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

丙型肝炎对拉丁裔胰岛素敏感性和胰岛素分泌的影响

• 批准号: 7579860
• 负责人: Mandana Khalili
• 金额: $ 46.35万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7579860
• 关键词: Accounting; Affect; Age-Years; Arts; Blood; Cell physiology; Cells; Cohort Studies; Compensatory Hyperinsulinemia; Data; Defect; Development; Diabetes Mellitus; Epidemiologic Studies; Ethnic Origin; Ethnic group; Etiology; Failure; Functional disorder; Glucose Intolerance; Goals; Hepatic; Hepatitis C; Hepatitis C virus; High Prevalence; Hyperglycemia; Impairment; Individual; Infection; Insulin; Insulin Resistance; Latino; Link; Liver; Measurement; Measures; Metabolic; Methodology; Muscle; Natural History; Non-Insulin-Dependent Diabetes Mellitus; Output; Pancreas; Pathogenesis; Patients; Peripheral; Persons; Physiological; Play; Population; Population Heterogeneity; Populations at Risk; Predisposition; Probability; Public Health; Race; Relative (related person); Research; Research Personnel; Risk; Risk Factors; Role; Signal Transduction; Stratification; Techniques; Testing; Time; United States; Variant; Viral; Virus; anti-hepatitis C; diabetes mellitus therapy; diabetes risk; glucose output; glucose production; high risk; improved; insulin secretion; insulin sensitivity; insulin signaling; non-diabetic; novel; prospective; public health relevance; racial and ethnic; research study

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.

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，但尚未确定因果关系。我们最近发现拉丁裔种族是 HCV 感染情况下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，而丙型肝炎病毒对拉丁美洲人患糖尿病风险的不良影响尚不清楚。我们相信 HCV 和糖尿病之间存在因果关系；因此，我们建议研究丙型肝炎病毒对导致高危拉丁美洲人葡萄糖不耐症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，我们希望能够激励人们为有患糖尿病风险的患者开发特定的治疗方法。 2 型糖尿病的特点是胰岛素抵抗和胰腺 β 细胞无法通过增加胰岛素输出进行适当补偿。使用替代测量的研究表明，HCV 的胰岛素抵抗有所增加。通过直接测量，我们发现 HCV 具有广泛的胰岛素敏感性和胰岛素分泌受损。拉丁美洲人是一个高风险群体，他们更容易患糖尿病，并且受丙型肝炎病毒的影响尤为严重。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情况。我们进一步假设某些因素在葡萄糖不耐症的发生中发挥着重要作用，并且在拉丁裔中存在 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 感染拉丁裔和健康拉丁裔对照者的胰岛素敏感性（目标 1）；确定与健康的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相对于胰岛素敏感性是否降低（目标 2）；并确定抗 HCV 治疗的 HCV 清除对非糖尿病 HCV 感染拉丁裔患者胰岛素作用的影响（目标 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，我们将采用最先进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，控制人口分层可能产生的混杂因素。此外，还将测量肝脏 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。 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高患病率人群（拉丁裔）中促进糖尿病的方式，并将刺激为其他高危人群开发特定治疗方法的努力，并允许对具有重大公共卫生影响的丙型肝炎患者进行糖尿病治疗的定制。