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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.

journal_name

Diabetologia

journal_title

Diabetologia

authors

Malmgren S,Ahrén B

doi

10.1007/s00125-015-3518-7

subject

Has Abstract

pub_date

2015-05-01 00:00:00

pages

1091-9

issue

5

eissn

0012-186X

issn

1432-0428

journal_volume

58

pub_type

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