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.