Restoration of the insulinotropic effect of glucose-dependent insulinotropic polypeptide contributes to the antidiabetic effect of dipeptidyl peptidase-4 inhibitors

Aims: To examine whether 12 weeks of treatment with a dipeptidyl peptidase-4 (DPP-4) inhibitor, sitagliptin, influences the insulin secretion induced by glucose, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) during a hyperglycaemic clamp in patients with type 2 diabetes (T2DM). Methods: A randomized, double-blind, placebo-controlled study was conducted over 12 weeks, during which 25 patients with T2DM completed treatment with either sitagliptin (100mg once daily) or placebo as add-on therapy to metformin [sitagliptin group (n=12): mean +/- standard error of the mean (s.e.m.) age 54 +/- 2.5 years, mean +/- s.e.m. HbA1c 7.8 +/- 0.2%; placebo group (n= 13): mean +/- s.e.m. age: 57 +/- 3.0 years, mean +/- s.e.m. HbA1c 7.9 +/- 0.2 %]. In weeks 1 and 12, the patients underwent three 2-h 15-mM hyperglycaemic clamp experiments with infusion of either saline, GLP-1 or GIP. beta-cell function was evaluated according to first-phase, second-phase, incremental and total insulin and C-peptide responses. Results: In the sitagliptin group, the mean HbA1c concentration was significantly reduced by 0.9% (p=0.01). The total beta-cell response during GIP infusion improved signficantly from week 1 to week 12, both within the sitagliptin group (p=0.004) and when compared with the placebo group (p=0.04). The total beta-cell response during GLP-1 infusion was significantly higher (p=0.001) when compared with saline and GIP infusion, but with no improvement from week 1 to week 12. No significant changes in beta-cell function occurred in the placebo group. Conclusions: Treatment with the DPP-4 inhibitor sitagliptin over 12 weeks in patients with T2DM partially restored the lost insulinotropic effect of GIP, whereas the preserved insulinotropic effect of GLP-1 was not further improved. A gradual enhancement of the insulinotropic effect of GIP, therefore, possibly contributes to the antidiabetic actions of DPP-4 inhibitors.