Regulation of Hepatic and Peripheral Glucose Metabolism

肝脏和外周葡萄糖代谢的调节

• 批准号: 8000968
• 负责人: RALPH A DEFRONZO
• 金额: $ 9.9万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-12-31 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8000968
• 关键词: Biopsy; Characteristics; Chronic; Defect; Diabetes Mellitus; Etiology; Evaluation; Fatty acid glycerol esters; Gene Expression; Genes; Glucosamine; Glucose; Glycogen; Grant; Hepatic; Hexosamines; Hyperglycemia; Impairment; In Vitro; Individual; Infusion procedures; Insulin; Insulin Resistance; Intervention; Kidney; Lipids; Lipolysis; Magnetic Resonance Spectroscopy; Malonyl Coenzyme A; Mediating; Metabolic; Mitochondria; Muscle; Non-Insulin-Dependent Diabetes Mellitus; Nonesterified Fatty Acids; Oxidative Phosphorylation; Pathway interactions; Peripheral; Physiological; Plasma; Regulation; Retinal Cone; Secondary to; Testing; Tissues; Tubular formation; acipimox; fatty acid metabolism; gene function; glucose disposal; glucose metabolism; glucose transport; improved; in vivo; inhibitor/antagonist; insight; insulin secretion; insulin sensitivity; insulin signaling; interest; mitochondrial dysfunction; novel therapeutic intervention; nrf1 protein; oxidation; vastus lateralis

DESCRIPTION (provided by applicant): Type 2 diabetes mellitus (T2DM) is characterized by defects in insulin action and insulin secretion. Disturbances in free fatty acid (FFA) metabolism also are a characteristic feature of T2DM and are observed in genetically predisposed individuals before the onset of overt diabetes. This raises the interesting possibility that FFA act as metabolic messengers which, when released in increased amounts, impair insulin action in insulin target tissues, i.e., "lipotoxicity". Much evidence also indicates that tissue fat content is increased in T2DM. We hypothesize that tissue lipid overload decreases expression of PGC-1, NRF-1, and multiple mitochondrial genes involved in oxidative phosphorylation. The resultant impairment in mitochondrial function leads to impaired substrate oxidation and accumulation of toxic lipid metabolites that inhibit insulin signaling and cause insulin resistance. In vivo and in vitro studies also suggest that increased hexosamine flux inhibits expression of PGC-1 and multiple mitochondrial genes involved in oxidative phosphorylation, i.e. "glucotoxicity". In the presence of hyperglycemia, an increase in malonyl CoA would be expected to further impair muscle fat and glucose oxidation by inhibiting CPTI, leading to an increase in toxic intracellular lipid metabolites and worsening of the insulin resistance, i.e. "glucolipotoxicity". In the present grant we shall examine the mechanisms of FFA-induced and hyperglycemia-induced insulin resistance. Using the insulin clamp with vastus lateralis muscle biopsy, magnetic resonance spectroscopy, and in vivo and in vitro evaluation of mitochondrial function, we shall examine the effect of elevated plasma FFA alone, increased glucosamine (glucose) alone, and the combination of elevated plasma glucosamine (glucose) plus elevated plasma FFA on whole body (muscle) insulin-stimulated glucose disposal/glucose oxidation/glycogen synthesis, insulin signaling, and mitochondrial gene expression and function in healthy NGT-insulin sensitive subjects. We also will examine the effect of acipimox (a potent inhibitor of lipolysis) and the effect of a highly specific inhibitor of renal tubular (SGLT2) glucose transport (BMS 512148) on the preceding parameters in T2DM subjects. These treatments reduce plasma FFA/deplete lipid from muscle and reduce plasma glucose levels, respectively. Therefore, we hypothesize that these interventions will increase PGC-1/NRF- 1/mitochondrial gene expression, improve mitochondrial function, and enhance insulin sensitivity/secretion. Lastly, we will examine the effect of combined acipimox/BMS 512148 therapy on the above paramters in T2DM. We believe that these studies will yield new insights into the etiology of insulin resistance in T2DM and identify novel therapeutic approaches to reverse the defects in insulin action and restore normoglycemia.

描述（申请人提供）：2型糖尿病（T2DM）的特征是胰岛素作用和胰岛素分泌缺陷。游离脂肪酸 (FFA) 代谢紊乱也是 T2DM 的一个特征，在明显糖尿病发病前的遗传易感人群中即可观察到。这提出了一个有趣的可能性，即 FFA 作为代谢信使，当其释放量增加时，会损害胰岛素靶组织中的胰岛素作用，即“脂毒性”。许多证据还表明，T2DM 患者的组织脂肪含量增加。我们假设组织脂质超载会降低 PGC-1、NRF-1 和参与氧化磷酸化的多个线粒体基因的表达。由此产生的线粒体功能损伤导致底物氧化受损和有毒脂质代谢物的积累，从而抑制胰岛素信号传导并导致胰岛素抵抗。体内和体外研究还表明，增加的己糖胺通量会抑制 PGC-1 和参与氧化磷酸化（即“葡萄糖毒性”）的多个线粒体基因的表达。在高血糖的情况下，丙二酰辅酶A的增加预计会通过抑制CPTI进一步损害肌肉脂肪和葡萄糖氧化，导致有毒细胞内脂质代谢物增加和胰岛素抵抗恶化，即“糖脂毒性”。在本次资助中，我们将研究 FFA 诱导和高血糖诱导的胰岛素抵抗的机制。使用胰岛素钳结合股外侧肌活检、磁共振波谱以及线粒体功能的体内和体外评估，我们将检查单独升高的血浆 FFA、单独升高的葡萄糖胺（葡萄糖）以及升高的血浆葡萄糖胺的组合的影响（葡萄糖）加上健康 NGT 胰岛素敏感受试者全身（肌肉）胰岛素刺激的葡萄糖处理/葡萄糖氧化/糖原合成、胰岛素信号传导以及线粒体基因表达和功能的血浆 FFA 升高。我们还将研究阿昔莫司（一种有效的脂解抑制剂）和高度特异性的肾小管 (SGLT2) 葡萄糖转运抑制剂 (BMS 512148) 对 T2DM 受试者上述参数的影响。这些治疗分别减少血浆 FFA/消耗肌肉中的脂质并降低血浆葡萄糖水平。因此，我们假设这些干预措施将增加 PGC-1/NRF-1/线粒体基因表达，改善线粒体功能，并增强胰岛素敏感性/分泌。最后，我们将检查阿西莫司/BMS 512148 联合治疗对 T2DM 中上述参数的影响。我们相信，这些研究将对 T2DM 胰岛素抵抗的病因学产生新的见解，并确定扭转胰岛素作用缺陷和恢复正常血糖的新治疗方法。