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

描述（由申请人提供）： 非酒精性脂肪性肝病（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，退伍军人人群的糖尿病患病率明显高于普通人群（20-25% vs. 6-8%），因此，预计NAFLD的患病率也会类似地更高。由于NAFLD导致大量肝硬化患者需要肝移植，因此这种情况是VA医疗保健系统的一个重要问题。尽管NAFLD和2型糖尿病之间存在很强的相关性，但对其统一的病理生理学仍知之甚少。该建议的总体假设是，由于肝线粒体功能障碍，导致肝脏葡萄糖输出失调，最终发展为2型糖尿病，从而导致肝脏脂质中间体/代谢物蓄积和肝脏胰岛素抵抗。此外，通过生活方式改变和/或药物干预靶向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。我们将在大冢Long-Evans德岛脂肪（OLETF）大鼠中进行研究，该大鼠是一种充分表征的摄食过多诱导的肥胖、NAFLD和2型糖尿病的啮齿动物模型，以检查以下特定目标。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，是否是2型糖尿病发展的重要因素。2)确定每日运动与热量限制（有和没有二甲双胍）治疗NAFLD和2型糖尿病的有效性。对于目标1，将在不同年龄的OLETF大鼠中研究前胰岛素抵抗、胰岛素抵抗和明显的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、二甲双胍或联合治疗。研究将采用体内高胰岛素-正常血糖钳夹法评估全身和肝脏胰岛素敏感性，并全面检查肝脏线粒体功能/含量和脂质中间体/代谢物蓄积。该项目非常新颖，因为它将研究肝脏线粒体功能障碍和肝脏胰岛素抵抗在全身性胰岛素抵抗和2型糖尿病的发生、发展和进展中的作用。此外，它还将全面研究生活方式改变和药物干预在治疗NAFLD和2型糖尿病中的有效性。这些研究将为降低退伍军人人群中2型糖尿病和NAFLD的发病率提供未来的见解。

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.