Chromium treatment of Obesity-related insulin resistance

描述（由申请人提供）：肥胖发病率的上升与心血管疾病和糖尿病等健康风险的增加有关。然而，糖尿病预防计划已经证明，胰岛素抵抗的早期治疗可以减少进展为显性糖尿病。由于胰岛素抵抗也是心血管疾病的独立危险因素，早期治疗将提供额外的好处。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。由于预防糖尿病可能比治疗更可取，本提案将集中于补充铬对胰岛素抵抗的肥胖（BMI大于30）受试者的影响，但没有明显的糖尿病。我们有初步的数据表明，铬补充剂可以改善艾滋病和多囊卵巢综合征患者的胰岛素敏感性。本提案的具体目标1将检查补充吡啶甲酸铬治疗肥胖相关胰岛素抵抗的安全性和有效性。胰岛素介导的葡萄糖处理的定量改善将在一项安慰剂对照研究中确定，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2个月的治疗，以1000ug （19.2 umol）铬作为吡啶酸铬补充铬。将评估安全性（肝肾功能和氧化应激）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）。体外研究表明，铬（作为铬调蛋白）可以增强胰岛素受体的活性。特异性目标2将评估铬补充剂改善胰岛素作用的机制。具体来说，这一目标将涉及血浆游离脂肪酸的变化，胰岛素抑制脂肪组织中脂肪分解的能力，以及脂肪组织中的胰岛素信号传导，包括胰岛素受体底物1的磷酸化和下游酶如糖原合成酶激酶3B的活性。因此，本研究将证明铬补充剂对胰岛素抵抗/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): The rising incidence of obesity is implicated in increased health risks including cardiovascular disease and diabetes. However, the Diabetes Prevention Program has demonstrated that early treatment of insulin resistance can reduce progression to overt diabetes. Since insulin resistance is also an independent risk factor for cardiovascular disease, early treatment would provide additional benefit. Chromium picolinate is a dietary supplement that has been shown to improve insulin sensitivity in patients with type 2 diabetes mellitus. Since prevention of diabetes may be preferable to treatment, this proposal will concentrate on the effect of chromium supplementation in obese (BMI greater than 30) subjects with insulin resistance, but without overt diabetes. We have preliminary data demonstrating that chromium supplements improve insulin sensitivity in patients with both HIV disease and polycystic ovarian syndrome. Specific Aim 1 of this proposal will examine the safety and efficacy of supplemental chromium picolinate in the treatment of insulin resistance in obesity-related insulin resistance. Quantitative improvements in insulin-mediated glucose disposal will be determined in a placebo-controlled study of chromium supplementation with 1000ug (19.2 umol) of chromium as chromium picolinate, over a 2-month course of therapy of subjects with glucose intolerance (defined with an oral glucose tolerance test, OGTT). Both safety (liver and renal function and oxidative stress) and efficacy (improved glucose disposal with a hyperinsulineminc, euglycemic clamp and insulin secretion, OGTT) will be evaluated. In vitro studies have demonstrated that chromium (as chromodulin) enhances the activity of the insulin receptor. Specific Aim 2 will assess the mechanism by which chromium supplementation improves insulin action. Specifically, this aim will access changes in plasma free fatty acids, the ability of insulin to suppress lipolysis in adipose tissue, and insulin signaling in adipose tissue including the phosphorylation of insulin receptor substrate 1 and activity of downstream enzymes such as glycogen synthase kinase 3B. Thus, this research will document the therapeutic benefit of chromium supplementation for insulin resistance/glucose intolerance and will also provide a mechanistic framework to explain how chromium supplementation enhances insulin action.