DIABETES AND LIPID

DIABETES AND LIPID S-KHALILZADEH

1Lipids are hydrophobic molecules that are insoluble in water. They are in cell membranes as a major form of stored nutrients (triglycerides), as precursors of adrenal and gonadal steroids and bile acids as extracellular and intracellular messengers (e.g., prostaglandins, phosphatidylinositol). Lipoproteins provide a vehicle for transporting the complex lipids in the blood as water-soluble complexes and deliver lipids to cells

2Fatty acids vary in length and in the number and position of double bonds Saturated fatty acids lack double bonds unsaturated fatty acids have one or more double bonds. Monounsaturated fatty acids have one double bond, and polyunsaturated fatty acids (PUFAs) have two or more. 3Cholesterol is a four-ring hydrocarbon with an eight-carbon side chain. It is a major component of cell membranes and as a precursor of steroid hormones (adrenal and gonadal hormones) and bile acids In the blood, about two thirds of the cholesterol is esterified 4

5Triglycerides consist of three fatty acid molecules esterified to a glycerol molecule Triglycerides store fatty acids and form large lipid droplets in adipose tissue. They are also transported as a component of certain lipoproteins. When triglycerides are hydrolyzed in adipocytes, free fatty acid (FFA) are released to be used as a source of energy6

7Chylomicrons are the largest of the plasma lipoproteins (>1000 in diameter) ,float after ultracentrifugation of plasma. They are composed of 98% to 99% lipid (85%-90% triglyceride) and 1% to 2% protein Chylomicrons are present in postprandial plasma (but are absent after an overnight fast) and contain apo-B48, apo-AI, apo-AIV, apo-E, and the C apolipoproteins 8VLDLs are particles 300 to 700 They are composed of 85% to 90% lipid (about 55% triglyceride, 20% cholesterol, and 15% phospholipid) and 10% to 15% protein. The distinctive apolipoprotein is apo-B100, the hepatic form of apo-B. VLDLs also contain apo-E and C apolipoproteins 9IDLs present in low concentrations in the plasma and are intermediate in size and composition between VLDL and LDL Their proteins are apo-B100 and apo-E. The IDLs are precursors of LDLs and represent metabolic products of VLDL catabolism in the plasma by the action of lipases. IDLs are often considered to be VLDL remnants and to be atherogenic.

10LDLs are about 200 in diameter, are the major cholesterol-carrying lipoproteins in the plasma; about 70% of total plasma cholesterol is in LDL. LDLs are composed of approximately 75% lipid (about 35% cholesteryl ester, 10% free cholesterol, 10% triglyceride, and 20% phospholipid) and 25% protein. Apo-B100 is the principal protein in these particles, with trace amounts of apo-E11The clearance of LDL is mediated by apo-B100. The affinity of apo-B100 for the LDL receptor is lower than that of apo-E, and clearance of LDL is much slower (with a half-life of 2 to 3 days). Compared with apo-B100containing LDLs, apo-Econtaining lipoproteins have 20-fold greater affinity for the LDL receptor12HDLs are small particles (70-120 in diameter) HDLs contain about 50% lipid (25% phospholipid, 15% cholesteryl ester, 5% free cholesterol, and 5% triglyceride) and 50% protein Their major apolipoproteins are apo-AI (65%), apo-AII (25%), and smaller amounts of the C apolipoproteins and apo-E 13Apo-E is a minor component of a subclass of HDL referred to as HDL1, but about 50% of total plasma apo-E is in this HDL fraction. The major classes of HDLs lack apo-E and do not interact with the LDL receptor

14ApolipoproteinsUnderstanding the major functions of the different apolipoproteins is important clinically, because defects in apolipoprotein metabolism lead to abnormalities in lipid handling15

16ApolipoproteinsA-I Structural protein for HDL; activator of lecithin-cholesterol acyltransferase (LCAT). A-II Structural protein for HDL; activator of hepatic lipase. A-IV Activator of lipoprotein lipase (LPL) and LCAT. B-100 Structural protein for VLDL, IDL, LDL, and Lp(a); ligand for the LDL receptor; required for assembly and secretion of VLDL. B-48 Contains 48 percent of B-100; required for assembly and secretion of chylomicrons; does not bind to LDL receptor.

