Mechanisms of Membrane-Based Insulin Resistance & Therapeutic Reversal Strategies

膜型胰岛素抵抗的机制

基本信息

批准号：
8212266
负责人：
JEFFREY S ELMENDORF
金额：
$ 32.83万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-03-15 至 2014-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8212266
关键词：
5&apos -AMP-activated protein kinase ADD-1 protein Acute Anabolism Animal Model Antidiabetic Drugs Attention Biochemical Biology Cell membrane Cellular Structures Characteristics Cholesterol Chronic Clinical 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 GLUT 4 protein GLUT4 gene Genetic Transcription Glucose Transporter Goals Health Hexosamines Hydroxymethylglutaryl-CoA reductase 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 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 improved in vivo insulin secretion insulin sensitivity interest novel therapeutics operation theories therapeutic target transcription factor

项目摘要

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）：密集研究，以了解与肥胖症和2型糖尿病相关的胰岛素抵抗的分子机制，这告诉我们，多种机制可能有助于最终表型。发表和初步发现与质膜（PM）和细胞骨架缺陷的理论是一致的，这是胰岛素受损葡萄糖转运蛋白glut4调节胰岛素调节受损的胰岛素耐药性中的重要，不受欢迎的危险。从机械上讲，膜/细胞骨架缺陷是由PM胆固醇应计引起的，该胆固醇是由生理高胰岛素血症引起的，该状态已知促进胰岛素抵抗的进展/恶化。有趣的是，去除过量的PM胆固醇完全恢复了从肥胖，耐胰岛素，Zucker（FA/FA）大鼠中分离出的培养细胞和骨骼肌中的胰岛素敏感性。新数据还表明，增加的六胺生物合成途径（HBP）活性促进PM胆固醇应计，膜/细胞骨架缺陷和胰岛素抵抗。与胆固醇还原相似，校正膜/细胞骨架相关的胰岛素抵抗，抑制HBP会阻断膜/细胞骨架缺陷并恢复胰岛素敏感性。因此，该应用的假设是HBP增加了胆固醇转录因子的转录活性。还观察到，AMP激活的蛋白激酶（AMPK）的激活是已知的抗糖尿病治疗靶标，与PM胆固醇的丧失有关。拟议的研究的中心假设是，肥胖和T2D的特征葡萄糖稳态的分解是脂肪和肌肉中PM胆固醇的继发。这也是一个预测，几种抗糖尿病疗法通过对持久胆固醇，耐胰岛素耐药性PM的有益作用来改善胰岛素作用。这将以三个具体目标进行测试。 1）定义GLUT4易位的到达/对接和/或融合步骤是否受到损害。初步数据表明这是可更正的远端缺陷。 2）剖析高胰岛素血症增加PM胆固醇的机制。证据支持了增加HBP活性与PM胆固醇应计的想法。这个概念的含义是巨大的，因为其他侮辱（例如高血糖和高脂血症）会构成相同的威胁，因此，PM胆固醇的积累可能是一种常见的机制，胰岛素抵抗的这三个后果促进了综合征的进展/恶化。 3）确定AMPK激活，运动和/或他汀类药物是否下PM胆固醇。这些结果将是显着的，因为它们有望为对越来越多的胰岛素耐药性个体而言重要的预防和治疗干预措施提供新的目标，这些人表现出不同的生化特征，但胰岛素敏感性的共同损失。公共卫生相关性：解决胰岛素抵抗如何发展并最终导致/恶化到2型糖尿病（T2D）仍然是生物学的基本挑战，并且在医学上是一个重大问题。我们的研究发现，肥胖和T2D的特征的葡萄糖稳态分解是脂肪和肌肉中质膜胆固醇的继发的。我们还确定了防止这种危险的手段，对所涉及机制的进一步调查将有望导致新的治疗策略，以减少T2D人群的加速扩张。