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The Dipeptidyl Peptidase IV Inhibitor Vildagliptin Suppresses Endogenous Glucose Production and Enhances Islet Function after Single-Dose Administration in Type 2 Diabetic Patients

Division of Diabetes (B.B., M.R.B., C.D., K.C., R.A.D.), Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229; Novartis Institutes for Biomedical Research (C.W., Y.-L.H.), Cambridge, Massachusetts 02139; PharmaWrite, L.L.C. (B.E.D.), Princeton, New Jersey 08540; Novartis Pharmaceuticals Corp. (M.L.-S., Y.W., J.E.F.), East Hanover, New Jersey 07054; Panum Institute (J.J.H., C.F.D.), University of Copenhagen, DK-2400 Copenhagen, Denmark; and Institute of Biomedical Engineering (A.M.), National Research Council, 35127 Padova, Italy

Address all correspondence and requests for reprints to: Bogdan Balas, M.D., Diabetes Division, University of Texas Health Science Center at San Antonio, 7703 Floyd Drive, MC 7886, San Antonio, Texas 78229. E-mail: balas{at}uthscsa.edu.

Aims/Hypothesis: Vildagliptin is a selective dipeptidyl peptidase IV inhibitor that augments meal-stimulated levels of biologically active glucagon-like peptide-1. Chronic vildagliptin treatment decreases postprandial glucose levels and reduces hemoglobin A_1c in type 2 diabetic patients. However, little is known about the mechanism(s) by which vildagliptin promotes reduction in plasma glucose concentration.

Methods: Sixteen patients with type 2 diabetes (age, 48 ± 3 yr; body mass index, 34.4 ± 1.7 kg/m²; hemoglobin A_1c, 9.0 ± 0.3%) participated in a randomized, double-blind, placebo-controlled trial. On separate days patients received 100 mg vildagliptin or placebo at 1730 h followed 30 min later by a meal tolerance test (MTT) performed with double tracer technique (3-³H-glucose iv and 1-¹⁴C-glucose orally).

Results: After vildagliptin, suppression of endogenous glucose production (EGP) during 6-h MTT was greater than with placebo (1.02 ± 0.06 vs. 0.74 ± 0.06 mg·kg^–1·min^–1; P = 0.004), and insulin secretion rate increased by 21% (P = 0.003) despite significant reduction in mean plasma glucose (213 ± 4 vs. 230 ± 4 mg/dl; P = 0.006). Consequently, insulin secretion rate (area under the curve) divided by plasma glucose (area under the curve) increased by 29% (P = 0.01). Suppression of plasma glucagon during MTT was 5-fold greater with vildagliptin (P < 0.02). The decline in EGP was positively correlated (r = 0.55; P < 0.03) with the decrease in fasting plasma glucose (change = –14 mg/dl).

Conclusions: During MTT, vildagliptin augments insulin secretion and inhibits glucagon release, leading to enhanced suppression of EGP. During the postprandial period, a single dose of vildagliptin reduced plasma glucose levels by enhancing suppression of EGP.

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