Targeting Inflammation to Improve Endothelial Function in Type 2 Diabetes: A Subs

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DESCRIPTION (provided by applicant): Atherosclerosis is the principal cause of death and disability in patients with diabetes mellitus. Diabetes exerts its pro-atherogenic actions, at least in part, by disturbing endothelial homeostasis. Insulin resistance states, including type 2 diabetes mellitus, are associated with decreased bioavailability of endothelium-derived nitric oxide (NO) and impaired endothelium-dependent vasodilation, and impaired endothelial function predicts cardiovascular events. Basic studies suggest that insulin receptor mediated activation of the PI-3 kinase pathway is important for normal endothelial nitric oxide synthase (eNOS) function. Recent studies demonstrate an important role for subacute, chronic inflammation, specifically mediated by the IKK¿/NF-kB pathway, in the development of insulin resistance and type 2 diabetes mellitus. We hypothesize that activation of IKK¿/NF-kB signaling pathways contributes to the development of atherosclerosis in patients with diabetes, in part by decreasing the bioavailability of nitric oxide and impairing endothelial function. Salicylates inhibit the NF-kB regulatory protein IKK¿, downregulate NF-kB activation, and appear to ameliorate insulin resistance and its associated metabolic abnormalities. Accordingly, we plan to determine whether inhibition of I[kappa] B kinase [beta] (IKK¿)/NF-[kappa]B, a master regulator of inflammation, with salsalate, will restore endothelium-dependent vasodilation in patients with type 2 diabetes. This is proposed as a substudy of TINSAL-T2D (Targeting INflammation using SALsalate for Type 2 Diabetes), a study funded by the NIH (No. UO1-DK074556). The overall objective of TINSAL-T2D is to determine whether salicylates represent a new pharmacological option for diabetes management. In this multicenter, double-masked, placebo-controlled trial, we will target inflammation using salsalate to study its effects on endothelial function and atherosclerotic risk. Flow mediated, endothelium-dependent vasodilation of the brachial (conduit) artery will be measured by high resolution vascular ultrasonography in patients with type 2 diabetes. In addition, change in endothelial function will be assessed as a function of change in glycemia and in circulating inflammatory mediators, as well as free fatty acids, adiponectin, and nitrotyrosine. It is anticipated that findings from this investigation will uncover an important pathophysiologic mechanism that accounts for abnormal vascular function and identify a potential therapy to reduce the risk of adverse cardiovascular events in patients with type 2 diabetes. This investigation is timely and important as it may provide the first information to suggest that targeting inflammation directly may improve endothelial function and atherosclerotic risk in patients with type 2 diabetes. These studies may provide initial evidence of a new pharmacologic strategy to treat or prevent cardiovascular disease in patients with diabetes or related insulin resistant syndromes associated with subacute chronic inflammation. (End of Abstract)