC >13 (>500)LDLIIaUsually develop xanthomas in adulthood and vascular disease in childhoodFamilial defective Apo B-100Heterozygotes TC = 713 (275500)LDLIIaPolygenic hypercholesterolemiaTC = 6.59 (250350)LDLIIaUsually asymptomatic until vascular disease develops; no xanthomasIsolated hypertriglyceridemiaFamilial hypertriglyceridemiaTG= 2.88.5 (250750)VLDLIVAsymptomatic; may be associated with increased risk of vascular diseaseFamilial LPL deficiencyTG>8.5 (750)Chylomicrons, VLDLI, VMay be asymptomatic; may be associated with pancreatitis, abdominal pain, hepatosplenomegalyFamilial Apo C-II deficiencyTG>8.5 (>750)Chylomicrons, VLDLI, VAs above

*DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy: A Pathophysiologic Approach, 7th Edition: http://www.accesspharmacy.com

Lipid PhenotypePlasma Lipid Levels [mmol/L (mg/dL)]Lipoprotein ElevatedPhenotypeClinical SignsHypertriglyceridemia and hypercholesterolemiaCombined hyperlipidemiaTG= 2.88.5 (250750); TC = 6.513 (250500)VLDL, LDLIIbUsually asymptomatic until vascular disease develops; familial form may present as isolated high TG or isolated high LDL cholesterolDysbetalipo-proteinemiaTG= 2.88.5 (250750); TC = 6.513 (250500)VLDL, IDL; LDL normalIIIUsually asymptomatic until vascular disease develops; may have palmar or tuboeruptive xanthomas

Many genetic abnormalities & environmental factors lead to lipoprotein abnormalitiesCurrent laboratory values can not define underlying abnormality2 hyperlipidemia should be initially managed by correcting underlying abnormality when possible**

Genetic disorder resulting in production of faulty HDL particles that cannot take up cholesterol from cellsHigh risk for developing cardiovascular disease

Image courtesy of the Internet Stroke Center at Washington University - www.strokecenter.orgCan see the platelet aggregation in response to the foam cell chemicals and tissue damageThe platelets will activate the coagulation cascade, resulting in the production of fibrin strands which trap platelets, red and white blood cells over the area = thrombusIn larger vessels, it takes longer to develop a thrombus big enough to completely block the vessel so you get warning signs (TIA, UA) of stroke and MIThis process happens everywhere (brain, heart)

Image courtesy of the Internet Stroke Center at Washington University - www.strokecenter.org

General term for all diseases of the heart and blood vesselsAtherosclerosis is the main cause of CVDAtherosclerosis leads to blockage of blood supply to the heart, damage occurs (coronary heart disease, CHD)Cardio = heartVascular = blood vesselsLipoproteins and cardiovascular disease (CVD) risk- LDL is positively associated with CVD

- HDL is negatively associated with CVD

*aDiabetes regarded as coronary heart disease (CHD) risk equivalent.bHDL cholesterol>60 mg/dL counts as "negative"risk factor; its presence removes one risk factor from the total count.DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy: A Pathophysiologic Approach, 7th Edition: http://www.accesspharmacy.com

AgeMen: 45 yearsWomen: 55 years or premature menopause without estrogen replacement therapyFamily history of premature CHD (definite myocardial infarction or sudden death before age 55 years in father or other male first-degree relative, or before age 65 years in mother or other female first-degree relative)Cigarette smokingHypertension (140/90 mm Hg or taking antihypertensive medication)Low HDL cholesterol (

AthrogenesisMVS 110: Lecture #11

MVS 110: Lecture #11

1. Vasodilatory Endothelial Dysfunction: Brachial Ultrasound Flow-Mediated Dilation.2. Atherosclerosis Burden/End-organ Damage: Carotid IMT, # plaques (based on carotid US), IVUS, EBCT, advanced CT, MRI3. General Inflammatory Marker: hs-C Reactive Protein4. Markers of Inflamed Endothelium: ICAM, VCAM, e-Selectin, vWf5. Other: Homocysteine

