Siri Malmgren1, Bo Ahrén. 1. Department of Clinical Sciences, Lund, Medicine, Biomedical Centre C11, Lund University, SE-221 84, Lund, Sweden, siri.malmgren@med.lu.se.
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.
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.
Authors: Michael A Nauck; Markus M Heimesaat; Kai Behle; Jens J Holst; Markus S Nauck; Robert Ritzel; Michael Hüfner; Wolff H Schmiegel Journal: J Clin Endocrinol Metab Date: 2002-03 Impact factor: 5.958
Authors: K Miyawaki; Y Yamada; H Yano; H Niwa; N Ban; Y Ihara; A Kubota; S Fujimoto; M Kajikawa; A Kuroe; K Tsuda; H Hashimoto; T Yamashita; T Jomori; F Tashiro; J Miyazaki; Y Seino Journal: Proc Natl Acad Sci U S A Date: 1999-12-21 Impact factor: 11.205
Authors: Nathalie Pamir; Francis C Lynn; Alison M J Buchan; Jan Ehses; Simon A Hinke; J Andrew Pospisilik; Kazumasa Miyawaki; Yuichiro Yamada; Yutaka Seino; Christopher H S McIntosh; Raymond A Pederson Journal: Am J Physiol Endocrinol Metab Date: 2003-01-21 Impact factor: 4.310