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

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 x 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 mu mol kg (-1) min (-1); p = 0.017) and in GCGR (-/-) mice (to 59.4 +/- 1.1 from 16.5 +/- 2.4 mu mol kg (-1) min (-1); p = 8.2 x 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 x min in controls; p = 0.039) and GIP (iAUC of fold change during clamp was 372 +/- 81 vs 161 +/- 40 FC x 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.