DIABETES AND LIPID. S-KHALILZADEH. Lipids 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
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Lipids 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
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.
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
Triglycerides 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 energy
Chylomicrons are the largest of the plasma lipoproteins (>1000 Å 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
IDLs 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.
LDLs are about 200 Å 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-E
The 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-B100–containing LDLs, apo-E–containing lipoproteins have 20-fold greater affinity for the LDL receptor
Apo-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
Apolipoproteins— Understanding the major functions of the different apolipoproteins is important clinically, because defects in apolipoprotein metabolism lead to abnormalities in lipid handling
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 .
D — 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.
Human 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.
Hepatic lipase is primarily a phospholipase but also possesses triglyceride hydrolase activity
It 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 estrogens
Within 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 esters
Triglycerides 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.
Apo 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.
The 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.
Some of the excess surface components in the remnant particle, including phospholipid, unesterified cholesterol, and apolipoproteins A, C and E, are transferred to HDL
VLDL 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.
LDL 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 form
Circulating 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 plaques
These 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 atherosclerosis
Plasma 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 atherogenic
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
Guidelines 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 years
The 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
Step 1 — The first step in determining patient risk is to obtain a fasting lipid profile
Step 2 — CHD equivalents, that is, risk factors that place the patient at similar risk for CHD events as a history of CHD itself, are identified :
Symptomatic carotid artery disease
Peripheral arterial disease
Abdominal aortic aneurysm
Multiple risk factors that confer a 10-year risk of CHD >20 percent
Step 3 — Major CHD factors other than LDL are identified:
Hypertension (BP ≥140/90 or antihypertensive medication)
Low HDL-C (<40 mg/dL)
Family history of premature CHD (in male first degree relatives <55 years, in female first degree relative <65 years)
Age (men ≥45 years, women ≥55 years)
HDL-C ≥60 mg/dL counts as a "negative" risk factor; its presence removes one risk factor from the total count
Step 5 — The last step in risk assessment is to determine the risk category that establishes the LDL goal, when to initiate therapeutic lifestyle changes, and when to consider drug therapy
ATP III identifies the non-HDL-C concentration as a secondary target of therapy in people who have high triglycerides ≥200 mg/dl.
The goal for non-HDL-C in this circumstance is a concentration that is 30 mg/dL (0.78 mmol/L) higher than that for LDL-C
A standard serum lipid profile consists of total cholesterol, triglycerides, and HDL-cholesterol. Lipoprotein analysis should be performed after 9 to 12 hours of fasting to minimize the influence of postprandial hyperlipidemia. Either a plasma or serum specimen can be used; the serum cholesterol is approximately 3 percent lower than the plasma value
Inhibition of hepatic cholesterol synthesis, results in increased expression of the LDL receptor gene
Patients 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
they can increase plasma triglyceride levels and must be used with caution in patients predisposed to hypertriglyceridemia.
because they bind negatively charged molecules in the intestine, these agents can interfere with the absorption of other medications, including levothyroxine, digoxin, warfarin, and thiazide diuretics. Therefore, resins are given at least 4 hours before or 1 hour after other medications. Colesevelam does not bind other drugs to the same extent as the resins cholestyramine and colestipol.
The most troublesome side effect of niacin is a flushing syndrome that occurs shortly after taking the medicine. Flushing can be minimized by initiating therapy with small doses (e.g., 100 mg) and gradually increasing the dosage to the therapeutic range over weeks to months.
The most serious complication of niacin therapy is hepatotoxicity, and therapy should be accompanied by monitoring of serum liver function tests
Side 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
Omacor 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%