Lipoic Acid and Insulin Resistance

描述(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，在欧洲用于治疗糖尿病周围神经病变已有20多年的历史。对胰岛素抵抗2型糖尿病(T2D)患者长时间输注LA的研究表明，LA显著改善胰岛素作用。然而，口服LA在T2D中的研究并未显示对这一功能的重大影响。推测LA的短血浆半部分及其快速消除限制了其作为胰岛素抵抗的口服药物的使用。最近，LA控释已成为可能，并似乎改善了T2D患者的糖尿病控制。因此，我们建议研究LA对胰岛素抵抗受试者中胰岛素刺激的葡萄糖摄取的影响。这些受试者是非肥胖、非糖尿病、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，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患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对公众健康产生重要影响。假设：1)LA将改善一般非肥胖、胰岛素抵抗、非糖尿病受试者的胰岛素敏感性；2)LA改善胰岛素的作用是由于其影响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)和/或胰岛素信号通路的调节器(PTP 1B、PC-1、IKK、NF-kB和PKC)。方法：用胰岛素敏感性指数初步评价180例受试者的胰岛素敏感性。胰岛素抵抗最严重的受试者随后将随机接受LA或安慰剂治疗6周。将测量氧化应激的几个标记物。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，治疗前后将进行正常血糖高胰岛素钳夹和肌肉活组织检查。 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；以及(3)形成一个更大的项目的基础，检验LA在预防T2D和CAD发展方面的长期有效性。

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.