Mechanisms of Vascular complications of Diabetes Mellitus

The mechanisms of diabetes that may predispose a hastening of the atherosclerotic process.

1)  Diabetes Mellitus and Cardiovascular Disease Risk
               As it relates to cardiovascular risk, notable differences exist between the two types of diabetes, with type II diabetic individuals developing CVD at a younger age, having a higher rate of multi- vessel disease and poorer outcomes post myocardial infarction than their type I.The Multiple Risk Factor Intervention Trial found diabetic men with one, two or three CVD risk factors experienced higher disease mortality than nondiabetic individuals with the same number of risk factors. Diabetes played an additive role when combined with one or more risk factors. The United Kingdom Prospective Study (UKPDS) following newly detected diabetic individuals, found increased risk of CVD was significantly associated with risk factors of increased LDL, decreased HDL increased HGB A1c, elevated systolic blood pressure and smoking when measured at baseline.  Despite the undeniable association of established CVD risk factors and diabetes, these risk factors account for only 50 per cent of the excess CVD in the diabetic. Hyperglycemia, hyperinsulinemia and insulin resistance, dyslipidemia, increased plasma oxidative stress, enhanced fibrinolysis and abnormal vasodilator function are some of the proposed mechanisms and novel risk factors for the accelerated development of atherosclerosis and diabetes.

2)  Mechanisms of Vascular Dysfunction in Diabetes

                  Numerous mechanisms contribute to the pathogenesis of diabetic vascular diseases, many of which are complex, incompletely understood and continue to be intensely investigated. The hallmark of diabetic vascular disease is thickening of the basement membranes, which develop in relation to the duration of diabetes and degree of glycemic control. The contribution of hyperglycemia, hyperinsulemia and dyslipidemia to diabetic vascular complications will be briefly reviewed. Hyperglycemia although still controversial, hyperglycemia has emerged as a leading candidate responsible for the excess of diabetes risk. It is unclear if there is a critical value that exists above which CVD raises. A number of mechanisms have been proposed for the contribution of hyperglycemia in CVD. Suggested mechanisms include: glycation of collagen and other vessel-wall proteins and lipoproteins; accelerated generation of reactive oxygen species; increased oxidative stress on glycated end products, LDL cholesterol, and vascular endothelial cells; alteration in haemorrheological characteristics or changes in vascular reactivity.  Extracellular glucose can glycate proteins without enzyme action and generate oxidative by-products. Glycated proteins (Advanced Glycation End-products) accumulate in the extracellular matrix and bind to specific AGE-receptors that are expressed on the cell surface. AGE receptors are being extensively investigated for their contribution to the accelerated vascular complications of diabetes.(26) Cells contain several receptors of AGEs that mediate their biological effects. Exposure to AGE modified proteins can elicit the production of inflammatory cytokines from vascular cells, cause impaired endothelial dependent vasodilator function and increase the expression of various leukocyte adhesion molecules implicated in atherosclerosis.  

                   Although it has been suggested that hyperinsulinemia may be the link between hyperglycemia and CVD. It is thought that insulin resistance and compensatory hyperinsulinemia may contribute to atherogenic risk through several different mechanisms. Insulin resistance commonly precedes hyperglycemia, and insulin resistance has been shown to have a positive correlation with CVD. Diabetes is frequently associated with the risk factors of obesity, dyslipidemia, and hypertension.

                Most individuals with this group of disorders also have insulin resistance. This group of disorders has been named syndrome X, the insulin resistance syndrome, and CVD metabolic syndrome. Insulin resistance syndrome includes glucose intolerance, and elevated levels of fasting insulin and triglycerides.  In normal conditions, insulin has a protective vasodilatory action that may be mediated by nitric oxide.  In insulin resistance states, the ability of insulin to induce vasodilation is low, suggesting an impairment or inactivation of nitric oxide. Increased insulin action is also thought to contribute to atherogenesis through smooth- muscle cell hypertrophy and hyperplasia and increased extracellular proteins. A hypothesis generated to explain data from the Framingham Offspring Study, suggested that the atherogenic effects of hyperglycemia or hyperinsulinemia might be mediated through factors predisposing to acute thrombosis.  Markers of decreased fibrinolytic potential include elevated levels of plasminogen activator inhibitor 1 (PAI-1) antigen or tissue-type plasminogen activator (tPA) antigen. These markers are associated with increased risk for CVD among non-diabetic individuals. Elevated levels of PAI-1 appear to increase the formation of acellular, thin-walled plaques susceptible to rupture. Increases of fibrinolytic markers have been shown to correlate with elevated markers of inflammation and endothelial dysfunction. Is fibrinolysis the cause or the effect of hyperinsulinemia.

                         Dyslipidemia and associated metabolic abnormalities. Dysplipidemia is the most thoroughly studied and established mechanism for the increased risk of atherogenesis identified in type II diabetes.  Dyslipidemia and diabetes have been done primarily with individuals with type II diabetes because of the increased incidence of dyslipidemia in this population.  In type l patients with good glycemic control, lipids may appear to be better than the average for subjects without diabetes. However lipoproteins may be abnormal in composition and as a result more atherogenic. Numerous studies have also shown that dyslipidemias are more prevalent in diabetic women, and probably a very important contributor to the increased CVD risk in this group. The most common dyslipidemias observed in type II diabetes are high triglycerides and reduced high-density lipoprotein (HDL) cholesterol. Low-density lipoprotein concentration is not usually higher than in individuals without diabetes, but the LDL particles themselves tend to be small and dense. Small dense LDL particles are believed to be more atherogenic because they are more easily glycated and susceptible to oxidation. Interventional studies have shown that the benefit of lowering LDL is similar in the diabetic and non-diabetic population.  Central to the pathogenesis of dyslipidemia in diabetes is the increased presentation of free fatty acids to the liver, which provide the substrate for triglyceride-rich lipoproteins - very low density (VLDL) production in the liver. Abdominal obesity, a common finding in type II diabetic men, provides a further source of free fatty acids which in turn fuel production of VLDL.

                     Contributing to the adverse effect of increased VLDL production is the decreased catabolism of triglyceride-rich lipoproteins. Liprotein lipase, an enzyme that plays a central role in clearing postprandial lipemia (consisting largely of triglyceride-rich particles), is decreased in uncontrolled type ll diabetes.  Contiguously, states of higher VLDL are associated with low HDL levels because of the intimate relationship between lipoprotein lipase activity (reduced in DM), cholesterol ester transfer protein activity, and efficient HDL. The protective role of HDL in shielding LDL from oxidation also appears to be diminished in diabetes, suggesting differences in the qualitative as well as quantitative aspects of HDL in diabetes.