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

描述(由申请人提供)：流行病学研究表明丙型肝炎病毒与2型糖尿病之间存在联系，但因果关系尚未确定。我们最近已经确定，在丙型肝炎病毒感染的背景下，拉丁裔种族是胰岛素抵抗的唯一独立危险因素。拉美裔人患2型糖尿病的风险很高，而丙型肝炎病毒对拉丁裔糖尿病风险的不良影响尚不清楚。我们认为，丙型肝炎病毒与糖尿病之间存在因果关系；因此，我们建议调查丙型肝炎病毒在高危拉美裔人群中导致葡萄糖耐量减低的病理生理机制中的确切作用。通过确定丙型肝炎病毒促进葡萄糖不耐受的方式，我们希望刺激努力，为有患糖尿病风险的患者开发特定的治疗方法。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进行适当的补偿。使用替代测量的研究表明，丙型肝炎病毒的胰岛素抵抗增加。使用直接测量，我们已经显示了丙型肝炎病毒的广泛的胰岛素敏感性和胰岛素分泌的障碍。拉丁裔是一个高危群体，有更高的糖尿病易感性，并且受丙型肝炎病毒的影响不成比例。因此，我们假设，丙型肝炎病毒影响细胞功能，导致易患胰岛素抵抗的拉丁裔人代偿性高胰岛素血症受损，根除丙型肝炎病毒可改善这些异常。我们进一步假设，某些因素在葡萄糖耐量异常的发展中起重要作用，在拉丁裔中存在丙型肝炎病毒感染的情况下，与这些因素相关的风险可能存在差异。为了验证这些假设，我们将比较非糖尿病的感染了丙型肝炎病毒的拉丁裔人和健康的拉丁裔对照组的胰岛素敏感性(目标1)；确定与健康的非糖尿病的拉丁裔对照组相比，非糖尿病的感染了丙型肝炎病毒的拉丁裔人的胰岛素分泌相对于胰岛素敏感性是否降低(目标2)；以及确定在非糖尿病的感染了丙型肝炎病毒的拉丁裔人中，丙型肝炎病毒清除和抗丙型肝炎病毒治疗对胰岛素作用的影响(目标3)。通过对感染和不感染丙型肝炎病毒的拉丁裔人进行前瞻性队列研究，我们将使用最先进的生理学技术来确认丙型肝炎病毒与胰岛素抵抗(外周和肝脏)之间的联系，并探索丙型肝炎病毒导致拉美裔人胰岛素分泌相对受损的可能性，同时控制人口分层可能造成的混杂，因为拉美裔人是一个高度混杂的人群。此外，还将测量肝脏IRS的表达，以进一步研究丙型肝炎病毒对肝脏中胰岛素信号的影响。我们将通过评估根除病毒后胰岛素作用的改善来评估原因。 公共卫生相关性：这项研究将确定丙型肝炎病毒在丙型肝炎病毒和糖尿病(拉丁裔)高流行率人群中促进糖尿病的手段，并将推动为其他高危人群开发特定治疗方法的努力，并允许为丙型肝炎患者量身定做对公共健康有重大影响的糖尿病治疗方法。

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.