Novel Therapy for Glucose Intolerance in HIV Disease

描述（由申请方提供）：HIV疾病的多药治疗方案与至少50%的胰岛素抵抗发生率相关。 胰岛素抵抗与血脂异常、2型糖尿病和高血压的发生有关。 这种代谢异常的组合已知会导致2型糖尿病患者加速动脉粥样硬化。美国糖尿病协会和美国内分泌学家学会的现行指南建议筛查葡萄糖耐受不良和治疗糖尿病高危患者。该提案旨在为艾滋病毒/艾滋病患者在转变为显性糖尿病之前的胰岛素抵抗/葡萄糖耐受不良建立一种治疗选择。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，在一项初步研究中，还可以改善HIV+患者的胰岛素敏感性。这种膳食补充剂具有广泛的安全范围，可以提供实质性的治疗益处，而没有严重的副作用。该提案将检验以下假设：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，导致磷脂酰肌醇3-激酶活性增加，从而改善胰岛素刺激的葡萄糖摄取。该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、安慰剂对照研究中评估胰岛素介导的葡萄糖处置的定量改善，该研究在葡萄糖耐受不良（通过口服葡萄糖耐量试验，OGTT定义）受试者中进行为期两个月的治疗过程，以1000 μ g（19.2 mu/mol）的铬（以吡啶甲酸铬形式）补充铬。将评价安全性和有效性（通过高胰岛素、正葡萄糖钳夹和胰岛素分泌、OGTT改善葡萄糖处置）。在具体目标2中，通过评估补充铬对脂肪组织活检中胰岛素受体底物-1-相关磷脂酰肌醇3-激酶的胰岛素刺激活性的影响，确定补充铬改善胰岛素敏感性的细胞机制。因此，这项研究将记录铬补充剂对HIV疾病中胰岛素抵抗/葡萄糖耐受不良的治疗益处，并将提供一个机制框架来解释铬补充剂如何增强胰岛素作用。

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.