Mechanisms of Membrane-Based Insulin Resistance & Therapeutic Reversal Strategies

膜型胰岛素抵抗的机制

• 批准号: 7566652
• 负责人: JEFFREY S ELMENDORF
• 金额: $ 36.96万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-15 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7566652
• 关键词: 5' -AMP-activated protein kinase; ADD-1 protein; Acute; Anabolism; Animal Model; Antidiabetic Drugs; Attention; Biochemical; Biology; Cell membrane; Cellular Structures; Characteristics; Cholesterol; Chronic; Clinical; Coenzyme A; Country; Coupled; Cultured Cells; Data; Defect; Diabetes Mellitus; Distal; Docking; Educational process of instructing; Employee Strikes; Endoplasmic Reticulum; Etiology; Event; Excision; Exercise; F-Actin; Fatty acid glycerol esters; GLUT4 gene; Genetic Transcription; Glucose Transporter; Goals; Hexosamines; Hyperglycemia; Hyperinsulinism; Hyperlipidemia; In Vitro; Individual; Insulin; Insulin Receptor; Insulin Resistance; Investigation; Lead; Link; Lipids; Medicine; Membrane; Membrane Fusion; Molecular; Muscle; Muscle Fibers; Non-Insulin-Dependent Diabetes Mellitus; Nonesterified Fatty Acids; Obesity; Operative Surgical Procedures; Oxidoreductase; Pathway interactions; Peripheral; Phenotype; Phosphatidic Acid; Phosphatidylinositol 4,5-Diphosphate; Phosphatidylinositols; Phospholipids; Physiological; Population; Publishing; Rattus; Receptor Signaling; Regulation; Research; Secondary to; Skeletal Muscle; Stimulus; Structure; Syndrome; System; Testing; Therapeutic; Therapeutic Intervention; Translating; Vesicle; base; blood glucose regulation; cost; glucose transport; glucose uptake; glycosylation; human TYRP1 protein; improved; in vivo; insulin secretion; insulin sensitivity; interest; novel therapeutics; public health relevance; theories; therapeutic target; transcription factor

DESCRIPTION (provided by applicant): Intensive research in pursuit of understanding the molecular mechanisms of insulin resistance associated with obesity and type 2 diabetes has taught us that more than one mechanism likely contributes to the final phenotype. Published and preliminary findings are consistent with the theory that plasma membrane (PM) and cytoskeletal defects are an important, unappreciated derangement in insulin resistance contributing to impaired glucose transporter GLUT4 regulation by insulin. Mechanistically, the membrane/cytoskeletal defects result from PM cholesterol accrual that is induced by physiological hyperinsulinemia, a state known to promote the progression/worsening of insulin resistance. Interestingly, removal of the excess PM cholesterol fully restores insulin sensitivity in cultured cells and skeletal muscle isolated from obese, insulin-resistant, Zucker (fa/fa) rats. New data also suggest that increased hexosamine biosynthesis pathway (HBP) activity promotes PM cholesterol accrual, membrane/cytoskeletal defects, and insulin resistance. Similar to cholesterol reduction correcting the membrane/cytoskeletal-associated insulin resistance, inhibition of the HBP blocks the membrane/cytoskeletal defects and restores insulin sensitivity. Therefore, a postulate of this application is that the HBP increases the transcriptional activity of cholesterogenic transcription factors. Also observed is that activation of AMP-activated protein kinase (AMPK), a known antidiabetic therapeutic target, is associated with a loss of PM cholesterol. The central hypothesis of the proposed research is that the breakdown of glucose homeostasis, characteristic of obesity and T2D, is secondary to PM cholesterol accrual in fat and muscle. It is also a prediction that several antidiabetic therapies improve insulin action via an unappreciated beneficial effect on cholesterol-laden, insulin-resistant PM. This will be tested in three Specific Aims. 1) Define if arrival/docking and/or fusion steps of GLUT4 translocation are compromised. Preliminary data suggest this to be a correctable distal defect. 2) Dissect the mechanism(s) by which hyperinsulinemia increases PM cholesterol. Evidence supports the idea that increased HBP activity is coupled to PM cholesterol accrual. The implications of this concept are tremendous, as other insults such as hyperglycemia and hyperlipidemia would pose the same threat and thus, accumulation of PM cholesterol may be a common mechanism by which these three consequences of insulin resistance promote the progression/worsening of the syndrome. 3) Determine if AMPK activation, exercise, and/or statins lower PM cholesterol. These results will be significant, because they are expected to provide new targets for the preventative and therapeutic interventions important to the growing numbers of insulin-resistant individuals in this country who display different biochemical signatures but a shared loss in insulin sensitivity. PUBLIC HEALTH RELEVANCE: Solving how insulin resistance develops and eventually progresses/worsens to type 2 diabetes (T2D) remains a fundamental challenge in biology and a significant issue in medicine. Our studies have discovered that the breakdown of glucose homeostasis, characteristic of obesity and T2D, is secondary to plasma membrane cholesterol accrual in fat and muscle. We have also identified means to protect against this derangement, and further investigation of the mechanisms involved will hopefully lead to new therapeutic strategies to curtail the accelerated expansion of the T2D population.

