Pathobiology of Prediabetes in A Bi-Racial Cohort

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This proposal is in response to ProgramAnnouncement Number PA-04-074, "Health Disparities inNIDDK Disease." In contrast to the widely reported ethnic differences in prevalence, the incidence of type 2 diabetes was surprisingly similar (~11%) among individuals from the different U.S. ethnic groups inthe Diabetes Prevention Program(DPP). Because DPP participants had impaired glucose tolerance (IGT) at baseline, the finding of similar incident diabetes rates led us to hypothesizethat ethnic disparities are initiated much earlier during the pathogenesis of type 2 diabetes than is commonly realized. We,therefore, propose to study ethnic disparities proximal to the stage of prediabetes (IGT and impaired fastingglucose {IFG}). We will compare the rates of progression from normal glucosetolerance (NGT) to prediabetes in 200 African-American and 200 Caucasian offspring of parents with type 2 diabetes. Compared with NGT subjects, persons with prediabetes (e.g., IGT) have a two-fold increased risk of fatal cardiovasculardisease (CVD). Yet, few prospective studies exist on the natural history, predictors, mechanisms, and mediatorsof progression from NGT to prediabetes in any population, and none in African-Americans. We arguethat focusing on this early period is of public health significance, because the IGT stage may already betoo late for complete reversal of metabolic and cardiovascular sequelae. In our proposed study, initially NGTsubjects at high risk for type 2 diabetes will undergo repeated metabolic assessments, including glucosetolerance, insulin sensitivity, beta cell function, adipocytokines, CVD risk markers,and socioeconomic and other pertinent endpoints for 5 years. DNAspecimens will be stored for future genetic analysis. The primary endpoint is progression from NGTto prediabetes. Secondaryendpoints include changes in caloricintake, physical activity, body composition, insulin sensitivity, insulin secretion, lipoproteins, adipocytokines, proinflammatory markers and other known or putative predictors of glycemic dysregulation. Bycomparing these endpoints between Progressorsand Nonprogressors and African-Americans vs. Caucasianswe hope to provide novel data on the natural history of prediabetes, and determine whether ethnic disparities are programmed during the transition from NGT to prediabetes. Increased understanding of the variousfactors that trigger the changefrom normal glucose to prediabetes would enable the discovery of early preventive interventions beforefull blown diabetes and its related complications become established. Furthermore, understanding howthese factors differ acrossethnic groups will improve our ability to better target preventive measuresin different communities.