title: Characterisation of the biological activity of xenin-25 degradation fragment peptides.
abstract: Xenin-25, a peptide co-secreted with the incretin hormone glucose-dependent insulinotropic polypeptide (GIP), possesses promising therapeutic actions for obesity-diabetes. However, native xenin-25 is rapidly degraded by serum enzymes to yield the truncated metabolites: xenin 9-25, xenin 11-25, xenin 14-25 and xenin 18-25. This study has examined the biological activities of these fragment peptides. In vitro studies using BRIN-BD11 cells demonstrated that native xenin-25 and xenin 18-25 possessed significant (P<0.05 to P<0.001) insulin-releasing actions at 5.6 and 16.7 mM glucose, respectively, but not at 1.1  mM glucose. In addition, xenin 18-25 significantly (P<0.05) potentiated the insulin-releasing action of the stable GIP mimetic (D-Ala²)GIP. In contrast, xenin 9-25, xenin 11-25 and xenin 14-25 displayed neither insulinotropic nor GIP-potentiating actions. Moreover, xenin 9-25, xenin 11-25 and xenin 14-25 significantly (P<0.05 to P<0.001) inhibited xenin-25 (10⁻⁶ M)-induced insulin release in vitro. I.p. administration of xenin-based peptides in combination with glucose to high fat-fed mice did not significantly affect the glycaemic excursion or glucose-induced insulin release compared with controls. However, when combined with (D-Ala²)GIP, all xenin peptides significantly (P<0.01 to P<0.001) reduced the overall glycaemic excursion, albeit to a similar extent as (D-Ala²)GIP alone. Xenin-25 and xenin 18-25 also imparted a potential synergistic effect on (D-Ala²)GIP-induced insulin release in high fat-fed mice. All xenin-based peptides lacked significant satiety effects in normal mice. These data demonstrate that the C-terminally derived fragment peptide of xenin-25, xenin 18-25, exhibits significant biological actions that could have therapeutic utility for obesity-diabetes.
authors: SAAD Centre for Pharmacy and Diabetes, University of Ulster, Coleraine, Northern Ireland, BT52 1SA, UK.
authors: Christine M A
authors: CM
authors: Martin
authors: Vadivel
authors: V
authors: Parthsarathy
authors: Varun
authors: V
authors: Pathak
authors: Victor A
authors: VA
authors: Gault
authors: Peter R
authors: PR
authors: Flatt
authors: Nigel
authors: N
authors: Irwin
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D059305:Diet, High-Fat; D004353:Drug Evaluation, Preclinical; D007004:Hypoglycemic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D008297:Male; D051379:Mice; D009496:Neurotensin / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D010446:Peptide Fragments / Q000378:metabolism* / Q000494:pharmacology*; D059748:Proteolysis; D012527:Satiation / Q000187:drug effects
chemical_list: D007004:Hypoglycemic Agents; D007328:Insulin; D010446:Peptide Fragments; C077659:xenin 25; D009496:Neurotensin
keywords: bioactivity; glucose-dependent insulinotropic polypeptide (GIP); high fat-fed mice; xenin-25