Libby et al. Circulation 2002;105:1135-1143.E-Selectin, P-SelectinLDLOxLDLL-Selectin, IntegrinsVCAM-1, ICAM-1M-CSFMCP-1MacrophageActivation & DivisionMonocyteIntimaMediaSmooth Muscle CellMigrationOther inflammatory triggers

Oxidation of low-density lipoprotein (LDL) initiates the atherosclerotic process in the vessel wall by acting as a potent stimulus for the induction of inflammatory gene products in vascular endothelial cells. By activating the nuclear factor B (NFB) transcription factor, oxidized LDL (oxLDL) stimulates increased expression of cellular adhesion molecules. There are several different types of adhesion molecules with specific functions in the endothelialleukocyte interaction: The selectins tether and trap monocytes and other leukocytes. Importantly, vascular cell adhesion molecules (VCAMs) and intercellular adhesion molecules (ICAMs) mediate firm attachment of these leukocytes to the endothelial layer.

OxLDL also augments expression of monocyte chemoattractant protein 1 (MCP-1) and macrophage-colony stimulating factor (M-CSF). MCP-1 mediates the attraction of monocytes and leukocytes and their diapedesis through the endothelium into the intima. M-CSF plays an important role in the transformation of monocytes to macrophage foam cells. Macrophages express scavenger receptors and take up and internalize oxLDL in their transformation into foam cells. Migration of smooth muscle cells (SMCs) from the intima into the media is another early event initiating a sequence that leads to formation of a fibrous atheroma.

Primary Pro-inflamatory Cytokines (eg, IL-1, TNF-a)IL-6Messenger CytokineICAM-1Selectins, HSPs, etc.Proinflammatory Risk FactorsEndotheliumand other cellsCRPSAACirculationAdapted from Libby and Ridker. Circulation. 1999;100:1148-1150.HSPs=heat shock proteins; SAA=serum amyloid-A.Liver

Total cholesterol: 6mmol/L)

LDL-C = (Past) < 130 mg/dl (2001 < 100)

LDL-C=total cholesterol - (HDL-C + .2TG)

HDL-C = (Past) >35 mg/dl (2001) > 40)HDL-C = > 60 mg/dl will negate one risk factor

Normal TG = < 200 mg/dlBorderline high = 200-400 mg/dlHigh = 400-1000 mg/dlVery High = > 1000 mg/dl

Life style interventionRisk factor modificationLife style is a Driver of CVD

At least 3 ofAbdominal obesity: waist circumference> 102 cm (M)> 88 cm (F)Hypertriglyceridemia> 150 mg/dlLow HDL cholesterol< 40 mg/dl (M)< 50 mg/dl (F)Hypertension (> 130/85 mm Hg)Impaired Fasting Glucose or Type 2 diabetes (> 100 mg/dl)(ATP III. JAMA 285:2486, 2001)

Type 2 DiabetesHypertensionDyslipidemiaCentral obesityInsulinResistance

Reilly & Rader 2003;Eckel et al 2005 Plaque rupture/thrombosisCardiovascular eventsAtherosclerosisInsulin resistance Tg Metabolic syndrome HDL BPInflammatory markersPathophysiology of the metabolic syndrome leading to atherosclerotic CV diseaseAdipocyteMonocyte/macrophageGenetic variationEnvironmental factorsAbdominal obesityCytokinesAdipokines

TreatmentNCEP ATP-III guidelinesModification of lipids and major risk factorsSee Table 15.9Medications See Table 15.10ProceduresAngioplasty CABG

Nicotinic Acid (Niaspan)Bile Acid Sequestrants (cholestyramine and colestipol)HMG CoA Reductase Inhibitors (lovastatin, pravastatin, simvastatin)Fibric Acid Derivatives (Clofibrate, gemfibrozil)Probucol

