resistance syndrome (IRS), a disorder characterized by hyperinsulinemia, lipoprotein abnormalities, and premature CVD. 7 The IRS, also called the metabolic syndrome, typically precedes and often also accompanies type 2 diabetes. 8 The IRS is also associated with obesity and cigarette smoking. It is being increasingly recognized in adolescents and young adults, largely because of the increasing incidence of obesity and inactivity in the young. 9 A number of epidemiological studies, but not all, have shown a correlation between hyperglycemia and CVD. 10–12 A debate still exists as to the importance of hyperglycemia per se in the atherosclerotic complications of diabetes independent of commonly associated atherogenic factors. Studies demonstrate a deleterious effect of high glucose levels on ECs and cell function in vitro and in vivo. Hyperglycemia disrupts function by increasing oxidative stress, diminishing NO, which leads to apoptosis and impaired function, and enhancing AGE formation. 1, 13 Increased glycation of circulating lipoproteins occurs with hyperglycemia. 2, 14 In addition, hyperglycemia can alter lipid metabolism in a way that can lead to activation of protein kinase C, 15 alter insulin signaling, 16 increase adhesion molecule gene expression on ECs, 17 and stimulate inflammation and SMC migration and proliferation. 18

Elevated plasma FFAs levels also may be directly detrimental. The effects of FFAs on vascular cells, however, has not been studied adequately. ECs can utilize FFA as a fuel, 19 and high levels of FFAs can lead to increased oxidative stress and diminished NO synthesis in such cells. 20 High FFA levels can impair fibrinolysis by augmenting concentrations of PAI-1 in blood. 21 Because high levels of FFAs are often found in both types 1 and 2 diabetes and in the IRS, their role in atherogenesis is currently under active investigation. Lipoprotein abnormalities are more common in people with type 2 than type 1 diabetes. The abnormalities frequently observed in type 2 diabetes include elevation of triglyceriderich lipoproteins (particularly smaller very-low-density lipoproteins) and low high-density lipoproteins (HDL). 22 Lowdensity lipoprotein (LDL) levels are similar to those in people without diabetes, but the particles are smaller, denser, and more atherogenic. In association with fasting hypertriglyceridemia, there is an elevation of postprandial triglyceride-rich lipoproteins, a factor emerging as an additional atherogenic determinant. 23 Lipoproteins interact with components of the arterial wall as described above. In addition, HDL can facilitate cholesterol efflux from cells in the arterial wall. Compositional abnormalities of HDL seen in diabetes and IRS, ie, triglyceride enrichment and glycosylation of apolipoprotein A-1, might adversely affect this process. 24 In addition to effects on atherosclerosis, these metabolic phenomena can alter cardiac function. This may result in part from the hypertension associated with diabetes and IRS. However, other factors, such as directly altered myocardial metabolism of FFAs, glucose, AGEs, and associated gene expression, may contribute.