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: 9885568
• 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/9885568
• 关键词: ATP Synthesis Pathway; Abdominal Muscles; Adipocytes; Adipose tissue; Affect; Age; Attention; Benign; Bioenergetics; Body Weight; Body fat; CD4/CD8 ratio procedure; Cardiovascular Diseases; Caring; Clinical assessments; Complex; Contracts; Data; Defect; Deposition; Development; Diabetes Mellitus; Disease; 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; 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; Phenotype; Plasma; Population; Production; Provider; Race; Regulation; Research; Research Personnel; Risk; Risk Factors; Role; Site; Skeletal Muscle; Testing; Time; Tissues; Triglycerides; United States; Veterans; X-Ray Computed Tomography; acylcarnitine; antiretroviral therapy; blood glucose regulation; cardiometabolism; cohort; comorbidity; demographics; density; diabetes risk; diabetic; experience; glucose metabolism; glucose tolerance; glucose uptake; health administration; 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.

退伍军人事务部是美国最大的艾滋病毒携带者医疗服务提供者 各州；2016年，约30,000名退伍军人接受了退伍军人健康管理局(VHA)的艾滋病毒治疗。 在过去的几十年里，抗逆转录病毒疗法(Art)对艾滋病毒感染的治疗取得了成功 改变了携带艾滋病毒的退伍军人的人口统计和表型。尽管HIV+退伍军人的寿命更长了， 其中78%的人超重或肥胖，他们患2型糖尿病的风险是普通人的两倍 与没有感染艾滋病毒的退伍军人相比。虽然关于艾滋病毒和代谢性疾病的大部分研究都集中在 肥胖和肝脏异位脂肪堆积之间的相互作用，最近的几项研究强调 骨骼肌异位脂肪在胰岛素抵抗和糖尿病发病机制中的中心作用。然而， 在艾滋病毒感染和骨骼的作用方面，这一重要现象几乎没有受到关注 肌肉异位脂肪在HIV和肥胖之间复杂的相互作用仍不清楚。 脂肪组织脂肪储存和调节的缺陷是HIV感染和肥胖的标志，肥胖会导致 到肝脏和骨骼肌等组织中异位脂肪高度堆积。虽然有几个 研究已经调查了异位肝脏脂肪是HIV患者糖尿病的危险因素，我们的新假设是 患有艾滋病和肥胖症的退伍军人的葡萄糖耐量是由不成比例的异位脂类引起的 骨骼肌(葡萄糖摄取的主要部位)的渗透促进受损的心肌细胞生物能量和 葡萄糖稳态(图1)。这得到了我们初步的CT成像、MRS成像和葡萄糖的支持 与HIV相关性糖耐量异常有关的骨骼肌病理的代谢数据：1)我们的CT数据 显示HIV阳性糖尿病患者的肌肉异位脂肪渗透比非糖尿病患者更大；2)我们的MRS数据显示 肌肉中甘油三酯的含量与ATP合成的速度较慢有关；3)我们的新陈代谢数据显示 血浆酰肉碱(表明线粒体氧化受损)与HIV患者的胰岛素抵抗相关。 在拟议的研究中，我们的目标是确定：a)在HIV+中骨骼肌中过量的脂肪沉积 退伍军人是一种独立于肝脏脂肪沉积的现象，也是该人群中T2 DM的一个标志(AIM 1)；b)非糖尿病超重/肥胖退伍军人的骨骼肌脂肪是否随着时间积累 伴随着肌肉线粒体氧化能力、三磷酸腺苷的产生和肌肉力量的减少(目的 2)；以及c)骨骼肌异位脂肪和线粒体氧化能力随时间的变化是否 伴随着胰岛素敏感性和糖耐量的降低(目标3)。 为了实现这些目标，我们将招募两批HIV+退伍军人进行长期抗逆转录病毒治疗，这两组人将进行匹配 按性别、年龄、种族、体重指数和CD4/CD8比率计算。第一组：45名患有艾滋病毒、肥胖和2型糖尿病的退伍军人； 2：45患有艾滋病毒、肥胖且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HIV中发展为葡萄糖耐量异常；2)识别时间变化并确定 HIV患者骨骼肌异位脂肪渗透与线粒体功能损害的关系；3)识别 骨骼肌异位脂肪、肝脏异位脂肪、线粒体的时间变化及相互关系 4)为未来针对异位脂肪沉积的研究奠定了基础 改善代谢健康；以及5)告知我们对脂质病理和糖尿病的发展的理解 在治疗艾滋病毒方面，为促进我们退伍军人的医疗保健提供了干预机会。