TAUROURSODEOXYCHOLIC ACID FOR PROTEASE-INHIBITOR ASSOCIATED INSULIN RESISTANCE

牛磺熊去氧胆酸治疗蛋白酶抑制剂相关的胰岛素抵抗

• 批准号: 8677885
• 负责人: Dominic N Reeds
• 金额: $ 33.06万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8677885
• 关键词: Adipocytes; Adipose tissue; Antidiabetic Drugs; Attenuated; Biogenesis; Biopsy; Body Weight decreased; CCL4 gene; Cardiovascular Diseases; Coronary heart disease; Data; Development; Diabetes Mellitus; Disease; Double-Blind Method; Euglycemic Clamping; General Population; Genes; Glucose Clamp; Goals; HIV; HIV Infections; HIV therapy; Human; IRS1 gene; In Vitro; Inflammation; Infusion procedures; Insulin; Insulin Resistance; Intervention; Iodide Peroxidase; Life; Lipolysis; Liver; MAPK8 gene; Measures; Metabolic; Mitochondria; Molecular; Molecular Chaperones; Mus; Muscle; Muscle Fibers; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Organ; Pathway interactions; Pharmaceutical Preparations; Pharmacotherapy; Phosphorylation; Placebos; Play; Population; Procedures; Protease Inhibitor; RNA Splicing; Randomized; Randomized Controlled Trials; Receptor Activation; Risk Factors; Ritonavir; Rodent Model; Role; Signal Transduction; Skeletal Muscle; Societies; Stable Isotope Labeling; Staging; Tracer; Woman; antiretroviral therapy; base; bile salts; clinical care; double-blind placebo controlled trial; effective therapy; endoplasmic reticulum stress; fatty acid oxidation; glucose production; glucose uptake; high risk; improved; in vivo; insulin sensitivity; insulin signaling; men; mortality; novel; protein folding; public health relevance; stable isotope; tauroursodeoxycholic acid; type 2 deiodinase (D2)

DESCRIPTION (provided by applicant): The introduction of protease-inhibitor based antiretroviral therapy (PI-ART) has reduced the mortality associated with HIV infection (HIV+). Unfortunately, PI-ART use is a major risk factor for insulin resistance, an important risk factor fr diabetes and coronary heart disease (CHD). Tauroursodeoxycholic acid (TUDCA), a naturally occurring bile salt, improves insulin sensitivity in insulin resistant people who do not have HIV. We have found that TUDCA markedly ameliorates ritonavir-induced insulin resistance in human myotubes and mice. The mechanism(s) responsible for these TUDCA-induced metabolic improvements are unclear, but could be related to: 1) TGR5 receptor activation, which upregulates cellular factors in muscle, including type 2 deiodinase (which increases intracellular triiodothryonine) and PGC-1 that increase mitochondrial biogenesis and fatty acid oxidation and/or 2) acting as chaperones that reduce endoplasmic reticulum (ER) stress by assisting protein folding. Initiation of ritonavir-boosted PI-ART worsens insulin sensitivity in HIV+ people and induces markers of ER stress in adipose tissue. We propose to perform a double-blind, randomized, controlled trial to determine if TUDCA improves insulin sensitivity in insulin-resistant, HIV+ people receiving PI-ART and to clarify the molecular mechanisms responsible for these improvements. We will randomly assign 48 insulin- resistant, HIV+ subjects to either placebo or TUDCA (1.75g/day x 30 days) and will measure multi-organ insulin sensitivity before and after the intervention by using a multistage hyperinsulinemic euglycemic clamp with infusion of stable isotope labeled tracers. To clarify the mechanisms responsible for the anticipated improvements in insulin sensitivity, we will examine the effect of TUDCA on TGR5 activation (type 2 deiodinase expression) in skeletal muscle biopsies and on ER stress by measuring Grp78 in adipose tissue biopsies taken before and after TUDCA administration. The results from this study will determine not only whether TUDCA may be effective for treatment of PI-associated insulin resistance but is also expected to identify new pathways by which TUDCA exerts insulin sensitizing effects. In addition to improving clinical care of people with HIV, the findings of this study may allow development of new drugs for treatment of type 2 diabetes.

描述（由申请人提供）：基于蛋白酶抑制剂的抗逆转录病毒疗法（PI-ART）的引入降低了与 HIV 感染（HIV+）相关的​​死亡率。不幸的是，PI-ART 的使用是胰岛素抵抗的主要危险因素，而胰岛素抵抗是糖尿病和冠心病 (CHD) 的重要危险因素。牛磺熊去氧胆酸 (TUDCA) 是一种天然存在的胆汁盐，可提高未感染 HIV 的胰岛素抵抗人群的胰岛素敏感性。我们发现 TUDCA 显着改善利托那韦诱导的人类肌管和小鼠的胰岛素抵抗。 TUDCA 诱导的代谢改善的机制尚不清楚，但可能与以下因素有关：1) TGR5 受体激活，上调肌肉中的细胞因子，包括 2 型脱碘酶（增加细胞内三碘甲状腺氨酸）和 PGC-1，增加线粒体生物合成和脂肪酸氧化和/或 2) 作为伴侣，通过协助蛋白质折叠来减少内质网 (ER) 应激。启动利托那韦增强的 PI-ART 会恶化 HIV 阳性人群的胰岛素敏感性，并在脂肪组织中诱导 ER 应激标志物。我们建议进行一项双盲、随机、对照试验，以确定 TUDCA 是否可以改善接受 PI-ART 的胰岛素抵抗、HIV+ 患者的胰岛素敏感性，并阐明导致这些改善的分子机制。我们将 48 名胰岛素抵抗、HIV + 受试者随机分配至安慰剂或 TUDCA（1.75 克/天 x 30 天）组，并通过使用多级高胰岛素正常血糖钳并输注稳定同位素来测量干预前后的多器官胰岛素敏感性标记的示踪剂。为了阐明胰岛素敏感性预期改善的机制，我们将通过测量 TUDCA 给药前后脂肪组织活检中的 Grp78 来检查 TUDCA 对骨骼肌活检中 TGR5 激活（2 型脱碘酶表达）和 ER 应激的影响。这项研究的结果不仅将确定 TUDCA 是否可以有效治疗 PI 相关的胰岛素抵抗，而且有望确定 TUDCA 发挥胰岛素增敏作用的新途径。除了改善 HIV 感染者的临床护理之外，这项研究的结果还可能有助于开发治疗 2 型糖尿病的新药。