Dipeptidyl Peptidase-4 Inhibition by Vildagliptin and the Effect on Insulin Secretion and Action in Response to Meal Ingestion in Type 2 Diabetes

OBJECTIVE - The purpose Of this Study was to determine the mechanism by which dipeptidyl peptidase-4 inhibitors lower postprandial glucose concentrations. RESEARCH DESIGN AND METHODS - We measured insulin secretion and action as well as glucose effectiveness in 14 subjects With type 2 diabetes who received vildagliptin (50 mg b.i.d.) or placebo for 10 days in random order separated by a 3-week washout. On day 9 of each period, subjects ate a mixed meal. Insulin sensitivity (S,), glucose effectiveness, and beta-cell responsivity indexes were estimated using the oral glucose and C-peptide minimal models. At 300 min 0.02 unit/kg insulin was administered intravenously. RESULTS - Vildagliptin reduced postprandial glucose concentrations (905 94 vs. 1,008 +/- 104 mmol/6 h, P = 0.02). Vildagliptin did not alter net S-1 (7.71 +/- 1.28 vs. 6.41 +/- 0.84 10(-4) dl.kg(-1).min(-1).mu U-1.ml(-1), P = 0.13) or glucose effectiveness (0.019 +/- 0.002 vs. 0.018 +/- 0.002 dl.kg(-1).min(-1), P = 0.65). However, the net P-cell responsivity index was increased (35.7 +/- 5.2 vs. 28.9 +/- 5.2 10(-9) min(-1), P = 0.03) as was total disposition index (381 +/- 48 vs. 261 +/- 35 10(-14) dl.kg(-1).min(-2).pmol(-1).l(-1), P=0.006). Vildagliptin lowered postprandial glucagon concentrations (27.0 +/- 1.1 vs. 29.7 +/- 1.5 mu g.l(-1).6 h(-1), P = 0.03), especially after administration of exogenous insulin (81.5 +/- 6.4 vs. 99.3 +/- 5.6 ng/l, P = 0.02). CONCLUSIONS - Vildagliptin lowers postprandial glucose concentrations by stimulating insulin secretion and suppressing glucagon secretion but not by altered insulin action or glucose effectiveness. A novel observation is that vildagliptin alters alpha-cell responsiveness to insulin administration, but the significance of this action is as yet unclear.