HCV-induced alterations in glucose metabolism

描述(申请人提供)：估计有400万美国人感染丙型肝炎病毒(丙型肝炎病毒)。流行病学研究表明，丙型肝炎病毒感染经常与2型糖尿病有关，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。我们认为在丙型肝炎病毒和糖尿病之间可能存在因果联系，我们在此建议研究在丙型肝炎病毒背景下葡萄糖耐量异常的潜在机制，以阐明这种因果关系。通过确定丙型肝炎病毒促进葡萄糖耐受的机制(S)，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B细胞无法通过增加胰岛素输出进行适当的补偿。使用替代测量胰岛素敏感性的研究表明，丙型肝炎病毒可能增加了胰岛素抵抗。考虑到胰岛素抵抗本身并不会导致高血糖，我们假设在易患胰岛素抵抗的个体中，丙型肝炎病毒会损害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与丙型肝炎病毒的基因相关。我们进一步假设，外周组织对胰岛素敏感的糖酵解处置葡萄糖--葡萄糖稳态的主要成分--因丙型肝炎病毒感染而减少。为了验证这些假说，我们提出了三个特定的目标：目的1：确定与乙肝患者相比，丙型肝炎病毒感染者的胰岛素分泌(相对于胰岛素敏感性)是否减少；目的2：研究丙型肝炎病毒1型患者的胰岛素分泌是否比基因型2或3的患者更显著；目的3：确定丙型肝炎患者体内葡萄糖的糖酵解处置是否减少。使用一组感染了丙型肝炎病毒的个体和感染了乙肝病毒的对照组，我们将使用特定的动态方法来测量与胰岛素抵抗和全身葡萄糖糖酵解处置有关的胰岛素分泌功能。此外，我们将评估宿主和病毒因素的影响，这些因素可能在葡萄糖耐量异常中起重要作用。我们预计，丙型肝炎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。拟议的研究将为在丙型肝炎背景下糖尿病的发病机制提供洞察力，因为我们将能够直接评估丙型肝炎引起的葡萄糖代谢的变化。

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