Molecular and physiologic actions of insulin related to production of nitric oxide in vascular endothelium

Abstract

Insulin has important vascular actions that regulate blood flow, in addition to its classical actions to coordinate glucose homeostasis. Insulin-stimulated production of nitric oxide in vascular endothelium results in capillary recruitment and vasodilation that diverts and increases blood flow to skeletal muscle and consequently increases glucose disposal. Thus, vascular actions of insulin may be essential for coupling hemodynamic and metabolic homeostasis. A complete biochemical signaling pathway linking the insulin receptor to activation of endothelial nitric oxide synthase in vascular endothelium has recently been elucidated. Moreover, the time course and dose response for capillary recruitment in response to physiologic concentrations of insulin parallels that of insulin-mediated glucose uptake in vivo. Taken together, these observations suggest a molecular mechanism that may help to explain how insulin resistance contributes to cardiovascular components of the metabolic syndrome and vascular complications of diabetes.

Fibrate therapy and flow-mediated dilation: A systematic review and meta-analysis of randomized placebo-controlled trials

“…Dogra et al [25] studied patients with chronic kidney disease (stages 3 to 5), reporting that both atorvastatin and gemfibrozil treatments have no effect on endothelial function. Indeed, as previously shown in other studies [58,62], in this population dyslipidemia seems not to be a primary contributor to arterial dysfunction. The other two studies administering gemfibrozil enrolled a small number of patients at low metabolic risk, in contrast to studies testing fenofibrate.…”

“…Findings from our meta-analysis may be influenced by participants in the studies testing fenofibrate [21][22][23]33,35,37,38]: they were obese and/or dyslipidemic and all had endothelial dysfunction at baseline (basal FMD < 6%, range 3.1-5%), representing a high-risk category, where improvement in the lipid profile is expected to exert beneficial effects on vascular health. Taking into account that low HDL-C and high triglycerides levels have been associated with reduced post-ischemic endothelial vasodilation, as shown in a cohort of patients with metabolic syndrome [58], findings of the present meta-analysis might contribute to the interpretation of results of FIELD and ACCORD trials [58,58,61].…”

“…It mimics the metabolic actions of insulin [56], which exerts many cardioprotective effects and may also directly increase production of NO in the vascular wall [57]. Furthermore, adiponectin is directly involved in endothelium protection through inhibition of adhesion molecules and proinflammatory cytokine production [50,58], and by stimulation of NO production from endothelium via activation of AMP-activated protein kinase [59].…”

“…A recent Cochrane systematic review including 13 trials and 16,112 participants [4] demonstrates that fibrates exerts protective effects over the primary composite outcome (non-fatal stroke, non.fatal myocardial infarction and vascular death); however, after excluding clofibrate trials, the remaining class of fibrates were no longer effective in preventing the primary composite outcome but remained effective in preventing myocardial infarction. Furthermore, large-scale trials demonstrated that fenofibrate therapy reduces the rate of cardiovascular events only in patients at high risk, such as those with diabetes mellitus and atherogenic dyslipidemia (low levels of HDL-C and increased triglycerides) [58,58,61]. It is conceivable that trial results may considerably differ according to the background cardiovascular risk of participants.…”

Co-effect of insulin resistance and biomarkers of inflammation and endothelial dysfunction on hypertension

“…Additional results indicate that IR may in turn exacerbate inflammation by increasing cytokine and adipochemokine expression (including TNF-a, interleukin-6, leptin and others), elevating free fatty acid levels, and impairing endothelial nitric oxide synthase activity. 35,36 Both inflammation and IR are two important links in the mechanism of hypertension; either systemic inflammation promotes the development of hypertension by introducing IR or IR promotes the development of hypertension by exacerbating inflammation. According to our findings that the coexistence of inflammation and IR increase the risk of hypertension, we presume that inflammation may partially and directly introduce hypertension by way of the inflammatory process in addition to IR; there is a co-effect between inflammation and IR on hypertension.…”