17C-I Activator of LCAT. C-II Essential cofactor for LPL. C-III Interferes with apo-E mediated clearance of triglyceride-enriched lipoproteins by cellular receptors ; inhibits triglyceride hydrolysis by lipoprotein lipase and hepatic lipase ,interferes with normal endothelial function .

18D May be a cofactor for cholesteryl ester transfer protein (CETP).

E Ligand for hepatic chylomicron and VLDL remnant receptor, leading to clearance of these lipoproteins from the circulation; ligand for LDL receptor. 19Human LPL is synthesized by adipocytes, by myocytes in skeletal and cardiac muscle, and by macrophages but is not produced by hepatocytes. LPL is transported to the capillary endothelial cells where it interacts with chylomicrons and VLDL in the circulation and mediates the hydrolysis of their triglycerides to FFAs. The fatty acids are stored as triglyceride in adipocytes and in the formation of hepatic VLDL.20Hepatic lipase is primarily a phospholipase but also possesses triglyceride hydrolase activityIt is synthesized by hepatocytes Hepatic lipase is transported from the liver to the capillary endothelium of the adrenals, ovaries, and testes, where it functions in the release of lipids from lipoproteins for use in these organs. Its activity is increased by androgens and reduced by estrogens21EXOGENOUS PATHWAY OF LIPID METABOLISMstarts with the intestinal absorption of dietary cholesterol and fatty acids The mechanisms regulating the amount of dietary cholesterol that is absorbed are unknown. Sitosterolemia is a rare autosomal recessive disorder associated with hyperabsorption of cholesterol and plant sterols from the intestine . 22Within the intestinal cell, free fatty acids combine with glycerol to form triglycerides, and cholesterol is esterified by acyl-coenzyme A:cholesterol acyltransferase (ACAT) to form cholesterol estersTriglycerides and cholesterol are assembled intracellularly as chylomicrons.The main apolipoprotein is B-48, but C-II and E are acquired as the chylomicrons enter the circulation. Apo B-48 permits lipid binding to the chylomicron but not to LDL receptor.

23Apo C-II is a cofactor for LPL which makes the chylomicrons smaller by hydrolyzing the core triglycerides and releasing free fatty acids. The free fatty acids are then used as an energy source, converted to triglyceride, or stored in adipose tissue. The end-products of chylomicron are chylomicron remnants that are cleared from the circulation by hepatic chylomicron remnant receptors for which apo E is a high-affinity ligand. 24

25ENDOGENOUS PATHWAY OF LIPID METABOLISMbegins with the synthesis of VLDL by the liver Microsomal triglyceride transfer protein is essential for the transfer of the bulk of triglycerides into the endoplasmic reticulum for VLDL assembly They include apo C-II which acts as a cofactor for LPL, apo C-III which inhibits this enzyme, and apo B-100 and E which serve as ligands for LDL receptor 26The triglyceride core of VLDL particles is hydrolyzed by lipoprotein lipase. During lipolysis, the core of the VLDL particle is reduced, generating VLDL remnant particles (also called IDL) that are depleted of triglycerides via a process similar to the generation of chylomicron remnants. 27Some of the excess surface components in the remnant particle, including phospholipid, unesterified cholesterol, and apolipoproteins A, C and E, are transferred to HDLVLDL remnants can either be cleared from the circulation by the apo B/E (LDL) or the remnant receptors or remodeled by hepatic lipase to form LDL particles. 28

