Lipoic Acid and Insulin Resistance

描述（由申请人提供）：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，已在欧洲用于治疗糖尿病周围神经病变超过20年。在胰岛素抵抗的2型糖尿病（T2 D）患者中延长LA输注的研究表明，LA显著改善胰岛素作用。然而，T2 D患者口服LA的研究并未显示对该功能的重大影响。据推测，LA的短血浆一半及其快速消除限制了其作为胰岛素抵抗口服药物的用途。最近，控释LA已上市，似乎可改善T2 D患者的糖尿病控制。因此，我们建议研究LA对胰岛素刺激的葡萄糖摄取的影响，在一个良好的特征人群的胰岛素抵抗受试者。这些受试者是非肥胖、非糖尿病且具有胰岛素抵抗的受试者。该人群是分析LA对胰岛素作用影响的理想人群，因为他们与T2 D患者一样具有胰岛素抵抗，但没有高血糖症和肥胖症的重要混杂因素。由于这些胰岛素抵抗受试者有发生T2 D、代谢综合征和冠状动脉疾病（CAD）的风险，因此LA对胰岛素作用的有益作用的证明最终可能具有重要的公共卫生后果。假设：1）LA将改善非肥胖、胰岛素抵抗、非糖尿病受试者的一般人群中的胰岛素敏感性;和2）LA对胰岛素作用的改善是由于其对胰岛素信号传导途径的主要组分的作用（胰岛素受体、IRS蛋白、PI 3-激酶、PKB/AKT和GLUT 4）;和/或胰岛素信号传导途径的调节剂（PTP 1B、PC-1、IKK、NF-kB和PKC）。方法：采用胰岛素敏感性指数对180例受试者进行胰岛素敏感性的初步评价。然后，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。将测量氧化应激的几个标志物。为了定量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常血糖高胰岛素钳夹和肌肉活检。 预期结果和意义：我们相信这些研究将（1）证实LA对胰岛素敏感性的有益作用;（2）进一步了解LA作用的分子机制;（3）为更大的项目奠定基础，检查LA在预防T2 D和CAD发展方面的长期疗效。

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.