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Submitted on August 28, 2006
Accepted on January 17, 2007
Division of Diabetes, Department of Medicine, University of Texas Health Science Center at San Antonio; Novartis Institutes for Biomedical Research, Cambridge, MA; PharmaWrite, LLC, Princeton, NJ; Novartis Pharmaceuticals Corp. East Hanover, NJ; Panum Institute, University of Copenhagen, Copenhagen, Denmark; Institute of Biomedical Engineering, National Research Council, Padova, Italy
* To whom correspondence should be addressed. E-mail: balas{at}uthscsa.edu.
Aims/hypothesis: Vildagliptin is a selective DPP-4 inhibitor that augments meal-stimulated levels of biologically active GLP-1. Chronic vildagliptin treatment decreases postprandial glucose levels and reduces HbA1c in type 2 diabetes (T2DM). However, little is known about the mechanism(s) by which vildagliptin promotes reduction in plasma glucose concentration.
Methods: 16 T2DM (age=48±3y; BMI=34.4±1.7 kg/m2; HbA1c=9.0±0.3%) participated in a randomized, double-blind, placebo-controlled trial. On separate days patients received 100 mg vildagliptin or placebo at 5:30PM followed 30 min later by a meal tolerance test (MTT) performed with double tracer technique (3-3H-glucose intravenously and 1-14C-glucose orally).
Results: Following vildagliptin, suppression of endogenous glucose production (EGP) during 6 hours MTT was greater than with placebo (1.02±0.06 vs 0.74±0.06 mg/kg•min, p=0.004), and insulin secretion rate (ISR) increased by 21% (p=0.003 vs PBO) despite significant reduction in mean plasma glucose (213±4 vs 230±4 mg/dl, p=0.006). Consequently, ISR[AUC] ÷ plasma glucose[AUC] 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 (
= -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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