TAUROURSODEOXYCHOLIC ACID FOR PROTEASE-INHIBITOR ASSOCIATED INSULIN RESISTANCE

描述（由申请人提供）：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，使用PI-ART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。牛磺酸去氧胆酸（TUDCA）是一种天然存在的胆盐，可以改善没有感染艾滋病毒的胰岛素抵抗者的胰岛素敏感性。我们发现，TUDCA可显著改善利托那韦诱导的人肌管和小鼠胰岛素抵抗。这些tudca诱导的代谢改善的机制尚不清楚，但可能与：1)TGR5受体激活，其上调肌肉中的细胞因子，包括2型脱碘酶（其增加细胞内三碘甘氨酸）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，通过协助蛋白质折叠减少内质网（ER）应激。启动利托那韦增强的PI-ART会使HIV+患者的胰岛素敏感性恶化，并诱导脂肪组织内质网应激标志物。我们建议进行一项双盲、随机、对照试验，以确定TUDCA是否能改善胰岛素抵抗、接受PI-ART治疗的HIV+患者的胰岛素敏感性，并阐明这些改善的分子机制。我们将随机分配48名胰岛素抵抗的HIV+受试者接受安慰剂或TUDCA治疗（1.75g/天x 30天），并通过使用多阶段高胰岛素正糖钳和输注稳定同位素标记示踪剂来测量干预前后的多器官胰岛素敏感性。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，研究TUDCA对骨骼肌活检中TGR5激活（2型脱碘酶表达）和内质网应激的影响。本研究的结果不仅将确定TUDCA是否可能有效治疗pi相关的胰岛素抵抗，而且还有望确定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，这项研究的发现可能会开发出治疗2型糖尿病的新药。

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.