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: 10651630
• 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 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10651630
• 关键词: ATP Synthesis Pathway; Abdominal Muscles; Adipocytes; Adipose tissue; Affect; Age; Attention; Benign; Bioenergetics; Body Weight; Body fat; Body mass index; CD8B1 gene; Cardiometabolic Disease; Cardiovascular Diseases; Caring; Clinical assessments; Complex; 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; 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; Risk Reduction; 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.

退伍军人事务部是美国最大的艾滋病毒感染者医疗服务提供者 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）在治疗艾滋病毒感染方面取得了成功 改变了感染艾滋病毒的退伍军人的人口统计和表型。尽管艾滋病病毒感染退伍军人的寿命更长， 其中 78% 超重或肥胖，他们患 2 型糖尿病的风险增加两倍 与没有艾滋病毒的退伍军人相比。虽然许多关于艾滋病毒和代谢疾病的研究都集中在 最近的几项研究强调了肥胖与肝脏异位脂肪积累之间的相互作用 骨骼肌异位脂肪在胰岛素抵抗和糖尿病发病机制中的核心作用。然而， 在艾滋病毒感染和骨骼的作用的背景下，这一重要现象很少受到关注 肌肉异位脂肪在艾滋病毒和肥胖之间复杂的相互作用仍不清楚。 脂肪组织脂质储存和调节的缺陷是 HIV 感染和肥胖的标志，这导致 导致肝脏和骨骼肌等组织中高度异位脂肪堆积。虽然有几个 研究调查了异位肝脏脂肪作为艾滋病毒中糖尿病的危险因素，我们的新假设是，异位肝脏脂肪受损 接受艾滋病毒治疗和肥胖的退伍军人的葡萄糖耐量是由异位脂质不成比例地增加引起的 骨骼肌（葡萄糖摄取的主要部位）的浸润促进受损的肌细胞生物能和 葡萄糖稳态（图1）。我们的初步 CT 成像、MRS 成像和葡萄糖支持了这一点 与 HIV 相关的葡萄糖耐受不良有关的骨骼肌病理学代谢数据：1) 我们的 CT 数据 研究表明，与非糖尿病患者相比，HIV+糖尿病患者的肌肉异位脂肪浸润更大； 2) 我们的 MRS 数据显示更高 肌肉甘油三酯含量与 ATP 合成速度较慢有关； 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）与艾滋病毒的胰岛素抵抗相关。 在拟议的研究中，我们的目标是确定：a) HIV+ 骨骼肌中是否沉积了过量的脂质 退伍军人是一种与肝脏脂肪沉积不同的现象，也是该人群中 T2DM 的标志（Aim 1）； b) 非糖尿病超重/肥胖退伍军人的骨骼肌脂肪是否会随着时间的推移而积累？ 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) 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葡萄糖耐量的降低（目标 3）。 为了实现这些目标，我们将招募两组接受长期抗逆转录病毒疗法的艾滋病毒+退伍军人，这些退伍军人将进行匹配 按性别、年龄、种族、BMI 和 CD4/CD8 比率。第 1 组：45 名患有 HIV、肥胖和 2 型糖尿病的退伍军人；团体 2：45 名退伍军人患有艾滋病毒、肥胖但没有糖尿病。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产生葡萄糖不耐受的关系； 2) 识别时间变化并确定 HIV 中骨骼肌异位脂肪浸润与线粒体功能损伤的关系； 3）识别 时间变化并阐明骨骼肌异位脂肪、肝脏异位脂肪、线粒体之间的关系 HIV 的功能和葡萄糖耐量； 4）为未来针对异位脂肪沉积的研究奠定基础 改善代谢健康； 5）让我们了解脂质病理学和糖尿病的发展 治疗艾滋病毒，为改善退伍军人医疗保健的干预措施提供机会。