The mechanisms responsible for the accelerated atherogenesis in the Syndrome of Insulin Resistance (SIR) and in non-insulin dependent Diabetes Mellitus (NIDDM) have not yet been thoroughly elucidated. A persistent, exaggerated or recurrent prothrombotic state secondary to impaired endogenous fibrinolysis has been implicated as one responsible factor. A hallmark of both SIR and NIDDM is elevated blood concentration of plasminogen activator inhibitor type 1 (PAI-1), which is a potent inhibitor of endogenous fibrinolysis. This project is designed to delineate the effects of hyperinsulinemia with or without an increase in plasma substrate concentrations (glucose, triglycerides) on the fibrinolytic system. Human subjects, with and without insulin resistance, will receive infusions of insulin (alone and in combination with substrates) designed to induce elevated concentrations simulating those found in the blood of patiens with insulin resistance (IR) and/or non- insulin dependent diabetes mellitus (NIDDM). The overall objective of the project is to determine the extent to which changes in the concentrations of insulin and/or substrates (glucose, triglycerides) imposed over relatively long intervals (6 hrs) modify fibrinolytic system activity in blood. An additional aspect entails induction of a diet and exercise program designed to improve metabolic control, decrease insulin resistance, and modify body composition in subjects with IR and/or NIDDM in order to determine the extent to which this intervention modifies the concentrations in blood of insulin, proinsulin, glucose and lipids, all of which have been implicated as contributors to the imbalance between coagulation and fibrinolysis identified.
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