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.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 pancreatic beta cell function, particularly in comparison to unsaturated vegetable and marine oil 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. The goal of these studies therefore, is to directly test the hypothesis that dietary saturated fatty acids time dependently both stimulate the insulin secretion more and then prevent compensatory insulin hypersecretion with prolonged exposure as compared to unsaturated fats using the novel method of in vivo stable isotope peptide pharmacokinetics. As beta cell hyperfunction decreases 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 hypothesis 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 closely 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. Participating subjects will undergo the following procedures as part of this study: magnetic resonance scans, infusion of lipid emulsions i.v., infusion or heparin, stable isotope labeled glucose, lipids and C-peptide, insulins at low doses (porcine, insulin aspart, insulin-arginine).
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