Effects of Elevated Free Fatty Acids on Endogenous Glucose Production in People With and Without Type 2 Diabetes Mellitus

The ultimate goal of this application is to determine the cause(s) of type 2 diabetes mellitus. The role of the liver in the evolution of type 2 diabetes has not been as extensively studied as that of muscle. This has been, in part, due to the inherent difficulty of measuring hepatic insulin action in humans under physiologic conditions. Plasma free fatty acids (FFA) can cause insulin resistance in non-diabetic humans and are commonly elevated in people with type 2 diabetes. We will re-examine the mechanism(s) by which elevated FFA cause hepatic insulin resistance in non-diabetic humans, will determine whether elevated FFA alter insulin induced suppression of endogenous glucose production (EGP) in diabetic humans and if so, whether this is due to changes in glycogenolysis and/or gluconeogenesis. We will also seek to determine whether treatment with a pioglitazone (a thiazolidinedione) blunts or prevents FFA induced hepatic (and extrahepatic) insulin resistance in people with type 2 diabetes and whether the effects of FFA on insulin action are influenced by gender. We will examine if use of thiazolidinediones reduces cortisol production by changing the overall activity of 11 beta hydroxysteroid dehydrogenase type 1. We will also investigate whether use of thiazolidinediones alters objectively measured breathing or sleepiness in people with type 2 diabetes.