In addition to its important role in the pathogenesis of type 2 diabetes, insulin resistance itself – independently of hyperglycemia and diabetes – is associated with increased vascular risk, according to an increasing body of evidence. Hyperinsulinemia has been shown to be a predictor of coronary artery disease in at least four prospective studies. These studies utilized fasting insulin concentrations as a marker of insulin sensitivity. In addition to these investigations, the Insulin Resistance Atherosclerosis Study (IRAS) in 1996 reported an association between insulin resistance (as measured by an intravenous glucose tolerance test), and atherosclerosis (as assessed by B mode ultrasound of carotid intimal-medial thickness), in approximately 1,600 subjects. Much of the original data describing the insulin resistance syndrome are derived from studies by Reaven, who initially described the syndrome as Syndrome X. Reaven has provided numerous insights into the mechanisms underlying the association between insulin resistance and atherosclerosis.
| Rosiglitazone and pioglitazone are approved for use in type 2 diabetes as monotherapy and in combination with sulfonylurea or metformin. |
Insulin resistance has been associated with a unique pattern of dyslipidemia characterized by elevated triglycerides, quantitatively normal but small, dense low-density lipoprotein (LDL) particles, and low high-density lipoprotein (HDL) cholesterol levels. The initial step in the genesis of this pattern appears to be the inability of insulin-resistant fat cells to store triglycerides, resulting in increased free fatty acid concentrations, which then drive hepatic assembly and secretion of very-low-density lipoprotein (VLDL). Hypertriglyceridemia also leads to low HDL cholesterol levels and propensity for small, dense LDL due to its effects on the actions of cholesterol ester transport protein (CETP). Small, dense LDL is well-documented to be a highly atherogenic molecule since it is particularly susceptible to oxidation and adherence to the intra-arterial endothelium. Insulin resistance has been associated with additional cardiovascular risk factors, including hypertension. The mechanism responsible relates to a failure of endothelial cells to appropriately stimulate secretion of nitric oxide, resulting in impaired blood flow and increased vascular resistance. The Heart Outcomes Prevention Evaluation (HOPE) Study has recently shown that treatment with an angiotensin-converting enzyme (ACE) inhibitor, ramipril, improves mortality in subjects with diabetes and additional coronary risk factors, and also reduces the incidence of new-onset diabetes. The mechanisms underlying these findings may relate to the effects of certain ACE inhibitors, including ramipril, to improve insulin resistance, although overall, studies in this regard have yielded conflicting results.
Finally, there is also evidence of increased abnormalities in levels and function of atherogenic clotting factors in individuals with insulin resistance. Fibrinogen levels may be adversely affected by obesity, and Factor VII activity has been shown to increase during postprandial lipemia. Plasminogen activator inhibitor-1 (PAI-1) concentrations, which had been found to be unusually high in young survivors of myocardial infarctions, have also been significantly associated with hyperinsulinemia, hypertriglyceridemia, and hypertension in 1,500 patients with angina in the European Concerted Action on Thrombosis (ECAT) and Disabilities Angina Pectoris Study.