Statin drugs inhibit the enzyme HMG-CoA reductaseThis is an enzyme in the synthesis pathway of cholesterolStatins also increase cholesterol uptake from the bloodstream by resulting in more LDL receptor expressionVytorin is actually a combination drug made of simvastatin and ezetimibe, (Zetia) which prevents cholesterol absorption from the digestive tract.*

Nutrition TherapyTherapeutic Lifestyle Changes (TLC) developed as component of ATP-IIIModifications in fat, cholesterolRich in fruits, vegetables, grains, fiberLimit sodium to 2400 mgInclude stanol estersSee the next Table for summary

Nutrient Intake Recommended Saturated fat< 7% of total caloriesPolyunsaturated fatUp to 10% of total caloriesMonounsaturated fatUp to 20% of total caloriesTotal fat25-30% of total caloriesCarbohydrates50-60% of total caloriesFiber20-30 grams/dayProtein calories Approx. 15% of totalLimit Cholesterol intake

Nutrition Therapy - OtherIncrease sources of soluble fiberIncrease intake of plant sterols

Weight loss BMI 18.5-24.9Regular physical activity

Coronary Angioplasty

Coronary Bypass Surgery (CABG)

Fish Oil (source of omega-3 polyunsaturated fatty acids)Salmon, flaxseed, canola oil, soybean oil and nutsAt high doses > 6 grams/day reduces TG by inhibition of VLDL-TG synthesis and apolipoprotein B Possibly decreases small LDL (by inhibiting CETP)Several studies have shown lower risk of coronary events2 servings of fish/week recommended??Pharmacologic use restricted to refractory hypertriglyceridemia Number of undesirable side effects (mainly GI)Soy Source of phytoestrogens inhibiting LDL oxidation25-50 grams/day reduce LDL by 4-8%Effectiveness in postmenopausal women is questionableGarlicMixed results of clinical trialsIn combination with fish oil and large doses (900-7.2 grams/d), decreases in LDL observedCholesterol-lowering MargarinesBenecol and Take Control containing plant sterols and stanolsInhibit cholesterol absorption but also promote hepatic cholesterol synthesis10-20% reduction in LDL and TC however no outcome studiesAHA recommends use only in hypercholesterolemia pts or those with a cardiac event requiring LDL treatment

Other agents include soluble fiber, nuts (esp. walnuts), green teaOverall a combination diet with multiple cholesterol-lowering agents causes much more significant LDL reductions Fiber: Decreases LDL; increases HDLCarrots/Grapefruit: Fiber and pectin (whole fruits most beneficial)Avocado: monounsaturated fatBeans: High in fiber, low fat; contain lecithin Phytosterols: sesame, safflower, spinach, okra, strawberries, squash, tomatoes, celery, ginger.Shiitake mushrooms: contain lentinan (25% reduction in animal studies)Garlic, onion oil: lowers chol. 10-33%Omega 3 fish oilsRed Yeast Rice: a natural substance that inhibits HMG-CoA reductase. Same ingredient in Lovastatin.

*Slide 1 *Key Point:***In addition to type 2 diabetes, insulin resistance is associated with the development of a broad spectrum of clinical conditions. These include hypertension, atherosclerosis, dyslipidemia, decreased fibrinolytic activity, impaired glucose tolerance, acanthosis nigricans, hyperuricemia, polycystic ovary disease, and obesity.

