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: 8603480
• 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/8603480
• 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（由申请方提供）：引入基于蛋白酶抑制剂的抗逆转录病毒疗法（PI-ART）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，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，可改善未感染HIV的胰岛素抵抗人群的胰岛素敏感性。我们已经发现，TUDCA显着改善利托那韦诱导的人肌管和小鼠的胰岛素抵抗。这些TUDCA诱导的代谢改善的机制尚不清楚，但可能与以下因素相关：1）TGR 5受体活化，其上调肌肉中的细胞因子，包括2型脱碘酶（其增加细胞内三碘甲状腺素）和PGC-1，其增加线粒体生物发生和脂肪酸氧化和/或2）作为伴侣蛋白，其通过辅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可降低HIV+患者的胰岛素敏感性，并诱导脂肪组织中的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是否能改善接受PI-ART的胰岛素抵抗、HIV+患者的胰岛素敏感性，并阐明这些改善的分子机制。我们将48例胰岛素抵抗、HIV+受试者随机分配至安慰剂组或TUDCA组（1.75 g/天× 30天），并将在干预前后使用多阶段高胰岛素血症正葡萄糖钳夹术测量多器官胰岛素敏感性，并输注稳定同位素标记的示踪剂。为了阐明预期改善胰岛素敏感性的机制，我们将研究TUDCA对骨骼肌活检组织中TGR 5活化（2型脱碘酶表达）的影响，并通过测量TUDCA给药前后脂肪组织活检组织中的Grp 78来研究TUDCA对ER应激的影响。本研究的结果不仅将确定TUDCA是否可有效治疗PI相关的胰岛素抵抗，还有望确定TUDCA发挥胰岛素增敏作用的新途径。除了改善艾滋病毒感染者的临床护理外，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。