Regulation of Hepatic and Peripheral Glucose Metabolism

描述（由申请方提供）：2型糖尿病（T2 DM）的特征为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T2 DM的特征性特征，在显性糖尿病发作前的遗传易感个体中观察到。这提出了一种有趣的可能性，即FFA作为代谢信使，当其以增加的量释放时，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，T2 DM中组织脂肪含量增加。我们推测，组织脂质过载降低了PGC-1，NRF-1和参与氧化磷酸化的多个线粒体基因的表达。线粒体功能的损伤导致底物氧化受损和毒性脂质代谢物的积累，这些代谢物抑制胰岛素信号传导并引起胰岛素抵抗。体内和体外研究还表明，增加的己糖胺通量抑制参与氧化磷酸化的PGC-1和多个线粒体基因的表达，即“葡萄糖毒性”。在存在高血糖症的情况下，预期丙二酰辅酶A的增加将通过抑制CPTI进一步损害肌肉脂肪和葡萄糖氧化，导致毒性细胞内脂质代谢物的增加和胰岛素抵抗的恶化，即“糖脂毒性”。在本研究中，我们将研究FFA诱导和高血糖诱导的胰岛素抵抗的机制。使用胰岛素钳夹和股外侧肌活检，磁共振波谱，以及线粒体功能的体内和体外评价，我们将检查单独升高的血浆FFA，单独升高的葡糖胺（葡萄糖），以及升高的血浆葡糖胺（葡萄糖）加升高的血浆FFA对全身（肌肉）胰岛素刺激的葡萄糖处置/葡萄糖氧化/糖原合成，胰岛素信号传导，以及健康NGT-胰岛素敏感受试者的线粒体基因表达和功能。我们还将在T2 DM受试者中检查阿昔莫司（一种强效脂解抑制剂）和一种高度特异性肾小管（SGLT 2）葡萄糖转运抑制剂（BMS 512148）对前述参数的影响。这些治疗分别降低血浆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，我们将检查阿昔莫司/BMS 512148联合治疗对T2 DM中上述参数的影响。我们相信，这些研究将产生新的见解，在T2 DM的胰岛素抵抗的病因，并确定新的治疗方法，以扭转胰岛素作用的缺陷，恢复正常的血糖。

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.