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感染经常与2型糖尿病相关，但因果关系尚未建立。糖尿病和胰岛素抵抗对肝脏疾病至关重要，并与加速丙型肝炎肝纤维化进展有关。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，我们希望刺激努力为有糖尿病风险的患者开发特定的治疗方法。2型糖尿病的特征在于胰岛素抵抗和胰腺B细胞无法通过增加胰岛素输出来适当补偿。使用胰岛素敏感性替代指标的研究表明，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B细胞功能和代偿性高胰岛素血症的易感个体胰岛素抵抗，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，胰岛素敏感的糖酵解处置葡萄糖的外周组织-一个主要组成部分的葡萄糖稳态-减少HCV感染。为了验证这些假设，我们提出了3个具体目标：目标1：确定胰岛素分泌是否与B肝炎（HBV）感染患者相比，HCV感染患者的胰岛素分泌（相对于胰岛素敏感性）降低;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患者更显著降低;目的3：确定丙型肝炎患者全身糖酵解处理葡萄糖是否减少。使用一组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，我们还将评估宿主和病毒因素对葡萄糖耐受不良的影响。我们预计，胰岛素分泌功能和全身糖酵解处置的葡萄糖将受损的HCV患者。这项研究将为HCV感染下糖尿病的发病机制提供新的认识，因为我们将能够直接评估HCV引起的葡萄糖代谢的改变

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