title: A novel chemically modified analogue of xenin-25 exhibits improved glucose-lowering and insulin-releasing properties.
abstract: BACKGROUND
  Xenin-25 is a K-cell derived gut peptide with insulin-releasing activity which is rapidly degraded following release into the circulation. We hypothesized that substitution of all naturally-occurring Lys and Arg residues with Gln would lead to prolonged enzyme resistance and enhanced biological efficacy.
  
  
  METHODS
  Peptide stability was assessed using murine plasma, in vitro insulin-releasing actions evaluated in BRIN-BD11 cells and acute glucose-lowering and insulin-releasing actions examined in high fat fed mice. For sub-chronic studies, a range of metabolic parameters and pancreatic histology were assessed in high fat fed mice which had received saline vehicle or xenin-25(gln) twice-daily for 21 days.
  
  
  RESULTS
  In contrast to native xenin-25, xenin-25(gln) was resistant to plasma-mediated degradation and significantly stimulated insulin secretion in BRIN-BD11 cells. Acute administration of xenin-25(gln) in high fat fed mice significantly reduced blood glucose and increased plasma insulin concentrations. Twice-daily administration of xenin-25(gln) in high fat fed mice did not affect food intake, body weight or circulating insulin concentrations but significantly decreased blood glucose from day 9 onwards. Furthermore, glucose tolerance, glucose-mediated insulin secretion, insulin sensitivity and GIP-stimulated insulin-release were significantly enhanced in xenin-25(gln)-treated mice. Pancreatic immunohistochemistry revealed decreased alpha cell area with increased beta cell area and beta-to-alpha cell ratio in xenin-25(gln)-treated mice. In addition, xenin-25(gln) exerted similar beneficial actions in ob/ob mice as demonstrated by reduced blood glucose, superior glycaemic response and glucose-mediated insulin release.
  
  
  CONCLUSIONS
  Xenin-25(gln) is resistant to plasma-mediated degradation and exerts sustained and beneficial metabolic actions in high fat fed and ob/ob mice.
  
  
  CONCLUSIONS
  Glutamine (gln)-modified analogues of xenin may represent an attractive therapeutic approach for type 2 diabetes.
authors.affiliation: SAAD Centre for Pharmacy and Diabetes, School of Biomedical Sciences, University of Ulster, Coleraine BT52 1SA, Northern Ireland, UK.
authors.forename: Vadivel
authors.initials: V
authors.lastname: Parthsarathy
authors.affiliation: SAAD Centre for Pharmacy and Diabetes, School of Biomedical Sciences, University of Ulster, Coleraine BT52 1SA, Northern Ireland, UK.
authors.forename: Nigel
authors.initials: N
authors.lastname: Irwin
authors.affiliation: SAAD Centre for Pharmacy and Diabetes, School of Biomedical Sciences, University of Ulster, Coleraine BT52 1SA, Northern Ireland, UK.
authors.forename: Annie
authors.initials: A
authors.lastname: Hasib
authors.affiliation: SAAD Centre for Pharmacy and Diabetes, School of Biomedical Sciences, University of Ulster, Coleraine BT52 1SA, Northern Ireland, UK.
authors.forename: Christine M
authors.initials: CM
authors.lastname: Martin
authors.affiliation: SAAD Centre for Pharmacy and Diabetes, School of Biomedical Sciences, University of Ulster, Coleraine BT52 1SA, Northern Ireland, UK.
authors.forename: Stephen
authors.initials: S
authors.lastname: McClean
authors.affiliation: SAAD Centre for Pharmacy and Diabetes, School of Biomedical Sciences, University of Ulster, Coleraine BT52 1SA, Northern Ireland, UK.
authors.forename: Vikas K
authors.initials: VK
authors.lastname: Bhat
authors.affiliation: SAAD Centre for Pharmacy and Diabetes, School of Biomedical Sciences, University of Ulster, Coleraine BT52 1SA, Northern Ireland, UK.
authors.forename: Ming T
authors.initials: MT
authors.lastname: Ng
authors.affiliation: SAAD Centre for Pharmacy and Diabetes, School of Biomedical Sciences, University of Ulster, Coleraine BT52 1SA, Northern Ireland, UK.
authors.forename: Peter R
authors.initials: PR
authors.lastname: Flatt
authors.affiliation: SAAD Centre for Pharmacy and Diabetes, School of Biomedical Sciences, University of Ulster, Coleraine BT52 1SA, Northern Ireland, UK. Electronic address: va.gault@ulster.ac.uk.
authors.forename: Victor A
authors.initials: VA
authors.lastname: Gault
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D002460:Cell Line; D003692:Delayed-Action Preparations / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy*; D004041:Dietary Fats / Q000008:administration & dosage / Q000009:adverse effects; D007328:Insulin / Q000097:blood*; D051379:Mice; D009496:Neurotensin / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology*
chemical_list: D001786:Blood Glucose; D003692:Delayed-Action Preparations; D004041:Dietary Fats; D007328:Insulin; C077659:xenin 25; D009496:Neurotensin
keywords: Glucose homeostasis; Gut hormone; Insulin secretion; Type 2 diabetes; Xenin-25