This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.While it is well established that type 2 diabetes mellitus (type 2 DM) is associated with accelerated macrovascular disease, it is now abundantly clear that this vascular pathology begins well before the onset of hyperglycemia, and is strongly associated with insulin resistance (IR) which precedes the clinical onset of diabetes. Central obesity, IR, hypertension, glucose intolerance, dyslipidemia, and abnormal fibrinolysis tend to cluster, and together partially account for the increased risk of macrovascular disease. Understanding the mechanistic links between obesity/IR and macrovascular disease is essential to devising effective therapeutic approaches to reduce the risk of cardiovascular events. We have recently found that obesity/IR is associated with impaired endothelial dependent vasodilation characterized by reduced nitric oxide release. This association was found to be independent of cholesterolemia, blood pressure, age and diabetes, factors known to impair endothelial function. Endothelial dysfunction is recognized as a potent pathogenic mechanism for macrovascular disease. Interestingly, we have observed that while insulin can enhance endothelial dependent vasodilation in insulin sensitive subjects, insulin paradoxically diminishes endothelial function in insulin resistant subjects, suggesting an effect of IR to alter the balance between vasoconstrictor and vasodilator forces. The overarching hypothesis of this proposal is that human obesity/IR is associated with an imbalance between the endothelial production of the potent vasodilator nitric oxide and vasoconstrictor endothelin 1 which contributes to abnormal vascular wall biology, vascular tone dysregulation and blood pressure elevation. The primary goal of the proposal is to determine the role of endothelin 1 (ET1) in the endothelial dysfunction observed in the human insulin resistant states of obesity and type 2 diabetes. To this end, we will address the following questions:1-Does excessive ET1 action contribute to impaired endothelium dependent vasodilation and vascular tone dysregulation in insulin resistant subjects? Lean control, obese non-diabetic, and type 2 diabetic subjects will be studied. Basal leg vascular resistance and endothelium dependent and independent vasodilation will be assessed with intra-arterial infusion of methacholine chloride and sodium nitroprusside, respectively. Subsequently, vascular resistance and endothelial function studies will be repeated during infusion of the endothelin A receptor antagonist BQ 123. It is expected that ET A antagonism will at least partially restore endothelial function in insulin resistant subjects. In keeping with the hypothesis that ET1 action is directly related to insulin sensitivity, endothelial function and ET1 dependent vascular tone will also be assessed in super-insulin sensitive highly trained athletes. We anticipate that enhanced insulin sensitivity will be associated with reduced ET1 dependent vascular tone.2-Does ET1 action contribute to impaired insulin mediated vasodilation and glucose uptake in insulin resistant states? In similar subject groups as in (1), leg glucose uptake, insulin mediated vasodilation, circulating ET1 levels and endothelial function will be assessed during euglycemic hyperinsulinemic clamp studies. Studies will be performed in the same individual with and without intra-arterial co-infusions of the endothelin A receptor antagonist BQ 123. We expect that ET A antagonism will ameliorate insulin mediated vasodilation and rates of insulin stimulated leg glucose uptake and largely restore insulin's ability to enhance endothelial dependent vasodilation in insulin resistant subjects.3-Does ET1 play a role in free fatty acid induced endothelial dysfunction and vascular reactivity? Elevation of FFA causes insulin resistance, endothelial dysfunction, and impaired insulin mediated vasodilation. We hypothesize that FFA's effect to alter vascular reactivity is mediated by increased ET1 release. In lean healthy subjects, we will assess endothelial function during elevations of circulating FFA achieved via the infusion of intralipid and heparin with and without intra-arterial infusions of the endothelin A receptor antagonist BQ 123. In a separate group of subjects the effect of FFA on insulin stimulated vasodilation and endothelial function and their respective ET1 dependence will also be assessed. We anticipate that FFA elevation causes vascular dysfunction via increased ET1 release, which is greater under insulin stimulated than under basal conditions and that ET A antagonism will ameliorate these FFA induced vascular abnormalities.4-Is coronary flow reserve impaired in insulin resistant subjects? 13N ammonia and positron emission tomography will be combined to compare coronary flow reserve in young healthy insulin sensitive and obese insulin resistant subjects. To better assess the effects of insulin resistance independent of confounding coronary risk factors associated with obesity, coronary flow reserve will also be assessed in subjects rendered insulin resistant via a prolonged infusion of lipid emulsion designed to raise circulating free fatty acids. To assess the contribution of ET1 to reduced coronary reserve in obese subjects we will also perform studies in conjunction with ET A antagonism. We expect that insulin resistance will be associated with diminished coronary flow reserve secondary to excessive ET1 action.
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