Hyperinsulinemia and Insulin Resistance in Fatty Liver

脂肪肝中的高胰岛素血症和胰岛素抵抗

• 批准号: 6871563
• 负责人: MANAL F. ABDELMALEK
• 金额: $ 12.34万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-06-15 至 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6871563
• 关键词: clinical research; diabetes mellitus; fatty liver; free fatty acids; glucose tolerance test; human subject; hyperinsulinism; insulin sensitivity /resistance; obesity; patient oriented research

DESCRIPTION (provided by applicant): Nonalcoholic fatty liver disease (NAFLD) is a prevalent condition which may progress to cirrhosis. Its pathogenesis is obscure and no effective therapy exists. Insulin resistance (IR) may play a central role in the pathogenesis of NAFLD but the underlying mechanism for this association is unclear. One potential mechanism linking IR to NAFLD is hypertriglyceridemia and increased hepatic influx of free fatty acids (FFAs). Data suggest that the prevalence of NAFLD is increasing in parallel with the rising prevalence of obesity and diabetes. Consequently, a cost-effective treatment is needed to prevent an epidemic of chronic liver disease related to IR. My preliminary data reveal that nearly 90%of patients with NAFLD have hyperinsulinemia, irrespective of the presence of obesity or overt diabetes. NAFLD may also represent an early clinical feature of IR that precedes the development of diabetes and/or obesity. I hypothesize that IR is characteristic of NAFLD and that improving insulin sensitivity (IS) will improve the metabolic and histologic features of this condition. I will test this hypothesis by accomplishing the following specific aims: Specific Aim #1: Conduct a case-control study to determine if IR is characteristic of NAFLD. To do this we will:  Measure IS and insulin clearance using intravenous glucose tolerance testing and Bergman Minimal Modeling in patients with NAFLD, healthy control subjects, and patients with non-steatotic liver disease.  Determine if IR is associated with increased circulating levels of triglycerides and FFAs compared to matched control groups. Specific Aim #2: Conduct a prospective randomized, double-blind, placebo-controlled trial using an insulin-sensitizing agent to treat patients with NAFLD. Study endpoints will include:  Measurements of IS, hepatic insulin clearance, triglycerides, and FFAs.  Change in the histologic features that define NAFLD and quantitative measures of visceral and peripheral fat. This project will determine whether IR and/or impaired insulin clearance is characteristic of NAFLD as compared to those with or without chronic non-steatotic liver disease, and whether improving IS will improve the clinical-pathologic features that define NAFLD. I will obtain an MPH degree with an emphasis in epidemiology for the purpose of studying NAFLD and the associated deregulation of insulin and lipid metabolism. The epidemic of obesity and diabetes requires skilled patient-oriented researchers knowledgeable in public health and epidemiology to establish health programs and treatment initiatives to decrease the anticipated morbidity and mortality of chronic liver disease related to IR.

描述（由申请人提供）：非酒精性脂肪性肝病（NAFLD）是一种可能发展为肝硬化的常见病。其发病机制尚不清楚，也没有有效的治疗方法。胰岛素抵抗（IR）可能在NAFLD的发病机制中起核心作用，但其潜在机制尚不清楚。将IR与NAFLD联系起来的一个潜在机制是高甘油三酯血症和游离脂肪酸（FFAs）肝内流增加。数据显示，NAFLD的患病率随着肥胖和糖尿病患病率的上升而上升。因此，需要一种具有成本效益的治疗方法来预防与IR相关的慢性肝病的流行。我的初步数据显示，近90%的NAFLD患者患有高胰岛素血症，无论是否存在肥胖或明显的糖尿病。NAFLD也可能代表IR的早期临床特征，先于糖尿病和/或肥胖的发展。我假设IR是NAFLD的特征，改善胰岛素敏感性（is）将改善这种疾病的代谢和组织学特征。我将通过实现以下具体目标来检验这一假设：具体目标#1：进行病例对照研究，以确定IR是否是NAFLD的特征。为此，我们将：