Lipoic Acid and Insulin Resistance

背景：α硫辛酸（LA）是一种天然产物，是一种有效的抗氧化剂。它具有良好的安全性，并已在欧洲用于治疗糖尿病周围神经病变超过20年。胰岛素抵抗型2型糖尿病患者（T2D）长期输注LA的研究表明，LA可显著改善胰岛素作用。然而，T2D患者口服LA的研究并未显示对该功能有重大影响。据推测，血浆中LA的短一半及其快速消除限制了其作为胰岛素抵抗口服药物的使用。最近控释LA已经可用，似乎可以改善t2dm患者的糖尿病控制。因此，我们建议在具有良好特征的胰岛素抵抗人群中研究LA对胰岛素刺激葡萄糖摄取的影响。这些受试者为非肥胖、非糖尿病且有胰岛素抵抗的受试者。这一人群是分析LA对胰岛素作用影响的理想人群，因为他们与T2D患者一样具有胰岛素抵抗性，但没有高血糖和肥胖的重要混杂因素。由于这些胰岛素抵抗的受试者有发生T2D、代谢综合征和冠状动脉疾病（CAD）的风险，因此证明LA对胰岛素作用的有益作用最终可能会产生重要的公共卫生后果。假设：1)LA将改善非肥胖、胰岛素抵抗、非糖尿病受试者的胰岛素敏感性；2) LA对胰岛素作用的改善是由于其对胰岛素信号通路的主要成分（胰岛素受体、IRS蛋白、PI 3-激酶、PKB/AKT和GLUT4）的影响；胰岛素信号通路的调节因子（PTP 1B、PC-1、IKK、NF-kB和PKC）。方法：采用胰岛素敏感性指数初步评估180例受试者的胰岛素敏感性。胰岛素抵抗最严重的受试者将随机接受6周的LA或安慰剂治疗。将测量几种氧化应激标志物。为了量化la诱导的胰岛素敏感性和胰岛素信号通路的改善，将在治疗前后进行正糖高胰岛素钳夹和肌肉活检。

DESCRIPTION (provided by applicant): Background: Alpha lipoic acid (LA) is a natural product that is a potent antioxidant. It has an excellent safety profile and has been used in Europe for over 2 decades for the treatment of diabetic peripheral neuropathy. Studies of prolonged LA infusions in insulin resistant type 2 diabetics (T2D) have indicated that LA markedly improves insulin action. However, studies of orally administered LA in T2D have not shown major effects on this function. It is hypothesized that the short plasma half of LA and its rapid elimination limits its use as an oral agent for insulin resistance. Recently controlled release LA has become available, and appears to improve diabetic control in T2D patients. We propose, therefore, to study LA's effects on insulin-stimulated glucose uptake in a well characterized population of insulin resistant subjects. These subjects are non- obese, non diabetic subjects with insulin resistance. This population is ideal for an analysis of the effects of LA on insulin action, because they are as insulin resistant as T2D patients but do not have the important confounders of hyperglycemia and obesity. Because these insulin resistant subjects are at risk for the development of T2D, the Metabolic Syndrome, and coronary artery disease (CAD), a demonstration of the beneficial effects of LA on insulin action could ultimately have important public health consequences. Hypotheses: 1) LA will improve insulin sensitivity in a general population of non-obese, insulin-resistant, non-diabetic subjects; and 2) The improvement of insulin action by LA is due to its effects on the major components of the insulin signaling pathway (insulin receptor, IRS proteins, PI 3-kinase, PKB/AKT and GLUT4); and/or regulators of the insulin signaling pathway (PTP 1B, PC-1, IKK, NF-kB and PKC). Methods: The insulin sensitivity of 180 subjects will be initially estimated by insulin sensitivity index. The most insulin resistant subjects will then be randomized to 6 weeks of therapy with either LA or placebo. Several markers of oxidative stress will be measured. To quantitate LA-induced improvements in both in insulin sensitivity and the insulin signaling pathway, euglycemic hyperinsulinemic clamps with muscle biopsies will be performed before and after treament. Anticipated Results and Significance: We believe these studies will (1) confirm the beneficial effect of LA on insulin sensitivity; (2) further our understanding of the molecular mechanisms of LA action; and (3) form a basis for a larger project examining the long term efficacy of LA in preventing the development of T2D and CAD.