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

描述（由申请人提供）：流行病学研究显示HCV与2型糖尿病之间存在关联，但因果关系尚未建立。我们最近发现，在HCV感染的情况下，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型糖尿病的风险较高，而HCV对拉丁美洲人患糖尿病风险的不良影响尚不清楚。我们认为HCV和糖尿病之间存在因果关系；因此，我们建议研究HCV在高危拉丁美洲人葡萄糖耐受不良发病的病理生理机制中的确切作用。通过确定HCV促进葡萄糖耐受不良的途径，我们希望刺激开发针对有糖尿病风险患者的特异性治疗方法。2型糖尿病的特点是胰岛素抵抗和胰腺细胞不能通过增加胰岛素输出来适当补偿。使用替代测量方法的研究表明HCV患者胰岛素抵抗增加。通过直接测量，我们发现HCV患者具有广泛的胰岛素敏感性和胰岛素分泌障碍。拉丁美洲人是一个高风险群体，他们有更高的糖尿病易感性和不成比例的HCV影响。因此，我们假设HCV影响细胞功能，导致易患胰岛素抵抗的拉丁美洲人代偿性高胰岛素血症受损，而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重要作用，并且在HCV感染存在的拉丁美洲人中，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型丙型肝炎感染的拉美裔和健康拉美裔对照的胰岛素敏感性（目的1）；确定与健康的非糖尿病拉丁裔对照相比，非糖尿病hcv感染拉丁裔患者的胰岛素分泌相对于胰岛素敏感性是否降低（目的2）；并确定HCV清除与抗HCV治疗对非糖尿病型HCV感染拉美人胰岛素作用的影响（目的3）。通过对感染和未感染HCV的拉丁美洲人进行前瞻性队列研究，我们将采用最新的动态生理技术来确认HCV与胰岛素抵抗（外周和肝脏）之间的联系，并探讨HCV导致拉丁美洲人胰岛素分泌相对受损的可能性，同时考虑到拉丁美洲人是一个高度混合的人群，控制人口分层可能造成的混淆。此外，将测量肝脏IRS表达以进一步研究HCV对肝脏胰岛素信号传导的影响。我们将通过评估病毒根除后胰岛素作用的改善来评估因果关系。

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.