Dipeptidyl Peptidase-4 Inhibition by Vildagliptin and the effect on insulin secretion and action in response to meal ingestion in type 2 Diabetes

Abstract

Objective-The purpose of this study was to determine the mechanism by which dipep-tidyl 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 (SI), glucose effectiveness, and β-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 I (7.71 ± 1.28 vs. 6.41 ±0.84 10-4 dl · kg-1 · min-1 · (μU-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 β-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 10-14dl. 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 (xg · l-1 · 6 h-1, P= 0.03), especially after administration of exogenous insulin (81.5 ± 6.4vs. 99.3 ± 5.6ng/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 a-cell responsiveness to insulin administration, but the significance of this action is as yet unclear. © 2009 by the American Diabetes Association.