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: To determine the mechanism by which Dipeptidyl peptidase 4 (DPP-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 (50mg bid) or placebo for 10-days in random order separated by a three-week washout. On day 9 of each period, subjects ate a mixed meal. Insulin sensitivity (S_I), Glucose effectiveness (GE) and β-cell responsitivity indices were estimated using the oral glucose and C-Peptide minimal model. At 300 minutes 0.02 Units per Kg insulin was administered intravenously.

Results: Vildagliptin reduced postprandial glucose concentrations (905±94 vs. 1008±104 mmol per 6h, p=0.02). Vildagliptin did not alter net insulin sensitivity (S_I, 7.71±1.28 vs. 6.41±0.84 10^-4 dl/kg/min/uU/ml, p=0.13) or glucose effectiveness, (GE, 0.019±0.002 vs. 0.018±0.002 dl/kg/min, p=0.65). However the net β-cell responsitivity index (ϕ_total)was increased (35.7±5.2 vs. 28.9±5.2 10^-9 min^-1, p=0.03) as was DI _total (381±48 vs. 261±35 10^-14 dl/kg.min^-2 per pmol/L, p=0.006). Vildagliptin lowered postprandial glucagon concentrations (27.0±1.1 vs. 29.7±1.5 μg/L per 6h, p=0.03), especially after administration of exogenous insulin (81.5±6.4 vs. 99.3±5.6 ng/l, p=0.02).

Conclusion: 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 α-cell responsiveness to insulin administration but the significance of this is as yet unclear.