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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2007-1369
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The Journal of Clinical Endocrinology & Metabolism Vol. 93, No. 2 459-464
Copyright © 2008 by The Endocrine Society

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

Koichiro Azuma1, Zofia Rádiková1, Juliet Mancino, Frederico G. S. Toledo, Ernestine Thomas, Cyrous Kangani, Chiara Dalla Man, Claudio Cobelli, Jens J. Holst, Carolyn F. Deacon, YanLing He, Monica Ligueros-Saylan, Denise Serra, James E. Foley and David E. Kelley

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 A1c 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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