Long term change of GLP-1 insulinotropic effect after GBP surgery

性状（由申请方提供）：肠促胰岛素GLP-1是一种强效葡萄糖介导的胰岛素促分泌素。2型糖尿病（DM 2）患者的肠促胰岛素对胰岛素分泌的作用减弱，但GLP-1的给药能够恢复DM患者的β细胞对葡萄糖的敏感性。胃旁路手术（GBP）后经历DM 2缓解的患者具有快速（数周内）和持续（数年）的餐后过度GLP-1释放，肠促胰岛素对胰岛素分泌的影响正常化。体外和/或啮齿动物研究显示， GLP-1可以刺激β细胞的生长和分化。GBP后持续增强的GLP-1释放是否会导致更大的β细胞功能尚不清楚。本研究将探讨：1）GLP- 1受体拮抗剂exendin 9-39对内源性GLP-1在葡萄糖诱导的β-细胞功能恢复中的作用; 2）GBP后β-细胞对葡萄糖输注和精氨酸给药的最大反应的变化; 3）严重肥胖和DM 2患者在GBP前和GBP后2年内的胰岛素敏感性和身体组成; 4）GBP后DM 2缓解的决定因素。了解GBP后DM 2缓解或缺乏的机制将有助于确定结果的预测因素，并开发治疗严重肥胖和DM 2的替代药物。

DESCRIPTION (provided by applicant): The intestinal incretin GLP-1 is a potent glucose-mediated insulin secretagogue. Patients with type 2 diabetes (DM2) have a blunted incretin effect on insulin secretion but the administration of GLP-1 is able to restore �-cell sensitivity t glucose in DM. Patients who experienced DM2 remission after gastric bypass surgery (GBP) have rapid (within weeks), and sustained (years), exaggerated post-prandial GLP-1 release, with normalization of the incretin effect on insulin secretion. In vitro and/or rodent studies show that GLP-1 can stimulate �-cell growth and differentiation. Whether the sustained enhanced GLP-1 release after GBP results in greater �-cell function is unknown. In this proposal we will examine: 1) The role of endogenous GLP-1 in the recovery of �-cell function in response to oral glucose, by using exendin 9-39, a GLP- 1 receptor antagonist; 2) The change of maximal �-cell response to glucose infusion and arginine administration after GBP; 3) Insulin sensitivity and body composition, in patients with severe obesity and DM2, before and up to 2 years after GBP; 4) Determinants of DM2 remission after GBP. Understanding the mechanisms of DM2 remission, or lack of, after GBP will help identify predictors of outcome as well as develop medical alternatives for the treatment of severe obesity and DM2.