Epidemiological studies have shown an association between HCV and type 2 diabetes mellitus, but a cause and effect relationship has not been established. We have recently identified Latino ethnicity as the only independent risk factor for insulin resistance in the setting of HCV infection. Latinos are at high risk of developing type 2 diabetes and the untoward effects of HCV on the risk of diabetes among Latinos are not known. We believe there is a causal link between HCV and diabetes; hence, we propose to investigate the precise contribution of HCV to pathophysiologic mechanisms responsible for the development of glucose intolerance among the at-risk Latinos. By identifying the means by which HCV promotes glucose intolerance, we hope to stimulate efforts to develop specific treatments for patients at risk of developing diabetes. Type 2 diabetes is characterized by insulin resistance and the failure of pancreatic ¿-cells to appropriately compensate by enhancing insulin output. Studies using surrogate measurements have suggested an increase in insulin resistance in HCV. Using direct measures, we have shown a wide range of insulin sensitivity with HCV and an impairment of insulin secretion. Latinos represent a high risk group having a higher predisposition to diabetes and being disproportionately affected by HCV. Thus, we hypothesize that HCV affects ¿-cell function resulting in impairment of compensatory hyperinsulinemia in predisposed Latinos with insulin resistance and that HCV viral eradication improves these abnormalities. We further hypothesize that certain factors play an important role in the development of glucose intolerance and that there may be differences in the risks associated with these factors in the presence of HCV infection in Latinos. To test these hypotheses, we will compare insulin sensitivity in non-diabetic HCV-infected Latinos and healthy Latino controls (Aim 1); determine whether insulin secretion relative to insulin sensitivity is decreased in non-diabetic HCV-infected Latinos compared to healthy non-diabetic Latino controls (Aim 2); and determine the impact of HCV clearance with anti-HCV therapy on insulin action in non-diabetic HCV-infected Latinos (Aim 3). Using a prospective cohort study of Latinos with and without HCV infection, we will employ dynamic state of- the art physiological techniques to confirm the connection between HCV and insulin resistance (peripheral and hepatic) and to explore the possibility that HCV results in a relative impairment of insulin secretion among Latinos while controlling for a possible confounding by population stratification given that Latinos are a highly admixed population. In addition, hepatic IRS expression will be measured to further investigate an HCV effect on insulin signaling in the liver. We will assess causation by evaluating the improvement of insulin action following viral eradication. Public Health Relevance: This study will identify the means by which HCV promotes diabetes in a population with a high prevalence of both HCV and diabetes (Latinos) and will stimulate efforts to develop specific treatments for other at risk populations and allows tailoring of diabetes therapy in HCV patients that has a significant public health impact.