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: 7585324
• 负责人: MANAL F. ABDELMALEK
• 金额: $ 12.34万
• 依托单位: DUKE UNIVERSITY
• 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 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7585324
• 关键词: Address; Age; Biochemistry; Biopsy; Cardiovascular Diseases; Case-Control Studies; Characteristics; Chronic; Cirrhosis; Clinical; Clinical Trials; Complication; Control Groups; Cryptogenic cirrhosis; Data; Development; Diabetes Mellitus; Double-Blind Method; Early treatment; Enzymes; Epidemic; Epidemiology; Fasting; Fatty Liver; Fatty acid glycerol esters; Funding; Future; Gender; Goals; Health; Healthcare; Hepatic; Hepatitis; Histologic; Hyperglycemia; Hyperinsulinism; Hyperlipidemia; Hypertension; Hypertriglyceridemia; Individual; Insulin; Insulin Resistance; Intervention; Link; Liver; Liver diseases; Measurement; Measures; Mentored Patient-Oriented Research Career Development Award; Metabolic; Metabolic syndrome; Metabolism; Metformin; Modality; Modeling; Morbidity - disease rate; Nonesterified Fatty Acids; Obesity; Pathogenesis; Pathologic; Patient Care; Patients; Peripheral; Pilot Projects; Plasma; Play; Prevalence; Public Health; Publishing; Randomized; Regulation; Research Personnel; Risk Factors; Rivers; Role; Safety; Scientist; Secondary to; Syndrome; Testing; Training; Triglycerides; United States National Institutes of Health; Visceral; Weight Gain; Work; care burden; career; cost; double-blind placebo controlled trial; effective therapy; glucose uptake; glycemic control; high risk; improved; insulin sensitivity; intravenous glucose tolerance test; lipid metabolism; mortality; multidisciplinary; non-alcoholic fatty liver; non-diabetic; patient oriented; patient registry; placebo controlled study; prevent; programs; prospective; research study; treatment program

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）是一种可能进展为肝硬化的常见疾病。其发病机制尚不清楚，目前尚无有效的治疗方法。胰岛素抵抗（IR）可能在NAFLD的发病机制中起重要作用，但这种关联的潜在机制尚不清楚。IR与NAFLD的一个潜在联系机制是高甘油三酯血症和游离脂肪酸（FFA）的肝内流增加。数据表明，NAFLD的患病率与肥胖和糖尿病患病率的上升同步上升。因此，需要一种经济有效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，其先于糖尿病和/或肥胖症的发展。我假设IR是NAFLD的特征，并且改善胰岛素敏感性（IS）将改善这种情况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：  在NAFLD患者、健康对照受试者和非脂肪性肝病患者中，使用静脉内葡萄糖耐量试验和Bergman最小模型测量IS和胰岛素清除率。  确定与匹配对照组相比，IR是否与甘油三酯和FFA的循环水平升高相关。具体目标#2：进行一项使用胰岛素增敏剂治疗NAFLD患者的前瞻性随机、双盲、安慰剂对照试验。研究终点将包括：  IS、肝脏胰岛素清除率、甘油三酯和FFA的测量。  定义NAFLD的组织学特征的变化以及内脏和外周脂肪的定量测量。该项目将确定IR和/或受损的胰岛素清除率是否是NAFLD的特征，与有或没有慢性非脂肪性肝病的患者相比，以及改善IS是否会改善定义NAFLD的临床病理特征。我将获得MPH学位，重点是流行病学，目的是研究NAFLD以及相关的胰岛素和脂质代谢失调。肥胖和糖尿病的流行需要熟练的以患者为导向的研究人员在公共卫生和流行病学方面的知识，以建立健康计划和治疗计划，以降低与IR相关的慢性肝病的预期发病率和死亡率。