The impact of dipeptidyl peptidase 4 inhibition on incretin effect, glucose tolerance, and gastrointestinal-mediated glucose disposal in healthy subjects

Objective: Inhibition of dipeptidyl peptidase 4 (DPP4) is thought to intensify the physiological effects of the incretin hormones. We investigated the effects of DPP4 inhibition on plasma levels of glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide 1 (GLP1), incretin effect, glucose tolerance, gastrointestinal-mediated glucose disposal (GIGD) and gastric emptying in healthy subjects. Design: A randomised, controlled and open-labelled study. Methods: Ten healthy subjects (six women; age, 40 +/- 5 years (mean +/- S.E.M.); BMI, 24 +/- 3 kg/m(2); fasting plasma glucose, 5.1 +/- 0.2 mmol/l and HbA1c, 34 +/- 1 mmol/mol (5.3 +/- 0.1%)) were randomised to two-paired study days comprising a 4-h 50 g oral glucose tolerance test (OGTT) with paracetamol (A) and an isoglycaemic intravenous (i.v.) glucose infusion (B), with (A(1)+B-1) and without (A(2+)B(2)) preceding administration of the DPP4 inhibitor sitagliptin. Results: Isoglycaemia was obtained in all subjects on the paired study days. Significant increases in fasting levels and OGTT-induced responses of active GLP1 and GIP were seen after DPP4 inhibition. No significant impact of DPP4 inhibition on fasting plasma glucose (5.1 +/- 0.1 vs 4.9 +/- 0.1 mmol/l, P=0.3), glucose tolerance (area under the curve (AUC) for plasma glucose, 151 +/- 35 vs 137 +/- 26 mmol/l x min, P=0.7) or peak plasma glucose during OGTT (8.5 +/- 0.4 vs 8.1 +/- 0.3 mmol/l, P=0.3) was observed. Neither incretin effect (40 +/- 9% (without DPP4 inhibitor) vs 40 +/- 7% (with DPP4 inhibitor), P=1.0), glucagon responses (1395 +/- 165 vs 1223 +/- 195 pmol/lxmin, P=0.41), GIGD (52 +/- 4 vs 56 +/- 5%, P=0.40) nor gastric emptying (T-max for plasma paracetamol: 86 +/- 9 vs 80 +/- 12 min, P=0.60) changed following DPP4 inhibition. Conclusions: These results suggest that acute increases in active incretin hormone levels do not affect glucose tolerance, GIGD, incretin effect, glucagon responses or gastric emptying in healthy subjects.