29LDL can be internalized by hepatic and nonhepatic tissues. Hepatic LDL cholesterol can be converted to bile acids and secreted into the intestinal lumen. LDL cholesterol internalized by nonhepatic tissues can be used for hormone production, cell membrane synthesis, or stored in the esterified form30Circulating LDL can also enter macrophages and some other tissues through the unregulated scavenger receptor. This pathway can result in excess accumulation of intracellular cholesterol and the formation of foam cells which contribute to the formation of atheromatous plaques31These cholesterol-enriched cells can rupture, releasing oxidized LDL, intracellular enzymes, and oxygen free radicals that can further damage the vessel wall. Oxidized LDL induces apoptosis of vascular smooth muscle and human endothelial cells via activation of a protease which suggests a mechanism for the response to injury hypothesis of atherosclerosis32

33anti-atherogenic effect of HDLApolipoprotein A-I on the surface of HDL serves as a signal to mobilize cholesterol esters from intracellular pools. After diffusion of cholesterol onto HDL, the cholesterol is esterified to cholesterol esters by LCAT, a plasma enzyme that is activated primarily by apolipoprotein A-I. HDL can act as an acceptor for cholesterol released during lipolysis of triglyceride-containing lipoproteins34

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37Diabetes mellitusinsulin deficiency and poor glycemic control lead to increases in the plasma levels of triglycerides and apo-Bcontaining lipoproteins insulin deficiency results in impaired LPL activity and diminished clearance of triglyceride-rich particles. Insulin deficiency also enhances lipolysis, which increases FFA flux to the liver, increased FFA flux drives triglyceride and VLDL synthesis and secretion. 38Plasma levels of LDL are increased in some but not all subjects. the hyperlipidemia in type 2 diabetes is often characterized by an increase in small, dense LDLs which are particularly atherogenica portion of the plasma LDL undergoes glycosylation, which can increase binding to arterial wall proteoglycans and susceptibility to oxidation.39(CHD) are common in industrialized societies There is a direct relation between the plasma levels of total and LDL cholesterol and the risk of CHD and mortality LDL cholesterol lowering in moderate to high-risk patients leads to a reduction in cardiovascular events Abnormalities of plasma lipids (dyslipidemia) other than LDL cholesterol are common in patients with early onset CHD HDL cholesterol levels are related to absolute CHD event rates in treated hypercholesterolemic subjects with and without baseline clinical CHD Screening tests for dyslipidemia are widely available

40Guidelines developed by the NCEP in 2001 recommend that a complete plasma lipid profile (total cholesterol, LDL-C, HDL-C, and triglycerides) be measured in all adults 20 years of age and older at least once every 5 years41The ATP III recommendations for the treatment of hypercholesterolemia are based on the LDL-cholesterol (LDL-C)and are influenced by the coexistence of CHD and the number of cardiac risk factors. There are five major steps to determining an individual's risk category, which serves as the basis for the treatment guidelines 42Step 1The first step in determining patient risk is to obtain a fasting lipid profile43Step 2CHD equivalents, that is, risk factors that place the patient at similar risk for CHD events as a history of CHD itself, are identified :Diabetes mellitus Symptomatic carotid artery disease Peripheral arterial disease Abdominal aortic aneurysm Multiple risk factors that confer a 10-year risk of CHD >20 percent

44Step 3Major CHD factors other than LDL are identified:Cigarette smoking Hypertension (BP 140/90 or antihypertensive medication) Low HDL-C ( atorvastatin > simvastatin > pravastatin = lovastatin > fluvastatin

67Nonlipid roles of statinsEndothelial FunctionPlaque StabilityInflammationLipoprotein OxidationCoagulation

68Statins and Endothelial FunctionStatin therapy enhances endothelial production of the vasodilator nitric oxide, leading to improved endothelial function after a month of therapy

69Statins and Plaque Stability.They reportedly inhibit monocyte infiltration into the artery wall in a rabbit modelInhibit macrophage secretion of matrix metalloproteinases in vitro modulate the cellularity of the artery wall by inhibiting proliferation of smooth muscle cells and enhancing apoptotic cell death

70Statins and InflammationStatins decreased the risk of CHD and levels of C-reactive protein (CRP, an independent marker for inflammation and high CHD risk) independently of cholesterol lowering71CoagulationStatins reduce platelet aggregationreduce the deposition of platelet thrombi in the porcine aorta modelthe different statins have variable effects on fibrinogen levels

72SECONDARY BENEFITSBone metabolismHypertensionHeart failureDementiaCancer preventionRenal functionSepsis and infections73HepatotoxicityElevation in hepatic transaminase to values greater than three times the upper limit of normalIncidence as great as 1%The incidence appeared to be dose relatedliver failure one case per million person-years of usemeasure alanine aminotransferase (ALT) at baseline and thereafter when clinically indicated.

