DPP-4 inhibition contributes to the prevention of hypoglycaemia through a GIP–glucagon counterregulatory axis in mice

Abstract

Aims/hypothesis: Glucose-lowering therapy with dipeptidyl peptidase-4 (DPP-4) inhibitors is associated with a low risk of hypoglycaemia. We hypothesise that DPP-4 inhibition prevents hypoglycaemia via increased glucagon counterregulation through the incretin hormone glucose-dependent insulinotropic polypeptide (GIP). Methods: Using a hyperinsulinaemic–hypoglycaemic clamp that targeted 2.5 mmol/l we examined the effects of the DPP-4 inhibitor vildagliptin and GIP infusion on steady state glucose infusion rate (GIR) and glucagon counterregulation in mice. Following up on this, we performed a hyperinsulinaemic–hypoglycaemic clamp in mice carrying a genetic deletion of the GIP receptor (GIPR−/− mice) or the glucagon receptor (GCGR−/− mice). Results: GIR was reduced by 89.0 ± 3.1% (p = 7.0 × 10−6) by vildagliptin and by 38.8 ± 12.6% (p = 0.040) by GIP in wild-type (wt) mice, whereas GIR was increased both in GIPR−/− (to 33.0 ± 6.8 from 14.0 ± 2.9 μmol kg−1 min−1; p = 0.017) and in GCGR−/− mice (to 59.4 ± 1.1 from 16.5 ± 2.4 μmol kg−1 min−1; p = 8.2 × 10−7) compared with wt. By contrast, neither vildagliptin nor GIP had any effect on GIR in GCGR−/− mice. Furthermore, vildagliptin increased intact GIP four- to eightfold during hypoglycaemia and the counterregulatory increase in glucagon levels during hypoglycaemia was augmented by vildagliptin (incremental AUC [iAUC] during clamp was 99.2 ± 22.5 vs 42.0 ± 4.5 pmol/l × min in controls; p = 0.039) and GIP (iAUC of fold change during clamp was 372 ± 81 vs 161 ± 40 FC × min with saline; p = 0.031). Conclusions/interpretation: Based on these results we propose that DPP-4 inhibition protects from hypoglycaemia by augmenting glucagon counterregulation through a GIP–glucagon counterregulatory axis.