Review
Insulin resistance and the endothelium

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Abstract

There is increasing evidence of a parallel progression between insulin resistance and endothelial dysfunction, suggesting a close association between insulin action and the endothelium. Numerous studies have demonstrated that endothelial dysfunction occurs early in the insulin-resistant state and is predictive of future cardiovascular events. Similarly, insulin resistance has been associated with the metabolic syndrome, which also increases the risk of adverse cardiovascular outcomes. Approaches that improve endothelial dysfunction, such as treatment with statins, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, or peroxisome proliferator-activated receptor γ ligands, have been shown to prevent both diabetes and cardiovascular disease. This article reviews the relation between endothelial dysfunction and cardiovascular disease, assesses the endothelium in the spectrum of insulin resistance, and examines the effect of the thiazolidinediones on endothelial function.

Section snippets

Endothelial dysfunction predicts cardiovascular disease

Endothelial function in a peripheral or coronary artery can be viewed as a vasodilatory response to acetylcholine or methacholine, which directly stimulate nitric oxide production, or to hyperemia, which can be achieved in a peripheral artery by blood pressure cuff inflation or cold pressor testing. Abnormal vasomotive responses occur in the presence of traditional risk factors, such as hypercholesterolemia, hypertension, smoking, diabetes, low high-density lipoprotein (HDL) cholesterol levels,

The endothelium in the spectrum of insulin resistance

Increasing evidence suggests that the progression of insulin resistance to type 2 diabetes parallels the progression of endothelial dysfunction to atherosclerosis (Figure). Insulin resistance is closely linked with visceral adiposity, and early data suggested that free fatty acids were responsible for this association, since free fatty acids are increased in adiposity as a result of increased lipolysis. Free fatty acids were found to inhibit insulin-mediated glucose uptake by decreasing

Improving endothelial function is associated with prevention of diabetes

A number of approaches that improve endothelial function prevent both diabetes and cardiovascular disease, underscoring the close relation between the endothelium and insulin action (Table 4). Statins, ACE inhibitors, and angiotensin receptor blockers improve endothelial function and, in major clinical trials, reduce both cardiovascular disease and new-onset type 2 diabetes 47, 48, 49. Exercise and weight loss also improve endothelial function. The recently completed Diabetes Prevention

The effect of thiazolidinediones on endothelial function

Thiazolidinediones are a class of therapeutic agents that activate peroxisome proliferator-activated receptor γ (PPAR-γ), a nuclear receptor that enhances insulin-mediated glucose uptake into insulin target tissues, such as the skeletal muscle, heart, and adipose (58). To date, only three drugs in this class have been approved for medical use: pioglitazone, rosiglitazone, and troglitazone, although troglitazone has since been withdrawn from the market. Thiazolidinediones have direct effects on

The effect of statins on endothelial function

Statins are the current drugs of choice for the treatment of hypercholesterolemia. They block the conversion of 3-hydroxy-3-methylglutaryl coenzyme A to mevalonate, thereby inhibiting an early rate-limiting step in cholesterol biosynthesis. Statins reduce serum LDL and increase HDL cholesterol levels, and liver LDL receptor expression, with an associated increase in cholesterol clearance.

Statins have beneficial effects on the vascular bed, increasing vascular eNOS activity and synthesis, while

Inhibition of the renin-angiotensin system and other approaches

Angiotensin II has several pro-oxidative effects on the vasculature, decreasing nitric oxide bioavailability and resulting in vascular injury. ACE inhibitors are known to improve endothelial dysfunction, but the ability of angiotensin receptor blockers to improve endothelial dysfunction is less clear 45, 94. Both drug classes consistently prevent coronary artery (particularly in the case of ACE inhibitors), stroke, and diabetic microvascular complications of nephropathy and retinopathy (95).

Conclusion

There is increasing evidence to suggest a parallel progression between insulin resistance and endothelial dysfunction. The PPAR-γ ligands clearly improve insulin sensitivity and endothelial function. They may slow the progression of carotid intima-media thickness, which mirrors atherosclerotic changes in the coronary arteries (98). Growing evidence on PPAR-γ ligands, including their effects on reversing the metabolic syndrome, inhibiting vascular inflammation, and improving endothelial

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