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Measurements of Islet Function and Glucose Metabolism with the Dipeptidyl Peptidase 4 Inhibitor Vildagliptin in Patients with Type 2 Diabetes

Division of Endocrinology and Metabolism (K.A., Z.R., J.M., F.G.S.T., E.T., C.K., D.E.K.), Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261; the Department of Information Engineering (C.D.M., C.C.), University of Padova, 35122 Padova, Italy; Department of Medical Physiology (J.J.H., C.F.D.), The Panum Institute, University of Copenhagen, DK-2200 Copenhagen, Denmark; Novartis Pharmaceuticals Corporation (Y.H.), Cambridge, Massachusetts 02139; and Novartis Pharmaceuticals Corporation (M.L.-S., D.S., J.E.F.), East Hanover, New Jersey 07936

Address all correspondence and requests for reprints to: James E. Foley, Ph.D., Novartis Pharmaceuticals Corporation, One Health Plaza, East Hanover, New Jersey 07936. E-mail: james.foley{at}novartis.com.

Objective: Pharmacological inhibition with the dipeptidyl peptidase 4 (DPP-4) inhibitor vildagliptin prolongs the action of endogenously secreted incretin hormones leading to improved glycemic control in patients with type 2 diabetes mellitus (T2DM). We undertook a double-blinded, randomized-order, crossover study to examine the vildagliptin mechanisms of action on islet function and glucose utilization.

Research Design and Methods: Participants with T2DM (n = 16) who had a baseline hemoglobin A_1c of 7.1 ± 0.2% completed a crossover study with 6 wk of treatment with vildagliptin and 6 wk with placebo. At the completion of each arm, participants had a study of postprandial metabolism and a two-step glucose clamp performed at 20 and 80 mU/min·m² insulin infusions.

Results: Vildagliptin increased postprandial glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide by 3- and 2-fold, respectively, reduced fasting plasma glucose and postprandial plasma glucose by 1.3 ± 0.3 mmol/liter and 1.6 ± 0.3 mmol/liter (both P <0.01), and improved glucose responsiveness of insulin secretion by 50% (P < 0.01). Vildagliptin lowered postprandial glucagon by 16% (P <0.01). Examined by glucose clamp, insulin sensitivity and glucose clearance improved after vildagliptin (P < 0.01).

Conclusions: Vildagliptin improves islet function in T2DM and improves glucose metabolism in peripheral tissues.

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