Ectopic Lipid in Skeletal Muscle is Associated with Glucose Intolerance in Veterans with HIV

骨骼肌中的异位脂质与感染艾滋病毒的退伍军人的葡萄糖不耐受有关

• 批准号: 10417013
• 负责人: John Koethe
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10417013
• 关键词: ATP Synthesis Pathway; Abdominal Muscles; Adipocytes; Adipose tissue; Affect; Age; Attention; Benign; Bioenergetics; Body Weight; Body fat; Body mass index; CD4/CD8 ratio procedure; Cardiometabolic Disease; Cardiovascular Diseases; Caring; Clinical assessments; Complex; Contracts; Data; Defect; Deposition; Development; Diabetes Mellitus; Endocrinology; Fatty acid glycerol esters; Foundations; Future; Glucose Intolerance; Glucose Transporter; Goals; HIV; HIV Infections; HIV Seronegativity; Health; Healthcare; Hepatic; Image; Impairment; Infiltration; Inflammation; Insulin Resistance; Interdisciplinary Study; Intervention; Link; Lipids; Liver; Liver diseases; Medical; Metabolic; Metabolic Diseases; Mitochondria; Modeling; Muscle; Muscle Cells; Muscle Mitochondria; Non-Insulin-Dependent Diabetes Mellitus; Nonesterified Fatty Acids; Obesity; Organ; Overweight; Pathogenesis; Pathologic; Pathology; Persons; Phenotype; Plasma; Population; Production; Provider; Race; Regulation; Research; Research Personnel; Risk; Risk Factors; Role; Site; Skeletal Muscle; Testing; Time; Tissues; Triglycerides; United States; United States Department of Veterans Affairs; Veterans; Veterans Health Administration; X-Ray Computed Tomography; acylcarnitine; antiretroviral therapy; blood glucose regulation; cohort; comorbidity; demographics; density; diabetes risk; diabetic; experience; glucose metabolism; glucose tolerance; glucose uptake; high risk; impaired glucose tolerance; improved; insulin secretion; insulin sensitivity; insulin signaling; mitochondrial dysfunction; muscle physiology; non-diabetic; novel; nutrition; oxidation; patient population; prevent; recruit; sex; success

The Department of Veterans Affairs is the largest provider of medical care to people with HIV in the United States; in 2016 ~30,000 Veterans received treatment for HIV from the Veterans Health Administration (VHA). Over the last several decades, the success of antiretroviral therapy (ART) treatment for HIV infection has changed the demographics and phenotype of Veterans living with HIV. Although HIV+ Veterans are living longer, 78% of them are overweight or obese, and they have a two-fold greater risk of developing type 2 diabetes compared to Veterans without HIV. While much of the research on HIV and metabolic disease has focused on the interaction between obesity and the accumulation of ectopic fat in the liver, several recent studies highlight the central role of ectopic fat in skeletal muscle in the pathogenesis of insulin resistance and diabetes. However, this important phenomenon has received little attention in the context of HIV infection and the role of skeletal muscle ectopic fat in the complex interaction between HIV and obesity remains unclear. Defects in adipose tissue lipid storage and regulation are hallmark of both HIV infection and obesity, which leads to a high degree of ectopic fat accumulation in tissues such as the liver and skeletal muscle. While several studies have investigated ectopic liver fat as a risk factor for diabetes in HIV, our novel hypothesis is that impaired glucose tolerance in Veterans with treated HIV and obesity is driven by disproportionately greater ectopic lipid infiltration of skeletal muscle (the primary site of glucose uptake) promoting impaired myocyte bioenergetics and glucose homeostasis (Fig.1). This is supported by our preliminary CT imaging, MRS imaging, and glucose metabolism data that implicate skeletal muscle pathology in HIV associated glucose intolerance: 1) Our CT data show ectopic fat infiltration in muscle is greater in HIV+ diabetics vs nondiabetics; 2) Our MRS data show higher muscle triglyceride content is associated with a slower rate of ATP synthesis; 3) Our metabolic data show lower plasma acylcarnitines (indicating impaired mitochondrial oxidation) correlates with insulin resistance in HIV. In the proposed study, we aim to determine: a) whether the deposition of excess lipid in skeletal muscle in HIV+ Veterans is a phenomenon separate from hepatic fat deposition and a hallmark for T2DM in this population (Aim 1); b) whether skeletal muscle fat accumulates over time in nondiabetic overweight/obese Veterans and is accompanied by reductions in muscle mitochondrial oxidative capacity, ATP production, and muscle force (Aim 2); and c) whether changes in skeletal muscle ectopic fat and mitochondrial oxidative capacity over time are accompanied by reductions in insulin sensitivity and glucose tolerance (Aim 3). To accomplish these aims, we will recruit two cohorts of HIV+ Veterans on long-term ART that will be matched by sex, age, race, BMI and CD4/CD8 ratio. Group 1: 45 Veterans with HIV, obesity and type 2 diabetes; Group 2: 45 Veterans with HIV, obesity and no diabetes. Our study will: 1) determine the contribution of ectopic fat in skeletal muscle vs liver to developing glucose intolerance in HIV; 2) identify temporal changes and determine relationships in skeletal muscle ectopic fat infiltration and impairments in mitochondrial function in HIV; 3) identify temporal changes and clarify relationships between skeletal muscle ectopic fat, liver ectopic fat, mitochondrial function, and glucose tolerance in HIV; 4) establish a foundation for future studies targeting ectopic fat deposition to improve metabolic health; and 5) inform our understanding of lipid pathology and the development of diabetes in treated HIV, yielding opportunities for interventions to advance the healthcare of our Veterans.

