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

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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.