74Patients taking 80-mg doses (or 40 mg of rosuvastatin) should have their ALT checked after 3 months. If the ALT values are normal, it is not necessary to repeal the ALT test unless clinically indicated

75Myopathymyopathy as any muscle diseasemyalgia as muscle ache or weakness without increased serum CK levelsmyositis as muscle symptoms with elevated CK levelsrhabdomyolysis as muscle symptoms with marked CK elevations (>10 times upper limit of normal [ULN]) plus an elevated serum creatinine.(FDA) defines rhabdomyolysis as organ damage, typically renal insufficiency, with a CK level greater than 10,000 IU/L

76Myopathymajor adverse effectThe incidence of myopathy is quite low (~0.0 1%). but the risk of myopathy and rhabdomyolysis increases in proportion to plasma statin concentrations Factors inhibiting statin catabolism are associated with increased myopathy risk, including advanced age (especially >80 years of age), hepatic or renal dysfunction. perioperative periods. multisystem disease (especially in association with diabetes mellitus), small body size, and untreated hypothyroidism

77RISK FACTORS FOR STATIN MYOPATHYconditions that increase statin serum and muscle concentrationfactors that increase muscle susceptibility to injury

78Asymptomatic patientsRoutine surveillance of CK levels is not required except in high-risk patientsIf CK measuredCK < 5 ULN: reassuranceCK 5 - 3 times normal. Because hepatotoxicity appears to be more common with sustained-release preparations of niacin, the immediate-release form is preferred. Other side effects of niacin therapy include impairment or worsening of glucose tolerance and hyperuricemia.87The fibric acid derivativesclofibrate, gemfibrozil, and fenofibratelower plasma triglycerides by about 40% and increase HDL-C levels by about 10% but have only minor effects on LDL-C. These agents act by activating the (PPAR) a, a nuclear hormone receptor that is expressed in the liver and other tissues. This results in increased fatty acid oxidation, increased LPL synthesis, and reduced expression of apo-CIII, all of which contribute to lowering plasma triglycerides.

88Side effects include gastrointestinal discomfort and possibly an increased incidence of cholesterol gallstones (documented for clofibrate). Fibric acid derivatives should be used with great caution in the setting of renal insufficiency Fenofibrate, which does not interfere with statin metabolism and has a much lower risk of causing myopathy, is the preferred fibrate to use in combination with a statin.89Omacor is prepared in capsule form containing a gram of oil, which includes a total of 840 mg of EPA plus DHA. At the recommended dosage of four capsules daily given to patients who have triglycerides of 500-2000 mg/dL, Omacor lowers triglycerides by about 50%, raises HDL-C by about 10%, lowers VLDL-C by about 40%, and raises LDL-C by about 50%. Overall the total cholesterol-to-HDL-C ratio is reduced by about 20% and the non-HDL-C is lowered by about 10%90

91Chylomicronemia SyndromePatients with the chylomicronemia syndrome often present with acute pancreatitis and severe hypertriglyceridemia (triglycerides >22.6 mm/L [2000 mg/dL]).These patients should be treated with total fat restriction until the triglyceride level falls to a safe range The goal is to maintain the triglyceride level at less than 11.3 mm/L (1000 mg/dL) and preferably less than 4.5 mm/L (400 mg/dL).such patients often require a triglyceride-lowering drug, such as a fibrate or niacin, to maintain the plasma triglyceride level in a range that prevents subsequent episodes of pancreatitis92

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