This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. OBJECTIVE/BACKGROUND: Type 2 diabetes mellitus is characterized by resistance to the action of insulin in liver. Type 2 diabetic subjects also have elevated basal FFA levels/lipid oxidation, which fail to suppress normally in response to insulin. Previous studies have suggested that elevated plasma FFA concentrations and/or lipid oxidation impair insulin's ability to suppress hepatic glucose production in type 2 diabetic subjects. However, it remains unclear whether elevated plasma FFA levels and/or lipid oxidation or some consequence of these abnormalities augments gluconeogenesis or glycogenolysis. It is also unclear whether, in the insulin resistant normal glucose tolerant offspring of two diabetic parents, elevated plasma FFA concentrations/lipid oxidation induce hepatic resistance to insulin. We will test this hypothesis by quantitating the effect of insulin on hepatic gluconeogenesis and glycogenolysis following prolonged Intralipid infusion. METHODS: Ten lean healthy non-diabetic subjects and 10 non-diabetic offspring of two diabetic parents will be studied. Subjects will undergo a baseline evaluation consisting of an oral glucose tolerance test and an insulin clamp study. Subjects will then receive an intralipid infusion for eight days to increase the plasma FFA concentration to levels observed in type 2 diabetic individuals. Before and following Intralipid infusion, subjects will receive a four hour euglycemic clamp with tritiated glucose (to measure total hepatic glucose production) and deuterated water (to measure gluconeogenesis) in the basal state and in response to physiologic hyperinsulinemia.
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