Molecular determinants of obesity and type 2 diabetes mellitus

Type 2 Diabetes Mellitus is an increasingly common disorder of carbohydrate and lipid metabolism. Approximately 16 million individuals in the United States have diabetes, and 800,000 new cases are identified each year. Two important characteristics of this disease are insulin resistance, the failure of peripheral tissues including liver, muscle and adipose to respond to physiological doses of insulin, and failure of pancreatic β-cells to properly secrete insulin in response to elevated blood glucose levels. However, the molecular mechanism for the development of insulin resistance and β-cell failure is unclear.; Obesity is a significant risk factor for the development of type 2 Diabetes Mellitus. Approximately 80% of individuals are obese however only 10% of obese individuals become diabetic. Furthermore, recent observations in extremely lean, lipoatrophic models have similarly revealed a predisposition for the development of diabetes. While it may seem paradoxical that both increased adiposity and severely reduced fat mass both cause diabetes, a common pathophysiologic process in fat may be responsible for both conditions' predisposition to develop hyperglycemia.; In this dissertation, I describe studies focused on determining the molecular determinants of obesity and type 2 Diabetes Mellitus. Chapter two details the changes in the insulin signal transduction cascade that accompany insulin resistance. Chapter three describes the changes in gene expression in adipose tissue that accompany the development of insulin resistance. Chapter four provides a genomic analysis of adipose tissue from genetically obese mice and the further changes in gene expression that accompany the development of diabetes. Chapter five reviews a theory on the development of type 2 diabetes and the relative roles of liver and adipose tissue in this diseases pathogenesis.