Adapted from Consensus Development Conference of theAmerican Diabetes Association. Diabetes Care. 1998;21:310-314.*Can see the platelet aggregation in response to the foam cell chemicals and tissue damageThe platelets will activate the coagulation cascade, resulting in the production of fibrin strands which trap platelets, red and white blood cells over the area = thrombusIn larger vessels, it takes longer to develop a thrombus big enough to completely block the vessel so you get warning signs (TIA, UA) of stroke and MIThis process happens everywhere (brain, heart)***Oxidation of low-density lipoprotein (LDL) initiates the atherosclerotic process in the vessel wall by acting as a potent stimulus for the induction of inflammatory gene products in vascular endothelial cells. By activating the nuclear factor B (NFB) transcription factor, oxidized LDL (oxLDL) stimulates increased expression of cellular adhesion molecules. There are several different types of adhesion molecules with specific functions in the endothelialleukocyte interaction: The selectins tether and trap monocytes and other leukocytes. Importantly, vascular cell adhesion molecules (VCAMs) and intercellular adhesion molecules (ICAMs) mediate firm attachment of these leukocytes to the endothelial layer. OxLDL also augments expression of monocyte chemoattractant protein 1 (MCP-1) and macrophage-colony stimulating factor (M-CSF). MCP-1 mediates the attraction of monocytes and leukocytes and their diapedesis through the endothelium into the intima. M-CSF plays an important role in the transformation of monocytes to macrophage foam cells. Macrophages express scavenger receptors and take up and internalize oxLDL in their transformation into foam cells. Migration of smooth muscle cells (SMCs) from the intima into the media is another early event initiating a sequence that leads to formation of a fibrous atheroma.

Kinlay S, Selwyn AP, Libby P, Ganz P. Inflammation, the endothelium, and the acute coronary syndromes. J Cardiovasc Pharmacol. 1998;32(suppl 3):S62-S66.Libby P, Ridker PM, Maseri A. Inflammation and atherosclerosis. Circulation. 2002;105:1135-1143.Newby AC, Zaltsman AB. Fibrous cap formation or destructionthe critical importance of vascular SMC proliferation, migration and matrix formation. Cardiovasc Res. 1999;41:345-360.*This diagram shows how primary proinflammatory risk factors result in hepatic production of acute-phase reactants, such as CRP. Vascular and extravascular inflammation due to risk factors, such as oxLDL and infectious agents, leads to production of primary proinflammatory cytokines, such as IL-1 and TNF-. These primary cytokines elicit production by endothelial and other cells of adhesion molecules, such as ICAM-1 and other mediators released in soluble form in the blood. They also lead to production of messenger cytokines, such as IL-6, which induce expression of hepatic genes encoding for CRP and other acute-phase reactants, such as serum amyloid-A (SAA). Libby P, Ridker PM. Novel inflammatory markers of coronary risk: theory versus practice. Circulation. 1999;100:1148-1150.**Type 2 diabetes often occurs in people presenting features of the Metabolic Syndrome, such as obesity, dyslipidemia and hypertension.These diseases are associated with the central player of the Metabolic Syndrome, namely insulin resistance. However, insulin resistance per se is not sufficient to cause diabetes.Indeed, only when the pancreas fails to compensate for this insulin resistance, the relative insulin deficiency will lead to a rise in glucose levels and the development of type 2 diabetes.*Pathophysiology of the metabolic syndrome leading to atherosclerotic CV diseaseA complex series of interactions of metabolic risk factors with genetic and environmental influences underlies the adverse influence of the metabolic syndrome on cardiovascular prognosis. Abdominal obesity is an important cause of multiple sources of cardiovascular risk within this system. Bioactive substances (adipokines, inflammatory cytokines and other agents) derived from intra-abdominal adipocytes, the liver and/or inflammatory cells help to drive the progression of the cluster of risk factors characteristic of the metabolic syndrome. In turn, exacerbation of these risk factors, in addition to the direct pro-atherogenic effects of adipokines, accelerates the atherosclerotic changes that increased the risk of an occlusive thromboembolic coronary event.It is difficult to intervene successfully once the vicious cycle of promotion of cardiovascular risk factors and atherogenesis is established. Intervening at an earlier stage, for example to combat directly the development of intra-abdominal adiposity, may provide a more successful prospect for intervention to reduce the risk of a cardiovascular event.

Reilly MP, Rader DJ. The metabolic syndrome: more than the sum of its parts? Circulation 2003;108:1546-51. Eckel RH, Grundy SM, Zimmet PZ. The metabolic syndrome. Lancet. 2005;365:1415-28.