HCV-induced alterations in glucose metabolism

描述（由申请人提供）：估计有400万美国人感染丙型肝炎病毒（HCV）。流行病学研究表明，HCV感染常与2型糖尿病相关，但尚未建立因果关系。糖尿病和胰岛素抵抗对肝脏疾病至关重要，并与丙型肝炎肝纤维化加速进展有关。我们认为HCV和糖尿病之间可能存在因果关系，我们在此建议研究HCV背景下葡萄糖耐受不良的潜在机制，以阐明这种因果关系。通过确定HCV促进葡萄糖耐受不良的机制，我们希望能够为有糖尿病风险的患者开发特异性治疗方法。2型糖尿病的特点是胰岛素抵抗和胰腺b细胞不能通过增加胰岛素输出来适当补偿。使用胰岛素敏感性替代测量方法的研究表明，HCV患者的胰岛素抵抗可能增加。鉴于胰岛素抵抗本身不会导致高血糖，我们假设HCV损害了胰岛素抵抗易感个体的b细胞功能和代偿性高胰岛素血症，并且b细胞功能的损害可能是HCV基因型依赖性的。我们进一步假设外周组织对葡萄糖的胰岛素敏感糖酵解处理（葡萄糖稳态的主要组成部分）因HCV感染而减少。为了验证这些假设，我们提出了3个具体目的：目的1：确定HCV感染患者的胰岛素分泌（相对于胰岛素敏感性）是否比乙型肝炎（HBV）感染患者减少；目的2：研究HCV基因型1患者的胰岛素分泌是否比基因型2或3患者更明显减少；目的3：确定HCV患者是否降低了葡萄糖的全身糖酵解处置。采用一组hcv感染者和hbv感染者对照，我们将采用特定的动态方法来测量胰岛素分泌功能与胰岛素抵抗和全身糖酵解处理葡萄糖的关系。此外，我们将评估宿主和病毒因素的影响，这些因素可能对葡萄糖耐受不良很重要。我们预计，HCV患者的胰岛素分泌功能和葡萄糖的全身糖酵解处置将受到损害。拟议的研究将为HCV背景下糖尿病的发病机制提供见解，因为我们将能够直接评估HCV诱导的糖代谢改变

DESCRIPTION (provided by applicant): An estimated 4 million Americans are infected with hepatitis C virus (HCV). Epidemiological studies have shown that HCV infection is frequently associated with type 2 diabetes mellitus, but a cause-and-effect relationship has not been established. Diabetes and insulin resistance are of critical importance to liver disease and have been linked to accelerated hepatitis C liver fibrosis progression. We believe there may be a causal link between HCV and diabetes, and we propose herein to investigate potential mechanisms of glucose intolerance in the setting of HCV that may elucidate this causal relationship. By identifying the mechanism(s) 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 B-cells to appropriately compensate by enhancing insulin output. Studies using surrogate measures of insulin sensitivity have suggested a possible increase in insulin resistance in HCV. Given that insulin resistance by itself does not result in hyperglycemia, we hypothesize that HCV impairs B-cell function and compensatory hyperinsulinemia in predisposed individuals with insulin resistance, and that impairment in B-cell function may be HCV genotype-dependent. We further hypothesize that insulin-sensitive glycolytic disposal of glucose by peripheral tissue - a major component of glucose homeostasis - is reduced by HCV infection. In order to test these hypotheses, we propose 3 specific aims: Aim 1: To determine whether insulin secretion (relative to insulin sensitivity) is decreased in patients with HCV infection compared to patients with hepatitis B (HBV) infection; Aim 2: To investigate whether insulin secretion is reduced more significantly in patients with HCV genotype 1 than in patients with genotype 2 or 3; Aim 3: To determine whether whole-body glycolytic disposal of glucose is reduced in HCV patients. Using a cohort of HCV-infected individuals and HBV-infected controls, we will employ specific dynamic methodologies to measure insulin secretory function in relation to insulin resistance and whole-body glycolytic disposal of glucose. Additionally, we will assess the impact of host and viral factors that may be important in glucose intolerance. We anticipate that insulin secretory function and whole-body glycolytic disposal of glucose will be impaired in HCV patients. The proposed studies will provide insight into the pathogenesis of diabetes in the setting of HCV because we will be able to directly evaluate alterations in glucose metabolism induced by HCV