Mechanisms of Insulin Resistance in Diabetes

 描述(由申请人提供)： 在1型和2型糖尿病患者中，高血糖都会加重骨骼肌中的胰岛素抵抗，而高糖会导致靶细胞中胰岛素刺激的葡萄糖运输的缺陷。 葡萄糖诱导的胰岛素抵抗(葡萄糖毒性)需要通过己糖胺生物合成途径进行葡萄糖代谢；然而，尽管经过20年的研究，己糖胺途径代谢与胰岛素作用缺陷之间的分子联系仍不清楚。我们已经报道，肌肉TRIB3与胰岛素敏感性呈负相关，与空腹血糖呈正相关。在人类患者中，TRIB3是由葡萄糖诱导的，这种诱导方式依赖于己糖胺途径，并介导了胰岛素刺激的葡萄糖在肌肉中的转运缺陷。除了它在慢性高血糖中的病理作用外，我们还定义了TRIB3在营养过剩和禁食条件下对营养代谢的急性调节中的新的调节作用。我们现在将确定葡萄糖诱导TRIB3表达的机制，并确定TRIB3是否介导了葡萄糖诱导的胰岛素抵抗，并调节了人类和转基因小鼠的燃料代谢。为了验证这些假说，我们的具体目标是：目标1：确定葡萄糖诱导TRIB3基因表达的机制(顺式元件和反式因子)。目的：在肌肉特异性转基因和基因敲除小鼠中，研究(I)糖尿病中葡萄糖诱导的胰岛素抵抗和(Ii)营养缺乏和过量的代谢效应是否以TRIB3依赖的方式介导。目的：从系统和骨骼肌水平评估肌肉TRIB3在调节胰岛素敏感性和代谢中的作用：(I)在正常血糖治疗前后的T2 DM患者中检测葡萄糖诱导的胰岛素抵抗；(Ii)在低热量喂养和稳定减肥期间的受试者中。因此，我们将首次阐明TRIB3在糖尿病中作为葡萄糖诱导的胰岛素抵抗的中介的病理生理学作用，以及在细胞内可用燃料储存的背景下，TRIB3作为葡萄糖运输和线粒体氧化的急性生理调节因子的能力。 在禁食和营养过剩的时期。这些在培养细胞、基因操作的小鼠和人类受试者中的数据将阐明TRIB3在葡萄糖诱导的胰岛素抵抗中的新的病理生理作用，以及在燃料代谢调节中的新的生理作用。这些研究将使TRIB3成为糖尿病治疗的新靶点。

 DESCRIPTION (provided by applicant): Hyperglycemia worsens Insulin resistance in skeletal muscle in both Type 1 and Type 2 diabetic patients, and high glucose induces defects in insulin-stimulated glucose transport in target cells. Glucose-induced insulin resistance (`glucose toxicity') requires glucose metabolism via the hexosamine biosynthetic pathway; however, despite 2 decades of study, the molecular link between hexosamine pathway metabolism and defects in insulin action remain unknown. We have reported that muscle TRIB3 is inversely correlated with insulin sensitivity and positively correlated with fasting glucose in human patients is induced by glucose in a manner that is dependent upon the hexosamine pathway, and mediates defects in insulin-stimulated glucose transport in muscle. In addition to its pathological role in chronic hyperglycemia, we have also defined a novel regulatory role for TRIB3 in the acute regulation of nutrient metabolism under conditions of nutrient excess and fasting. We will now identify mechanism by which glucose induces TRIB3 expression and determine whether TRIB3 mediates glucose induced insulin resistance and regulates fuel metabolism in humans and genetically manipulated mice. To test these hypotheses, our specific aims will be: Aim 1: Identify the mechanisms (cis elements and trans factors) by which glucose induces TRIB3 gene expression. Aim 2: In muscle-specific transgenic and knockout mice, examine whether (i) glucose-induced insulin resistance in diabetes and (ii) the metabolic effects of nutrient deprivation and excess, are mediated in a TRIB3 dependent manner. Aim 3: Assess contribution of muscle TRIB3 in regulating insulin sensitivity and metabolism, both systemically and at the level of skeletal muscle, in: (i) T2DM patients before and after euglycemic therapy to examine glucose-induced insulin resistance, and (ii) in subjects during hypocaloric feeding and stable weight loss. Thus, we will elucidate fo the first time a pathophysiological role for TRIB3 as a mediator of glucose- induced insulin resistance in diabetes, and the ability of TRIB3 to act as an acute physiological regulator of glucose transport and mitochondrial oxidation in the context of available intracellular fuel stores during periods of fasting and nutrient excess. These data in cultured cells, genetically-manipulated mice, and human subjects will elucidate a novel pathophysiological role for TRIB3 in glucose-induced insulin resistance, and a novel physiological role in the regulation of fuel metabolism. These studies will develop TRIB3 as a new target for therapy in diabetes.