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（由申请人提供）：2型糖尿病（T2DM）以胰岛素作用和胰岛素分泌缺陷为特征。游离脂肪酸（FFA）代谢紊乱也是2型糖尿病的一个特征，在显性糖尿病发病前的遗传易感个体中也有观察到。这提出了一种有趣的可能性，即FFA作为代谢信使，当其大量释放时，会损害胰岛素靶组织中的胰岛素作用，即“脂肪毒性”。大量证据还表明，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。由此导致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。体内和体外研究也表明，己糖胺通量的增加抑制了PGC-1和参与氧化磷酸化的多个线粒体基因的表达。“glucotoxicity”。在高血糖的情况下，丙二醇辅酶a的增加可能会通过抑制CPTI进一步损害肌肉脂肪和葡萄糖氧化，导致细胞内有毒脂质代谢物的增加和胰岛素抵抗的恶化。“glucolipotoxicity”。在本研究中，我们将研究游离脂肪酸诱导和高血糖诱导的胰岛素抵抗的机制。利用胰岛素钳和股外侧肌活检、磁共振波谱以及体内和体外线粒体功能评估，我们将研究单独升高的血浆FFA、单独升高的葡萄糖胺（葡萄糖）以及血浆葡萄糖胺（葡萄糖）联合升高的血浆FFA对全身（肌肉）胰岛素刺激下的葡萄糖处理/葡萄糖氧化/糖原合成、胰岛素信号传导、胰岛素信号传导和胰岛素信号传导的影响。线粒体基因的表达和功能。我们还将研究阿昔莫司（一种有效的脂肪分解抑制剂）和一种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。这些处理分别降低血浆FFA/消耗肌肉脂质和降低血浆葡萄糖水平。因此，我们假设这些干预会增加PGC-1/NRF- 1/线粒体基因表达，改善线粒体功能，增强胰岛素敏感性/分泌。最后，我们将研究阿昔莫司/BMS 512148联合治疗对T2DM患者上述参数的影响。我们相信这些研究将为T2DM患者胰岛素抵抗的病因提供新的见解，并确定新的治疗方法来逆转胰岛素作用缺陷并恢复正常血糖。