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Diabetes and vascular disease — a single process?

Each hour, 178 people die from complications set off by diabetes. For 80 percent of these patients the killer is atherosclerosis involving the large blood vessels supplying heart and brain. Patients with diabetes are four times as likely as nondiabetic individuals to die of an MI. With endothelial dysfunction a primary cause, type-2 diabetes is a high-risk condition for heart attack and stroke. The American Diabetes Association is launching a program “Make the Link!” a new initiative aimed at making patients aware of the association between diabetes and cardiovascular disease. But these two entities might not be separate diseases at all but rather part of the same disease process. Besides being involved in mediating inflammation, endothelial dysfunction (perhaps from inflammation) may lead to increased coagulation of blood, leaky blood vessels, increased vascular tone or constriction causing hypertension, elevated TGs and lowered HDL. The dysfunctional endothelium also secretes growth factors that stimulate blood-vessel walls to expand or hypertrophy, narrowing the blood vessels’ opening. Leaky endothelium and diminished peripheral blood flow may limit insulin delivery and promote insulin resistance. 62

Diabetes is a huge risk factor for coronary-artery disease. The risk for MI is higher for diabetic patients with no prior MI than for nondiabetic patients who have survived a prior MI. The greater risk is by no means clearly understood, but can be better appreciated if we assume that atherosclerosis-related heart disease and diabetes share an underlying pathology: endothelial dysfunction and inflammation.

Generalized Endothelial Dysfunction– This common underlying pathology explains microalbuminuria, elevated triglycerides, low HDL, and insulin resistance.

Microalbuminuria (MA) is a powerful independent risk factor for CHD and is closely linked to the insulin resistance syndrome (IRS) while an elevated plasma triglyceride (TG) to HDL ratio (TG:HDL) is an independent predictor of MA that is also associated with insulin resistance 2, 121-123 and CHD. 124 The high TG and low HDL levels found in those with insulin resistance is associated with low lipoprotein lipase (LPL) activity. 125, 126 Widespread endothelial damage occurs in patients with insulin resistance leading to MA and a decrease in the lipoprotein lipase moiety (LPL) bound to the endothelium. 32, 122 This impairs the clearing and catabolism of TG-rich lipoproteins allowing TGs to rise. 122 The TG:HDL ratio is a strong predictor of MI, 124 perhaps because it reflects endothelial function.

The Characteristic Dyslipidemia of Diabetes
The characteristic dyslipidemia of insulin resistance and diabetes consists of elevated TGs and low HDL 10 . There is some evidence that in the insulin-resistance syndrome increased free fatty-acid flux from the adipose tissue causes the liver to secrete more TG-rich VLDL particles. This effect may be additive to the means by which impaired LPL also contributes to decreased clearance of TGs. The numerous TGs used to make LDL and HDL cholesteryl esters are mediated by cholesterol ester transfer protein (CETP). These now TG-rich LDL and HDL particles are susceptible to hydrolysis by hepatic lipases, resulting in small, dense LDLs, and small HDLs. The small, dense LDLs are more vulnerable to oxidation and are more atherogenic than large, buoyant LDL particles. Small HDLs are more easily cleared from the plasma (they have lower affinity for apoprotein A-I, leading to rapid dissociation). This sequence results in fewer HDL particles in the blood, a condition indicating high risk for a cardiovascular event.

Although LDL levels in diabetes may be normal, elevated, or low, they are usually the small, dense, more atherogenic LDL which are independently associated with insulin resistance and hyperinsulinemia 127, 128 129 . These LDL can more easily penetrate damaged endothelium where they become oxidized. The injured endothelium then secretes white blood cell adhesion molecules 130, 131 27 inflammatory substances, and procoagulants, which create a plaque that is likely to rupture, thrombose, and cause a cardiovascular event. 132, 133 In patients with diabetes the type of plaque may be more important than the extent of advanced atherosclerotic lesions. Existing vascular lesions may be more likely to rupture.

Lowering TGs is accompanied by increase in size of LDL particles, but this result will not be obvious until TGs are low enough, usually less than 100. Note also that LDL is not routinely measured directly—it is calculated using the Friedewald equation: LDL = total cholesterol – HDL – TG/5. 134 Therefore, the common “LDL measurement” on a typical lab slip includes the sum of LDL, plus other things like Lp(a), and IDL (intermediate-density lipoprotein). If TG-lowering efforts are effective, the LDL level may calculate to be greater, even though it hasn’t changed, simply because the equation needs to be balanced. Increases in the percentage of large, buoyant LDL particles is associated with a decrease in TG:HDL, insulin resistance, and improvement in endothelial function. 135-138 Unlike their small, dense counterparts, these LDLs are less likely to become oxidized and induce an cardiac event 139 Yet LDL particles are rarely measured directly and an elevated LDL automatically triggers a drug prescription. Also, if HDL increases, total cholesterol has to increase. Therefore cardiac risk may decrease in the face of increasing total cholesterol.

