Novel Therapy for Glucose Intolerance in HIV Disease

描述(由申请人提供)：HIV疾病中的多种药物方案与至少50%的胰岛素抵抗发生率有关。胰岛素抵抗与血脂异常、2型糖尿病和高血压的发生有关。这一系列代谢异常被认为会导致2型糖尿病患者动脉粥样硬化的加速。美国糖尿病协会和美国内分泌学家学会目前的指南建议对糖尿病高危患者进行糖耐量异常筛查和治疗。这项建议寻求在过渡到明显的糖尿病之前，为艾滋病毒/艾滋病患者建立一种胰岛素抵抗/葡萄糖不耐受的治疗方案。吡啶甲酸铬是一种膳食补充剂，已被证明可以改善2型糖尿病患者的胰岛素敏感性，在初步研究中，对HIV+患者也是如此。这种膳食补充剂有很大的安全边际，可以提供实质性的治疗效果，而不会产生严重的副作用。这项提议将检验以下假设：吡啶甲酸铬通过增加胰岛素受体介导的胰岛素受体底物-1的酪氨酸磷酸化，从而增加磷脂酰肌醇3-激酶的活性，从而改善胰岛素刺激的葡萄糖摄取。这一假设将在两个具体目标中得到解决。具体目标1将在一项双盲、安慰剂对照的研究中评估胰岛素介导的葡萄糖处置的数量改善。在两个月的治疗过程中，补充1000微克(19.2微克/摩尔)的铬作为吡啶甲酸铬，以口服葡萄糖耐量试验(OGTT)定义。安全性和有效性(通过高胰岛素、正常血糖钳和胰岛素分泌改善的葡萄糖处理，OGTT)都将被评估。补充铬改善胰岛素敏感性的细胞机制将在特定的目标2中确定，方法是评估补充铬对脂肪组织活检组织中胰岛素受体底物-1相关磷脂酰肌醇3-激酶的胰岛素刺激活性的影响。因此，这项研究将记录补充铬对HIV疾病中胰岛素抵抗/葡萄糖耐受的治疗益处，并将提供一个机制框架来解释补充铬如何增强胰岛素的作用。

DESCRIPTION (provided by applicant): Multi-drug regimens in HIV disease are associated with an incidence of insulin resistance of at least 50%. Insulin resistance is associated with the development of dyslipidemia, type 2 diabetes, and hypertension. This constellation of metabolic abnormalities is known to cause accelerated atherosclerosis in patients with type 2 diabetes. The current guidelines from the American Diabetes Association and the American College of Endocrinologists recommends screening for glucose intolerance and treatment for patients at high risk of diabetes. This proposal seeks to establish a treatment option for insulin resistance / glucose intolerance in HIV/AIDS prior to the transition to overt diabetes. Chromium picolinate is a dietary supplement that has been shown to improve insulin sensitivity in patients with type 2 diabetes mellitus and, in a preliminary study, in HIV+ patients. This dietary supplement has a wide margin of safety and may provide substantial therapeutic benefit without serious side-effects. This proposal will test the hypothesis that chromium picolinate improves insulin-stimulated glucose uptake by increasing the insulin receptor-mediated tyrosine phosphorylation of insulin receptor substrate-1, resulting in increased activity of phosphatidylinositol 3-kinase. The hypothesis will be addressed in two specific aims. Specific Aim 1 will assess quantitative improvements in insulin-mediated glucose disposal in a double-blind, placebo-controlled study of chromium supplementation with 1000 microgram (19.2 mu/mol) of chromium as chromium picolinate, over a two month course of therapy of subjects with glucose intolerance (defined with an oral glucose tolerance test, OGTT). Both safety and efficacy (improved glucose disposal with a hyperinsulineminc, euglycemic clamp and insulin secretion, OGTT) will be evaluated. The cellular mechanism for improved insulin sensitivity with chromium supplementation will be determined in Specific Aim 2 by assessing the effect of chromium supplementation on the insulin-stimulated activity of insulin receptor substrate-1-associated phosphatidylinositol 3-kinase in biopsies of adipose tissue. Thus, this research will document the therapeutic benefit of chromium supplementation for insulin resistance / glucose intolerance in HIV disease and will provide a mechanistic framework to explain how chromium supplementation enhances insulin action.