EFFECTS OF LAF237 ON MAX INSULIN SECRETION IN PTS WITH TYPE 2 DIABETES

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。所列机构为中心机构，不一定为研究者机构。一种有前途的治疗2型糖尿病的新方法利用了GLP-1的生理作用。GLP-1是一种肠促胰岛素激素，由回肠的L细胞响应肠道中的营养物质而释放。活性GLP-1具有许多降低葡萄糖水平的急性效应，包括以葡萄糖依赖性方式刺激胰岛素分泌和抑制胰高血糖素分泌、延迟胃排空和增加外周胰岛素作用。长期而言，GLP-1可能对β细胞具有营养作用，以增加功能性β细胞质量。天然GLP-1具有有限的治疗价值，因为需要注射，并且因为活性GLP-1在循环中的半衰期仅为1-2分钟。GLP-1的失活由酶二肽基肽酶IV（DPP-4）催化，该酶切割N-末端2个氨基酸。DPP-4抑制剂在动物模型和2型糖尿病患者中导致较高的活性GLP-1水平和较低的葡萄糖水平。在这项研究中，我们评估了一种新型DPP-4抑制剂LAF 237（vildagaline，Novartis Pharmaceuticals Corp.），对胰岛素分泌和功能性β细胞质量的影响。本研究采用双盲、安慰剂对照、随机、平行组研究设计。每例患者将参加21天筛选期、基线期（第-2天和第-1天）和12周治疗期。患者将随机接受LAF 237（50 mg bid）或安慰剂。将在第-1天和第12周和第14周进行静脉葡萄糖耐量试验和最大胰岛素分泌评估（25 mM葡萄糖下精氨酸刺激的胰岛素释放，AIRmax）。完成14周评估后，将进行研究结束评价。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. A promising new approach to the treatment of type 2 diabetes leverages the physiological effects of GLP-1. GLP-1 is an incretin hormone released by the L-cells of the ileum in response to nutrients in the gut. Active GLP-1 has a number of acute effects to lower glucose levels including stimulating insulin secretion and suppressing glucagon secretion in a glucose-dependent manner, delaying gastric emptying and increasing peripheral insulin action. Chronically, GLP-1 may have trophic effects on the beta-cell to increase functional beta-cell mass. Native GLP-1 is of limited therapeutic value, because of the need for injection and because active GLP-1 has a half-life of only 1-2 minutes in the circulation. The inactivation of GLP-1 is catalyzed by the enzyme dipeptidyl-peptidase IV (DPP-4) which cleaves the N-terminal 2 amino acids. Inhibitors of DPP-4 result in higher active GLP-1 levels and lower glucose in animal models and in humans with type 2 diabetes. In this study, we are evaluating the effects of a novel DPP-4 inhibitor, LAF237 (vildagliptin, Novartis Pharmaceuticals Corp.), on insulin secretion and functional Beta-cell mass. This study employs a double-blind, placebo-controlled, randomized, parallel-group study design. Each patient will participate in a 21-day screening period, a baseline period (Days -2 and -1) and a 12-week treatment period. Patients will be randomized to receive either LAF237 (50 mg bid) or placebo. An intravenous glucose tolerance test and a maximum insulin secretion assessment (arginine stimulated insulin release at 25 mM glucose, AIRmax) will be conducted on Day -1 and Weeks 12 and 14. An end-of-study evaluation will be conducted following the completion of the 14-week assessments.