描述（由申请人提供）：深入研究以了解与肥胖和2型糖尿病相关的胰岛素抵抗的分子机制，已经告诉我们不止一种机制可能导致最终表型。已发表的和初步的研究结果是一致的理论，质膜（PM）和细胞骨架缺陷是一个重要的，未被重视的紊乱胰岛素抵抗的葡萄糖转运蛋白GLUT4的胰岛素调节受损。从机制上讲，膜/细胞骨架缺陷是由生理性高胰岛素血症诱导的PM胆固醇累积引起的，这是一种已知促进胰岛素抵抗进展/恶化的状态。有趣的是，去除多余的PM胆固醇完全恢复了从肥胖、胰岛素抵抗、Zucker（fa/fa）大鼠分离的培养细胞和骨骼肌中的胰岛素敏感性。新的数据还表明，增加己糖胺生物合成途径（HBP）的活动，促进PM胆固醇积累，膜/细胞骨架缺陷，和胰岛素抵抗。与胆固醇降低纠正膜/细胞骨架相关的胰岛素抵抗类似，HBP的抑制阻断膜/细胞骨架缺陷并恢复胰岛素敏感性。因此，本申请的假设是HBP增加胆固醇生成转录因子的转录活性。还观察到AMP-活化蛋白激酶（AMPK）（一种已知的抗糖尿病治疗靶点）的活化与PM胆固醇的损失相关。提出的研究的中心假设是，葡萄糖稳态的破坏，肥胖和T2D的特征，是继发于PM胆固醇在脂肪和肌肉中的积累。这也是一个预测，几种抗糖尿病治疗通过对胆固醇负载的胰岛素抵抗PM的未被认识到的有益作用来改善胰岛素作用。这将在三个具体目标中得到检验。1)定义GLUT4易位的到达/对接和/或融合步骤是否受损。初步数据表明这是一个可纠正的远端缺陷。2)剖析高胰岛素血症增加PM胆固醇的机制。有证据支持HBP活性增加与PM胆固醇累积相关的观点。这一概念的含义是巨大的，因为其他损伤如高血糖症和高脂血症将构成相同的威胁，因此，PM胆固醇的积累可能是胰岛素抵抗的这三种后果促进综合征进展/恶化的常见机制。3)确定AMPK激活、运动和/或他汀类药物是否能降低PM胆固醇。这些结果将是重要的，因为它们有望为预防和治疗干预提供新的靶点，这些干预对该国越来越多的胰岛素抵抗个体很重要，这些个体显示出不同的生化特征，但胰岛素敏感性共同丧失。公共卫生相关性：解决胰岛素抵抗如何发展并最终发展/转化为2型糖尿病（T2D）仍然是生物学中的一个基本挑战，也是医学中的一个重要问题。我们的研究已经发现，葡萄糖稳态的破坏，肥胖和T2D的特征，是继发于脂肪和肌肉中的质膜胆固醇积累。我们还确定了防止这种紊乱的方法，对所涉及机制的进一步研究将有望导致新的治疗策略，以遏制T2D人群的加速扩张。