Although hyperglycemia plays an essential role in the pathophysiology of DM, elevated serum insulin levels may also play an important role in atherogenesis, specifically in noninsulin DM. Furthermore, insulin resistance is a known cardiac risk factor.
Insulin mediates NO production through specific pathway, which includes insulin receptor tyrosine, phosphatidyl inositol 3-kinase and its downstream effector, akt (118,119). This increase in NO release, in turn, results in vasodilation (120). This endot-helial-dependent relaxation is accompanied by an increase in glucose transport and metabolism (121,122) and may also potentially result in the removal of postprandial glucose. Therefore, endothelial dysfunction may lead to insulin resistance. This argument is further strengthened by the findings of Petrie and coworkers (123), which showed a correlation between basal endothelial function and insulin sensitivity in healthy controls. This relationship was not seen with either nitroprusside or acetylcholine, suggest ing that this decreased sensitivity is not associated with a reduced ability of the vascular endothelium to synthesize NO when stimulated or with a reduction in sensitivity of vascular smooth muscle to NO released from the endothelium. Similar correlations between the degree of basal endothelial dysfunction and insulin sensitivity were seen in subjects with both hypertension and adult-onset DM (124), although this was not a consistent finding (125). However, Bursztyn and colleagues (126) demonstrated that inhibition of NO in an animal model did not result in glucose intolerance or hyperinsulinemia. These findings suggesting that endothelial function contributes to insulin sensitivity and, conversely, that insulin resistance is as a result of endothelial dysfunction) offer important new treatment options particularly in patients with adult-onset DM.
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