退伍军人事务部是联合国艾滋病毒患者的最大医疗服务提供商 国家2016年，大约30,000名退伍军人接受了退伍军人卫生管理局（VHA）的艾滋病毒治疗。 在过去的几十年中，抗逆转录病毒疗法（ART）治疗HIV感染的成功已有 改变了患有艾滋病毒的退伍军人的人口统计和表型。尽管艾滋病毒+退伍军人的寿命更长，但 其中78％的人超重或肥胖，他们患2型糖尿病的风险更大 与没有艾滋病毒的退伍军人相比。虽然关于艾滋病毒和代谢疾病的大部分研究都集中在 肥胖与异位脂肪在肝脏中的积累之间的相互作用，最近的几项研究突出了 异位脂肪在骨骼肌中的核心作用在胰岛素抵抗和糖尿病的发病机理中。然而， 在艾滋病毒感染和骨骼的作用中，这种重要现象几乎没有得到关注 艾滋病毒与肥胖之间复杂相互作用中的肌肉异位脂肪尚不清楚。 脂肪组织脂质储存和调节的缺陷既是HIV感染和肥胖的标志， 在肝脏和骨骼肌等组织中高度的异位脂肪积累。而几个 研究已经研究了异位肝脂肪作为HIV中糖尿病的危险因素，我们的新假设是受损 治疗艾滋病毒和肥胖症的退伍军人的葡萄糖耐受性是由异位脂质不成比例的 骨骼肌的浸润（葡萄糖摄取的主要部位）促进了肌细胞生物能力受损和 葡萄糖稳态（图1）。这是我们的初步CT成像，MRS成像和葡萄糖支持的 代谢数据暗示艾滋病毒相关的葡萄糖不耐症中骨骼肌病理学：1）我们的CT数据 在HIV+糖尿病患者与非糖尿病患者中，肌肉中的异位脂肪浸润更大。 2）我们的MRS数据显示更高 肌肉甘油三酸酯的含量与ATP合成速率较慢有关。 3）我们的代谢数据显示较低 血浆酰基肉碱（表明线粒体氧化受损）与HIV中的胰岛素抵抗有关。 在拟议的研究中，我们旨在确定：a）艾滋病毒+骨骼肌中过量脂质的沉积是否存在 退伍军人是与肝脂肪沉积分开的现象，在该人群中是T2DM的标志（AIM 1）; b）骨骼肌脂肪是否在非糖尿病/肥胖的退伍军人中会随着时间的流逝而累积 伴随着肌肉线粒体氧化能力，ATP产生和肌肉力量的降低（AIM 2）; c）随着时间的推移，骨骼肌异位脂肪和线粒体氧化能力的变化是否是 伴随着胰岛素敏感性和葡萄糖耐受性的降低（AIM 3）。 为了实现这些目标，我们将在长期艺术上招募两名艾滋病毒+退伍军人队列 按性别，年龄，种族，BMI和CD4/CD8比率。第1组：45名艾滋病毒，肥胖和2型糖尿病的退伍军人；团体 2：45名艾滋病毒，肥胖症和无糖尿病的退伍军人。我们的研究将：1）确定异位脂肪在 骨骼肌与肝脏在艾滋病毒中发展葡萄糖不耐症； 2）确定时间变化并确定 HIV中线粒体功能的骨骼肌异位脂肪浸润和障碍的关系； 3）识别 时间变化并阐明骨骼肌异位脂肪，肝异位脂肪，线粒体之间的关系 HIV中的功能和葡萄糖耐受性； 4）为针对异位脂肪沉积的未来研究建立基础 改善新陈代谢的健康； 5）告知我们对脂质病理学和糖尿病的发展的理解 在接受治疗的艾滋病毒中，带来了干预措施的机会，以推动退伍军人的医疗保健。