SGLT2 INHIBITION AND STIMULATIION OF ENDOGENOUS GLUCOSE PRODUCTION

 描述（由申请人提供）： 抑制肾脏SGLT 2转运蛋白已被证明是降低2型糖尿病患者血糖水平和HbA 1c的有效治疗干预。SGLT 2抑制剂的降糖疗效由两种不同的机制引起：（i）诱导糖尿， 其相当于每天约70-90克和（ii）改善葡萄糖毒性，导致肌肉中胰岛素敏感性增加和β细胞功能改善（JCI 124：509-514，2014）。然而，SGLT 2抑制剂的临床疗效被内源性葡萄糖生成（EGP）的增加抵消，后者抵消了约50%的尿液中排泄的葡萄糖量。EGP的增加与血浆胰高血糖素浓度的升高和血浆胰岛素浓度的下降相关。在本研究中，我们将定义：（1）导致EGP增加的器官，肝脏和/或肾脏（方案一）;（2）血浆胰高血糖素增加、血浆胰岛素下降、血糖浓度下降的作用（方案二）;和（3）达格列净抑制肾脏SGLT 2转运蛋白后，肾神经在EGP增加中的作用（方案三）。在方案4中，我们将检查GLP-1受体激动剂艾塞那肽（刺激胰岛素并抑制胰高血糖素分泌）是否可以阻断达格列净抑制SGLT 2后EGP的增加。

 DESCRIPTION (provided by applicant): Inhibition of the renal SGLT2 transporter has proven to be an effective therapeutic intervention to reduce plasma glucose levels and HbA1c in type 2 diabetic patients. The glycemic-lowering efficacy of the SGLT2 inhibitors results from two distinct mechanisms: (i) induction of glucosuria, which amounts to ~70-90 grams per day and (ii) amelioration of glucotoxicity leading to increased insulin sensitivity in muscle and improved beta cell function (JCI 124:509-514, 2014). However, the clinical efficacy of the SGLT2 inhibitors is countered by an increase in endogenous glucose production (EGP) that offsets by ~50% the amount of glucose excreted in the urine. The increase in EGP is associated with a rise in plasma glucagon concentration and decline in plasma insulin concentration. In the present grant we will define: (1) the organ, liver and/or kidney, responsible for the increase in EGP (Protocol One); (2) the role of increased plasma glucagon, decline in plasma insulin, fall in plasma glucose concentration (Protocol Two); and (3) the role of the renal nerves in the increase in EGP (Protocol Three) following inhibition of the renal SGLT2 transporter with dapagliflozin. In Protocol Four, we will examine whether the GLP-1 receptor agonist, exenatide, which stimulates insulin and inhibits glucagon secretion, can block the increase in EGP following SGLT2 inhibition with dapagliflozin.