Role of Free Fatty Acids in Human Insulin Metabolism

Increased availability of lipid substrates, particularly plasma non-esterified free fatty acids and intracellular triglyceride stores have been linked to many aspects of the insulin resistance syndrome including obesity, dyslipidemia and Type 2 diabetes. Epidemiologic and animal data suggest that saturated fats have differential effects on the induction of insulin resistance as well as their effects (both stimulatory and inhibitory) on beta cell function compared to unsaturated fats. Current medical guidelines suggest limiting fat, particularly saturated fat intake. Surprisingly, considering the potential public health implications of dietary fat intake, little direct experimental data exists for human subjects in this area, and available data is contradictory. The goal of these studies, therefore, is to explore the effect of lipids on normal beta cell physiology and then to directly test the hypothesis that dietary saturated fatty acids time dependently stimulate insulin secretion more and then induce greater degrees of insulin secretory dysfunction with prolonged exposure as compared to unsaturated fats using the novel method of in vivo stable isotope peptide pharmacokinetics. As beta cell function deteriorates with prolonged NEFA exposure, hyperinsulinemia matching the degree of insulin resistance will be maintained by decreases in systemic and hepatic insulin clearance. We will also test the proposition that subjects at risk for Type 2 diabetes will be more sensitive to the effects of saturates compared to normal controls. Lastly we hypothesize that for the group as a whole, defects in insulin action, insulin clearance and finally beta cell secretory function will be exactly paralleled by accumulations of intracellular triglycerides in multiple tissues including within hepatocytes and skeletal myocytes as monitored non-invasively by magnetic resonance proton spectroscopy and that this provides the unifying link to systemic organ dysfunction with abnormal lipid metabolism in the insulin resistance syndromes. Preliminary data support the feasibility of our approach as well as our hypothesis. An improved understanding of beta cell - lipid interactions should provide evidence for future dietary recommendations to prevent type 2 diabetes.