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 hyperinsulinaemichypoglycaemic 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 ) by vildagliptin and by 38.8±12.6% (p=0.040) by GIP in wildtype (wt) mice, whereas GIR was increased both in GIPR ) 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.

Glucagon – Early breakthroughs and recent discoveries

“…In the 1970s it was also demonstrated that glucagon levels increased during hypoglycaemia [28][29][30]. In fact, the glucagon counter-regulation to hypoglycaemia is a key mechanism for preventing and defending hypoglycaemia as demonstrated in glucagon receptor knock-out mice, who have a defective counterregulation as evident from hypoglycemic clamp studies [31]. Several mechanisms may explain this, as is illustrated in Fig.…”

Improved glucose regulation in type 2 diabetic patients with DPP-4 inhibitors: focus on alpha and beta cell function and lipid metabolism

“…This suggests that the increase in GIP levels by DPP-4 inhibition may be the mechanism by which glucagon counter-regulation to hypoglycaemia is sustained or augmented by these drugs. Support for this comes from animal studies showing that mice with genetic deletion of the GIP receptors have a poorer glucagon counter-regulation to hypoglycaemia during vildagliptin treatment compared with normal mice with intact GIP receptors [71]. Therefore, although the reduction of glucagon during hyperglycaemia seems to be mediated by GLP-1, stimulation by DPP-4 inhibition of glucagon secretion during hypoglycaemia may be mediated by GIP.…”

Defective insulin secretion by chronic glucagon receptor activation in glucose intolerant mice

“…For the highest ZP-GA-1 dose (1500 ng/h), postprandial (120 min) ZP-GA-1 levels in plasma were measured to 136G19 pM (Fig. 1B), which is w100 times higher than that of native basal glucagon in mice (Malmgren & Ahren 2015), however, only two times higher than that of the glucagon response to hypoglycemia (Berglund et al 2008). The elevation of plasma ZP-GA-1 resulted in a significant lowering of insulin secretion in response to glucose compared to control (Fig.…”