Effects of Dipeptidyl Peptidase-4 Inhibition on Gastrointestinal Function, Meal Appearance, and Glucose Metabolism in Type 2 Diabetes

Abstract

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 Ϯ 0.5 vs. 7.9 Ϯ 0.5 mmol/l) and peak postprandial (14.1 Ϯ 0.6 vs. 15.9 Ϯ 0.9 mmol/l) glucose concentrations were lower (P Ͻ 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 Ϯ 1.6 vs. 23.7 Ϯ 1.3 mg/ml per 5 h, P Ͻ 0.05), and glucagon-like peptide 1 (GLP-1) concentrations were higher (1,878 Ϯ 270 vs. 1,277 Ϯ 312 pmol/l per 5 h, P ϭ 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.

Effects of Sitagliptin on Glycemia, Incretin Hormones, and Antropyloroduodenal Motility in Response to Intraduodenal Glucose Infusion in Healthy Lean and Obese Humans and Patients With Type 2 Diabetes Treated With or Without Metformin

“…This might relate to the effects of peptide YY (PYY), whose degradation from PYY1-36 to PYY3-36, which has more potent effects to slow gastric emptying, is prevented by DPP-4 inhibition (50). The current data are thus in keeping with the majority of evidence that DPP-4 inhibition does not influence gastric emptying (17)(18)(19)21,22), although a recent study reported slowing of oral glucose emptying after sitagliptin in type 2 diabetic patients (20). Metformin was reported to slow gastric emptying in mice (25), but we did not observe any effect on APD motility in the current experimental setting.…”

“…The majority of studies have reported a lack of effect of DPP-4 inhibitors on gastric emptying for unclear reasons (16)(17)(18)(19)(20)(21)(22). Although endogenous GLP-1 slows gastric emptying through suppression of antral motility and stimulation of pyloric contractions (6,7), the effect of DPP-4 inhibitors on these motor mechanisms has not been assessed.…”

Dipeptidyl Peptidase-4 Inhibitors

“…Furthermore, vildagliptin did not affect the rate of gastric emptying of a tracerenriched meal (52).…”

Does dipeptidyl peptidase-4 inhibition prevent the diabetogenic effects of glucocorticoids in men with the metabolic syndrome? A randomized controlled trial

“…On the other hand, exenatide infusions, resulting in pharmacological levels of GLP1, were shown to prevent the acute diabetogenic effects of prednisolone in healthy volunteers (15). An additional mechanism by which GLP1 receptor agonist treatment, in contrast to DPP-4 inhibitors (35,36), may prevent GC-induced hyperglycemia is by reducing gastric emptying rate -an effect attributed to the higher pharmacological levels of GLP1.…”