Novel Therapy for Glucose Intolerance in HIV Disease

描述（由申请人提供）：HIV疾病的多药方案与至少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。已知这些代谢异常会导致2型糖尿病患者动脉粥样硬化加速。美国糖尿病协会（American Diabetes Association）和美国内分泌学会（American College of Endocrinologists）目前的指导方针建议对糖尿病高危患者进行葡萄糖耐受不良筛查和治疗。本研究旨在为HIV/AIDS患者在转变为显性糖尿病之前建立胰岛素抵抗/葡萄糖耐受不良的治疗方案。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，在一项初步研究中，也可以改善HIV阳性患者的胰岛素敏感性。这种膳食补充剂具有广泛的安全性，并可能提供实质性的治疗效益，而没有严重的副作用。这一提议将验证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的假设。该假设将在两个具体目标中得到解决。特异性目标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理的定量改善，该研究对葡萄糖耐受不良（通过口服葡萄糖耐量试验，OGTT）的受试者进行为期两个月的治疗，以1000微克（19.2 μ /mol）铬作为吡啶酸铬补充铬。安全性和有效性（通过高胰岛素治疗改善葡萄糖处理，血糖钳夹和胰岛素分泌，OGTT）将进行评估。通过在脂肪组织活检中评估铬补充剂对胰岛素刺激的胰岛素受体底物-1相关磷脂酰肌醇3-激酶活性的影响，将在Specific Aim 2中确定铬补充剂改善胰岛素敏感性的细胞机制。因此，本研究将证明铬补充剂对艾滋病患者胰岛素抵抗/葡萄糖耐受不良的治疗效果，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.