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: 8698282
• 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/8698282
• 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; 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）： 非酒精性脂肪肝病（NAFLD）是一种慢性，进行性肝病，影响了美国所有成年人的30％。 NAFLD与2型糖尿病密切相关，估计有80％的2型糖尿病患者患有NAFLD。不幸的是，退伍军人人口的糖尿病患病率明显高于一般人群（20-25％比6-8％），因​​此，NAFLD的患病率同样更高。由于NAFLD导致大量肝硬化患者和肝移植的需求，因此对于VA医疗保健系统来说，这种情况是一个重要的问题。尽管NAFLD与2型糖尿病之间存在密切的关联，但统一的病理生理学仍然知之甚少。该提案的总体假设是，由于肝线粒体功能障碍，肝脂质中间/代谢物积累和肝胰岛素抵抗会发展出来，从而导致肝葡萄糖输出失调，最终导致2型糖尿病的发展。此外，靶向肝线粒体功能障碍和肝胰岛素抵抗具有生活方式修饰和/或药理干预措施，将有效治疗NAFLD和2型糖尿病。我们将在大巨星Tokushima Fatty（OLETF）大鼠中进行研究，这是一种表征良好的啮齿动物诱导的肥胖，NAFLD和2型糖尿病的啮齿动物模型，以检查以下特定目的。 1）确定与NAFLD相关的肝胰岛素耐药性是否发展为继发于线粒体功能障碍，并且是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）在NAFLD和2型糖尿病治疗中的有效性。对于AIM 1，将在整个胰岛素前耐药性，胰岛素抵抗和Frank 2型糖尿病的发育中研究OLETF大鼠。对于AIM 2，OLETF大鼠将通过运动，热量限制，二甲双胍或联合疗法进行治疗。这些研究将采用体内高胰岛素 - 埃格血糖夹来评估全身性和肝胰岛素敏感性，并彻底检查肝线粒体功能/含量和脂质中间/代谢物积累。该项目非常新颖，因为它将在整个全身性胰岛素抵抗和2型糖尿病的开始，发育和进展中检查肝线粒体功能障碍和肝胰岛素抵抗的作用。此外，它将全面研究生活方式修饰和药理干预措施在NAFLD和2型糖尿病治疗中的有效性。这些研究将提供未来的见解，以减少我们退伍军人人口中2型糖尿病和NAFLD的发生率。