Hepatic Mitochondria and Insulin Resistance in Fatty Liver and Type 2 Diabetes

脂肪肝和 2 型糖尿病中的肝线粒体和胰岛素抵抗

• 批准号: 8402120
• 负责人: RANDY SCOTT RECTOR
• 金额: --
• 依托单位: HARRY S. TRUMAN MEMORIAL VA HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8402120
• 关键词: Adult; Affect; Age; Behavior Therapy; Body Weight decreased; Caloric Restriction; Chronic; Cirrhosis; Combined Modality Therapy; Development; Diabetes Mellitus; Diet; Disease; Effectiveness; Euglycemic Clamping; Exercise; Fatty Liver; Functional disorder; Future; General Population; Glucose Clamp; Goals; Health Personnel; Health Professional; Healthcare Systems; Hepatic; High Prevalence; Human; Hyperglycemia; Hyperphagia; Hypoglycemia; Inbred OLETF Rats; Incidence; Individual; Insulin Resistance; Intervention; Lead; Link; Lipids; Liver; Liver Mitochondria; Liver diseases; Metformin; Mitochondria; Modeling; Morbidity - disease rate; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Oral; Pathogenesis; Patients; Peripheral; Pharmaceutical Preparations; Population; Prevalence; Resistance development; Rodent Model; Role; Scientist; Secondary to; Therapeutic; Transcriptional Regulation; Transplantation Conditioning; Veterans; Work; diabetic; glucose output; in vivo; insight; insulin sensitivity; liver transplantation; mitochondrial dysfunction; mortality; non-alcoholic fatty liver; novel; oxidation; prevent; public health relevance; sedentary; therapeutic target

DESCRIPTION (provided by applicant): Nonalcoholic fatty liver disease (NAFLD) is a chronic, progressive liver disease that affects 30% of all US adults. NAFLD is strongly linked to type 2 diabetes, with an estimated 80% of type 2 diabetics having NAFLD. Unfortunately, the Veteran population has a significantly higher prevalence of diabetes than the general population (20-25% vs. 6-8%), and, therefore, it would be expected to have a similarly higher prevalence of NAFLD. Because NAFLD leads to a significant number of patients with cirrhosis and need for liver transplantation, this condition is an important issue for the VA healthcare system. Despite the strong association between NAFLD and type 2 diabetes, a unifying pathophysiology remains poorly understood. The overall hypothesis of this proposal is that hepatic lipid intermediate/metabolite accumulation and hepatic insulin resistance develops due to hepatic mitochondrial dysfunction, which leads to dysregulated hepatic glucose output and ultimately development of type 2 diabetes. In addition, targeting hepatic mitochondrial dysfunction and hepatic insulin resistance with lifestyle modifications and/or pharmacological interventions will effectively treat NAFLD and type 2 diabetes. We will conduct studies in the Otsuka Long-Evans Tokushima Fatty (OLETF) rat, a well characterized rodent model of hyperphagia-induced obesity, NAFLD, and type 2 diabetes to examine the following specific aims. 1) Determine whether hepatic insulin resistance associated with NAFLD develops secondary to mitochondrial dysfunction and is a significant contributing factor in the development of type 2 diabetes. 2) Determine the effectiveness of daily exercise vs. caloric restriction (with and without metformin) in the treatment of NAFLD and type 2 diabetes. For Aim 1, OLETF rats will be studied at different ages throughout the spectrum of pre-insulin resistance, insulin resistance, and development of frank type 2 diabetes. For Aim 2, OLETF rats will be treated with exercise, caloric restriction, metformin, or combination therapies. The studies will employ in-vivo hyperinsulinemic-euglycemic clamps to assess systemic and hepatic insulin sensitivity and thorough examinations of hepatic mitochondrial function/content and lipid intermediate/metabolites accumulation. This project is extremely novel as it will examine the role of hepatic mitochondrial dysfunction and hepatic insulin resistance throughout the initiation, development, and progression of systemic insulin resistance and type 2 diabetes. In addition, it will comprehensively examine the effectiveness of lifestyle modifications and pharmacological interventions in the treatment of NAFLD and type 2 diabetes. These studies will provide future insight into reducing the incidence of type 2 diabetes and NAFLD in our Veteran population.

描述（由申请人提供）： 非酒精性脂肪肝 (NAFLD) 是一种慢性进行性肝病，影响 30% 的美国成年人。 NAFLD 与 2 型糖尿病密切相关，估计 80% 的 2 型糖尿病患者患有 NAFLD。不幸的是，退伍军人群体的糖尿病患病率明显高于普通人群（20-25% vs. 6-8%），因此，预计其 NAFLD 患病率也同样较高。由于 NAFLD 导致大量患者出现肝硬化并需要肝移植，因此这种情况对于 VA 医疗保健系统来说是一个重要问题。尽管 NAFLD 与 2 型糖尿病之间存在密切关联，但其统一的病理生理学仍然知之甚少。该提议的总体假设是，肝脂质中间体/代谢物积累和肝胰岛素抵抗是由于肝线粒体功能障碍而产生的，这导致肝葡萄糖输出失调并最终发展为2型糖尿病。此外，通过改变生活方式和/或药物干预来针对肝线粒体功能障碍和肝胰岛素抵抗，将有效治疗 NAFLD 和 2 型糖尿病。我们将在 Otsuka Long-Evans Tokushima Fatty (OLETF) 大鼠（OLETF）中进行研究，这是一种经过充分表征的啮齿动物模型，患有过度进食引起的肥胖、NAFLD 和 2 型糖尿病，以检查以下具体目标。 1) 确定与 NAFLD 相关的肝脏胰岛素抵抗是否继发于线粒体功能障碍，并且是 2 型糖尿病发生的重要因素。 2) 确定每日运动与热量限制（使用或不使用二甲双胍）在 NAFLD 和 2 型糖尿病治疗中的有效性。对于目标 1，将对不同年龄的 OLETF 大鼠进行研究，涵盖胰岛素抵抗前、胰岛素抵抗和 2 型糖尿病的发展。对于目标 2，OLETF 大鼠将接受运动、热量限制、二甲双胍或联合疗法的治疗。这些研究将采用体内高胰岛素-正常血糖钳来评估全身和肝脏胰岛素敏感性，并彻底检查肝线粒体功能/含量和脂质中间体/代谢物积累。该项目非常新颖，因为它将研究肝线粒体功能障碍和肝胰岛素抵抗在全身胰岛素抵抗和 2 型糖尿病的起始、发展和进展过程中的作用。此外，还将全面考察生活方式改变和药物干预治疗 NAFLD 和 2 型糖尿病的有效性。这些研究将为未来降低退伍军人群体中 2 型糖尿病和 NAFLD 的发病率提供见解。