Saylan, Monica Ligueros

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 (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 SI (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 10−14 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 μg · 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 α-cell responsiveness to insulin administration, but the significance of this action is as yet unclear.

OBJECTIVE— We sought to determine whether alterations in meal absorption and gastric emptying contribute to the mechanism by which inhibitors of dipeptidyl peptidase-4 (DPP-4) lower postprandial glucose concentrations. RESEARCH DESIGN AND METHODS— We simultaneously measured gastric emptying, meal appearance, endogenous glucose production, and glucose disappearance in 14 subjects with type 2 diabetes treated with either vildaglipitin (50 mg b.i.d.) or placebo for 10 days using a double-blind, placebo-controlled, randomized, crossover design. RESULTS— Fasting (7.3 ± 0.5 vs. 7.9 ± 0.5 mmol/l) and peak postprandial (14.1 ± 0.6 vs. 15.9 ± 0.9 mmol/l) glucose concentrations were lower (P < 0.01) after vildagliptin treatment than placebo. Despite lower glucose concentrations, postprandial insulin and C-peptide concentrations did not differ during the two treatments. On the other hand, the integrated (area under the curve) postprandial glucagon concentrations were lower (20.9 ± 1.6 vs. 23.7 ± 1.3 mg/ml per 5 h, P < 0.05), and glucagon-like peptide 1 (GLP-1) concentrations were higher (1,878 ± 270 vs. 1,277 ± 312 pmol/l per 5 h, P = 0.001) during vildagliptin administration compared with placebo. Gastric emptying and meal appearance did not differ between treatments. CONCLUSIONS— Vildagliptin does not alter gastric emptying or the rate of entry of ingested glucose into the systemic circulation in humans. DPP-4 inhibitors do not lower postprandial glucose concentrations by altering the rate of nutrient absorption or delivery to systemic circulation. Alterations in islet function, secondary to increased circulating concentrations of active GLP-1, are associated with the decreased postprandial glycemic excursion observed in the presence of vildagliptin.