Mechanisms of Insulin Resistance in Diabetes

糖尿病胰岛素抵抗的机制

• 批准号: 8922734
• 负责人: W Timothy GARVEY
• 金额: --
• 依托单位: BIRMINGHAM VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-10-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8922734
• 关键词: Acute; Address; Affect; Blood Glucose; Body Weight decreased; Cell Culture System; Cells; Chronic; Clinical; Coupled; Cultured Cells; Data; Defect; Development; Diabetes Mellitus; Diabetic mouse; Disease; Dose; Elements; Energy Metabolism; Fasting; GLUT4 gene; Gene Expression; Genes; Genetic Transcription; Glucose; Glycogen; Hexosamines; Homologous Gene; Human; Hyperglycemia; Individual; Insulin; Insulin Resistance; Knockout Mice; Link; Lipids; Mediating; Mediator of activation protein; Metabolic; Metabolic syndrome; Metabolism; Mitochondria; Molecular; Mus; Muscle; Muscle Cells; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Pathway interactions; Patients; Physiological; Prediabetes syndrome; Process; Protein Glycosylation; Proteins; Protocols documentation; Publishing; Regulation; Regulatory Element; Reporter Genes; Reporting; Rodent Model; Role; Severities; Skeletal Muscle; Streptozocin; Testing; Therapeutic; Time; Toxic effect; Transgenic Mice; Transgenic Organisms; Translational Research; base; blood glucose regulation; deprivation; diabetes control; diabetic patient; disorder control; fasting glucose; feeding; glucose metabolism; glucose tolerance; glucose transport; glucose uptake; glycemic control; glycosylation; human subject; improved; in vivo; insight; insulin secretion; insulin sensitivity; insulin signaling; link protein; mouse model; novel; nutrient metabolism; overexpression; oxidation; promoter; public health relevance; research study; targeted treatment

 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.

 描述（由申请人提供）： 高血糖症1型和2型糖尿病患者骨骼肌中的胰岛素抵抗，高葡萄糖诱导靶细胞中胰岛素刺激的葡萄糖转运缺陷。 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，尽管进行了20年的研究，但己糖胺途径代谢与胰岛素作用缺陷之间的分子联系仍然未知。我们已经报道，肌肉TRIB 3与胰岛素敏感性呈负相关，与人类患者的空腹葡萄糖呈正相关，其以依赖于己糖胺途径的方式由葡萄糖诱导，并介导肌肉中胰岛素刺激的葡萄糖转运缺陷。除了其在慢性高血糖症中的病理作用外，我们还确定了TRIB 3在营养过剩和禁食条件下急性调节营养代谢中的新调节作用。我们现在将确定葡萄糖诱导TRIB 3表达的机制，并确定TRIB 3是否介导葡萄糖诱导的胰岛素抵抗，并调节人类和遗传操作小鼠的燃料代谢。为了验证这些假设，我们的具体目标是：目标1：确定葡萄糖诱导TRIB 3基因表达的机制（顺式元件和反式因子）。 目标二：在肌肉特异性转基因和基因敲除小鼠中，检查（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TRIB 3依赖性方式介导。 目标三：评估肌肉TRIB 3在调节胰岛素敏感性和代谢中的贡献，在全身和骨骼肌水平，在：（i）正常血糖治疗之前和之后的T2 DM患者中，以检查葡萄糖诱导的胰岛素抵抗，和（ii）在低热量喂养和稳定的体重减轻期间的受试者中。 因此，我们将首次阐明TRIB 3作为糖尿病中葡萄糖诱导的胰岛素抵抗的介导剂的病理生理学作用，以及TRIB 3在可用的细胞内燃料储存的背景下作为葡萄糖转运和线粒体氧化的急性生理调节剂的能力。 在禁食和营养过剩期间。在培养细胞、基因操作小鼠和人类受试者中的这些数据将阐明TRIB 3在葡萄糖诱导的胰岛素抵抗中的新的病理生理学作用，以及在调节燃料代谢中的新的生理学作用。这些研究将开发TRIB 3作为糖尿病治疗的新靶点。