title: Biological Activity and Antidiabetic Potential of C-Terminal Octapeptide Fragments of the Gut-Derived Hormone Xenin.
abstract: Xenin is a peptide that is co-secreted with the incretin hormone, glucose-dependent insulinotropic polypeptide (GIP), from intestinal K-cells in response to feeding. Studies demonstrate that xenin has appetite suppressive effects and modulates glucose-induced insulin secretion. The present study was undertaken to determine the bioactivity and antidiabetic properties of two C-terminal fragment xenin peptides, namely xenin 18-25 and xenin 18-25 Gln. In BRIN-BD11 cells, both xenin fragment peptides concentration-dependently stimulated insulin secretion, with similar efficacy as the parent peptide. Neither fragment peptide had any effect on acute feeding behaviour at elevated doses of 500 nmol/kg bw. When administered together with glucose to normal mice at 25 nmol/kg bw, the overall insulin secretory effect was significantly enhanced in both xenin 18-25 and xenin 18-25 Gln treated mice, with better moderation of blood glucose levels. Twice daily administration of xenin 18-25 or xenin 18-25 Gln for 21 days in high fat fed mice did not affect energy intake, body weight, circulating blood glucose or body fat stores. However, circulating plasma insulin concentrations had a tendency to be elevated, particularly in xenin 18-25 Gln mice. Both treatment regimens significantly improved insulin sensitivity by the end of the treatment period. In addition, sustained treatment with xenin 18-25 Gln significantly reduced the overall glycaemic excursion and augmented the insulinotropic response to an exogenous glucose challenge on day 21. In harmony with this, GIP-mediated glucose-lowering and insulin-releasing effects were substantially improved by twice daily xenin 18-25 Gln treatment. Overall, these data provide evidence that C-terminal octapeptide fragments of xenin, such as xenin 18-25 Gln, have potential therapeutic utility for type 2 diabetes.
authors.affiliation: SAAD Centre for Pharmacy and Diabetes, Biomedical Sciences Research Institute, University of Ulster, Coleraine, Northern Ireland, United Kingdom.
authors.forename: Christine M
authors.initials: CM
authors.lastname: Martin
authors.affiliation: SAAD Centre for Pharmacy and Diabetes, Biomedical Sciences Research Institute, University of Ulster, Coleraine, Northern Ireland, United Kingdom.
authors.forename: Vadivel
authors.initials: V
authors.lastname: Parthsarathy
authors.affiliation: SAAD Centre for Pharmacy and Diabetes, Biomedical Sciences Research Institute, University of Ulster, Coleraine, Northern Ireland, United Kingdom.
authors.forename: Annie
authors.initials: A
authors.lastname: Hasib
authors.affiliation: SAAD Centre for Pharmacy and Diabetes, Biomedical Sciences Research Institute, University of Ulster, Coleraine, Northern Ireland, United Kingdom.
authors.forename: Ming T
authors.initials: MT
authors.lastname: Ng
authors.affiliation: SAAD Centre for Pharmacy and Diabetes, Biomedical Sciences Research Institute, University of Ulster, Coleraine, Northern Ireland, United Kingdom.
authors.forename: Stephen
authors.initials: S
authors.lastname: McClean
authors.affiliation: SAAD Centre for Pharmacy and Diabetes, Biomedical Sciences Research Institute, University of Ulster, Coleraine, Northern Ireland, United Kingdom.
authors.forename: Peter R
authors.initials: PR
authors.lastname: Flatt
authors.affiliation: SAAD Centre for Pharmacy and Diabetes, Biomedical Sciences Research Institute, University of Ulster, Coleraine, Northern Ireland, United Kingdom.
authors.forename: Victor A
authors.initials: VA
authors.lastname: Gault
authors.affiliation: SAAD Centre for Pharmacy and Diabetes, Biomedical Sciences Research Institute, University of Ulster, Coleraine, Northern Ireland, United Kingdom.
authors.forename: Nigel
authors.initials: N
authors.lastname: Irwin
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D001835:Body Weight / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy*; D059305:Diet, High-Fat; D002149:Energy Intake / Q000187:drug effects; D005768:Gastrointestinal Hormones / Q000737:chemistry / Q000627:therapeutic use*; D005951:Glucose Tolerance Test; D007004:Hypoglycemic Agents / Q000737:chemistry / Q000627:therapeutic use*; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D009496:Neurotensin / Q000737:chemistry / Q000627:therapeutic use*
chemical_list: D001786:Blood Glucose; D005768:Gastrointestinal Hormones; D007004:Hypoglycemic Agents; D007328:Insulin; C077659:xenin 25; D009496:Neurotensin