Lipoic Acid and Insulin Resistance

硫辛酸和胰岛素抵抗

• 批准号: 7462326
• 负责人: IRA D. GOLDFINE
• 金额: $ 22.69万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7462326
• 关键词: 1-Phosphatidylinositol 3-Kinase; Aftercare; Antioxidants; Biological Factors; Biopsy; Coronary Arteriosclerosis; Daily; Development; Enrollment; Europe; GLUT4 gene; General Population; Human; Hyperglycemia; Individual; Infusion procedures; Insulin; Insulin Receptor; Insulin Resistance; Insulin Signaling Pathway; Measures; Metabolic syndrome; Methods; Molecular; Muscle; NF-kappa B; Non obese; Obesity; Oral; Oxidative Stress; PTPN1 gene; Patients; Peripheral Nervous System Diseases; Phosphorylation; Placebos; Plasma; Population; Proteins; Public Health; Randomized; Receptor Signaling; Risk; Safety; Signal Pathway; Skeletal Muscle; Testing; Thioctic Acid; Time; Week; base; cohort; controlled release; diabetic; glucose uptake; improved; indexing; insulin sensitivity; insulin signaling; non-diabetic; placebo controlled study; prevent; treatment program

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.

描述（由申请人提供）：背景：α氟酸（LA）是一种天然产物，是有效的抗氧化剂。它具有出色的安全性，在欧洲已使用了20多年，用于治疗糖尿病周围神经病。对胰岛素耐药2型糖尿病患者（T2D）的长时间LA输注的研究表明，LA显着改善了胰岛素作用。但是，在T2D中对口服LA的研究尚未显示出对此功能的重大影响。假设LA的短等离子体一半，其快速消除限制了其用作胰岛素抵抗的口服剂。最近受控释放LA已成为可用的，并且似乎可以改善T2D患者的糖尿病控制。因此，我们建议研究LA对胰岛素耐药受试者群体中胰岛素刺激的葡萄糖摄取的影响。这些受试者是非肥胖的非糖尿病患者，具有胰岛素抵抗。该人群是分析LA对胰岛素作用的影响的理想选择，因为它们与T2D患者一样具有胰岛素耐药性，但没有重要的高血糖和肥胖症的重要混杂因素。由于这些耐胰岛素的受试者有T2D，代谢综合征和冠状动脉疾病（CAD）的发展风险，因此证明了LA对胰岛素作用的有益作用的证明最终可能会带来重要的公共健康后果。假设：1）LA将改善非肥胖，耐胰岛素，非糖尿病患者的一般人群中的胰岛素敏感性； 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的影响（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剂（PTP 1B，PC-1，IKK，NF-KB和PKC）。方法：最初将通过胰岛素灵敏度指数估算180名受试者的胰岛素灵敏度。然后，最大的胰岛素耐药受试者将被随机分为LA或安慰剂治疗6周。将测量几种氧化应激标记。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，将在进行之前和之后，在胰岛素高胰岛素夹中使用肌肉活检。 预期的结果和意义：我们认为这些研究将（1）证实LA对胰岛素敏感性的有益作用； （2）进一步了解我们对LA作用的分子机制； （3）构成了一个较大项目的基础，该项目研究了LA在防止T2D和CAD开发方面的长期疗效。