title: DPP-4 inhibition contributes to the prevention of hypoglycaemia through a GIP-glucagon counterregulatory axis in mice.
abstract: OBJECTIVE
  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
  Based on these results we propose that DPP-4 inhibition protects from hypoglycaemia by augmenting glucagon counterregulation through a GIP-glucagon counterregulatory axis.
authors: Department of Clinical Sciences, Lund, Medicine, Biomedical Centre C11, Lund University, SE-221 84, Lund, Sweden, siri.malmgren@med.lu.se.
authors: Siri
authors: S
authors: Malmgren
authors: Bo
authors: B
authors: Ahrén
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology*; D005749:Gastric Inhibitory Polypeptide / Q000378:metabolism* / Q000494:pharmacology; D005934:Glucagon / Q000378:metabolism*; D007003:Hypoglycemia / Q000378:metabolism / Q000517:prevention & control*; D051379:Mice; D018345:Mice, Knockout; D009570:Nitriles / Q000494:pharmacology*; D011759:Pyrrolidines / Q000494:pharmacology*; D011964:Receptors, Gastrointestinal Hormone / Q000235:genetics / Q000378:metabolism; D018027:Receptors, Glucagon / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D000077597:Vildagliptin
chemical_list: D001786:Blood Glucose; D054873:Dipeptidyl-Peptidase IV Inhibitors; D009570:Nitriles; D011759:Pyrrolidines; D011964:Receptors, Gastrointestinal Hormone; D018027:Receptors, Glucagon; D005749:Gastric Inhibitory Polypeptide; D005934:Glucagon; C041086:gastric inhibitory polypeptide receptor; D000077597:Vildagliptin; D000218:Adamantane