LDL is not a strong predictor of CHD—further evidence

A team led by Antonio Gotto, past president of the American Heart Association, examined the 5-year histories of over 6,600 men and women between 45 and 73 years of age and found that blood levels of LDL cholesterol, according to Gotto, “didn’t predict MI risk at all.” Low HDL cholesterol levels which may be a better indicator of endothelial dysfunction, were found to be fairly good predictors of risk. 114 Seven years earlier, in 1993, in the same journal (Circulation: Journal of the American Heart Association) Phillips et al. followed 335 patients with established atherosclerosis of the coronary arteries. 140 Angiography was performed every two years over a four to six year period. Similar to Gotto’s findings, a decreased level of HDL was associated with progression of coronary atherosclerosis, but they found no such relation for the level of LDL. It should also be noted that LDL is not routinely measured but rather it is calculated using the Friedewald equation: LDL = total cholesterol – HDL – TG/5. From this you can see that as triglycerides (TG) drop, LDL automatically go up, but these are the larger, fluffy, buoyant, and the kind less likely to oxidize and cause problems. In fact, what is commonly regarded as LDL-cholesterol includes particles other than LDL. It is actually the sum of LDL plus Lp(a) and intermediate density lipoprotein (IDL). These are lipids plus protein molecules (lipoproteins) that some have associated with increased risk of atherosclerosis. Non-HDL cholesterol has been proposed to be a better predictor of CHD mortality especially in patients with type 2 diabetes. 141, 142

Homocysteine – a forgotten major risk factor

Several studies have targeted the effects of homocysteine on the vascular endothelium. Folate deficiency may predispose endothelial cells to damage and homocysteine may have a direct cytotoxic effect on vascular endothelium. Impaired endothelium vasodilation has also been observed in patients with elevated homocysteine levels, which involves oxidant stress and decreased nitric oxide bioavailability induced by homocysteine’s toxic effects. 143 144 Homocysteine plasma levels are independently associated with insulin resistance in apparently healthy normal weight, overweight and obese pre-menopausal women, thus suggesting a possible role of insulin resistance and/or hyperinsulinaemia in increasing homocysteine plasma levels. Since homocysteine is a well-known cardiovascular risk factor, higher homocysteine plasma levels may well be a further mechanism explaining the higher risk of coronary heart disease in patients affected by insulin resistance. 145 Although homocysteine is not necessarily associated with abnormalities in serum lipid levels, recent research provides biochemical evidence that homocysteine upregulates HMG-CoA reductase resulting in increased cholesterol production and incorporation into endothelial cells. 144

Free radicals and insulin resistance

Free radicals are molecules that are highly reactive because of their unpaired electrons, they are effective in many cellular processes that generate energy, and they protect us by attacking invading bacteria and viruses. In excess, though, the highly reactive free radicals steal electrons or “oxidize” and damage proteins, fats, and DNA, causing widespread damage to cells and contributing to more than a hundred disease states. Free radicals can oxidize LDL cholesterol particles, making them directly toxic to endothelial cells. Oxidation is everywhere, from rusted iron to butter left out overnight that turns rancid. Fortunately, we have a defense force of antioxidants for the counterattack. Among these include a number of enzymes and assorted molecules, including vitamins C and E, that can intercept these oxidizing free radicals by binding to them before they reach cells, preventing damage to human tissue, including endothelial cells. Because it interfaces with the blood and other tissues and directly contacts free radicals in the blood, the endothelium is especially vulnerable.

Several studies show that people with diabetes have excessive free radicals or oxidants and are deficient in antioxidants. Gerald Reaven’s group at Stanford established that not only do patients with diabetes experience more oxidation, but that even apparently healthy nondiabetic individuals can reveal evidence of increased oxidation that is directly related to their risk for contracting diabetes. 19 These people had early, mild resistance to insulin and normal glucose tolerance. These findings suggest that increased free-radical activity and oxidation occur very early in those who are insulin resistant, even before diabetes appears. The more resistant subjects were to insulin, the higher the quantity of oxidation. Degree of resistance to insulin is also related to consumption of such antioxidant vitamins as vitamin E and others supplied by the diet. Low vitamin E concentrations are more common in insulin- resistant people and can help in predicting diabetes, whereas consuming more raw vegetables, which are rich in E and other antioxidant vitamins, has been linked to decreased risk for diabetes. Healthy endothelial cells carry an arsenal of various antioxidants and antioxidant co-factors including: vitamins C and E, glutathione, the enzymes superoxide dismutase, catalase, and co-factors such as selenium and magnesium, which is technically not an antioxidant co-factor but if deficient can lead to increased insulin resistance and thromboxane synthesis. 146

Mohanty et al demonstrated the protective effect of antioxidants on endothelial function in healthy volunteers. Challenged with an oral glucose load (75 grams) the subjects demonstrated impaired endothelial function and increased free radicals (oxidative stress), both of which were prevented for those who first ingested 2 grams of vitamin C and 800 international units (IU) of vitamin E. 18 Of note, statin agents such as simvastatin lower vitamin E, CoQ-10, beta carotene, and raise insulin levels. 147