Impact of Hepatitis C on Insulin Sensitivity and Insulin Secretion in Latinos

描述（由申请人提供）：流行病学研究表明HCV与2型糖尿病之间存在关联，但尚未建立因果关系。我们最近发现，在HCV感染的背景下，拉丁裔是胰岛素抵抗的唯一独立危险因素。拉丁美洲人患2型糖尿病的风险很高，HCV对拉丁美洲人患糖尿病风险的不利影响尚不清楚。我们认为HCV和糖尿病之间存在因果关系，因此，我们建议调查HCV对葡萄糖耐受不良发生的病理生理机制的确切贡献。通过确定丙型肝炎病毒促进葡萄糖不耐受的方式，我们希望刺激为有患糖尿病风险的患者开发特定治疗方法的努力。2型糖尿病的特征是胰岛素抵抗和胰腺细胞无法通过增加胰岛素输出来适当补偿。使用替代测量的研究表明HCV的胰岛素抵抗增加。使用直接测量，我们已经显示了广泛的胰岛素敏感性与HCV和胰岛素分泌的损害。拉丁美洲人是一个高风险群体，具有更高的糖尿病易感性，并受到HCV的不成比例的影响。因此，我们假设HCV影响胰岛细胞功能，导致有胰岛素抵抗倾向的拉丁美洲人代偿性高胰岛素血症受损，HCV病毒根除可改善这些异常。我们进一步假设，某些因素在葡萄糖耐受不良的发展中起着重要作用，并且在拉丁美洲人中存在HCV感染的情况下，与这些因素相关的风险可能存在差异。为了检验这些假设，我们将比较非糖尿病HCV感染的拉丁美洲人和健康拉丁美洲人对照的胰岛素敏感性（目的1）;确定与健康非糖尿病拉丁美洲人对照相比，非糖尿病HCV感染的拉丁美洲人的胰岛素分泌是否相对于胰岛素敏感性降低（目的2）;并确定在非糖尿病HCV感染的拉丁美洲人中，抗HCV治疗对HCV清除率对胰岛素作用的影响（目的3）。使用前瞻性队列研究的拉丁美洲人与丙型肝炎病毒感染和不感染，我们将采用动态状态-最先进的生理技术，以确认丙型肝炎病毒和胰岛素抵抗（外周和肝脏）之间的联系，并探讨丙型肝炎病毒的可能性，导致相对损害的胰岛素分泌拉丁美洲人，同时控制可能的混杂人口分层，因为拉丁美洲人是一个高度混合的人口。此外，将测量肝脏IRS表达以进一步研究HCV对肝脏中胰岛素信号传导的影响。我们将通过评价病毒根除后胰岛素作用的改善来评估因果关系。 公共卫生相关性：这项研究将确定HCV促进糖尿病在HCV和糖尿病（拉丁美洲人）高患病率人群中的方法，并将刺激为其他高危人群开发特定治疗方法的努力，并允许在HCV患者中定制具有显著公共卫生影响的糖尿病治疗。

DESCRIPTION (provided by applicant): 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.