A novel chemically modified analogue of xenin-25 exhibits improved glucose-lowering and insulin-releasing properties

Journal article


Parthsarathy, Vadivel, Irwin, Nigel, Hasib, Annie, Martin, Christine M., McClean, Stephen, Bhat, Vikas K., NG, Ming T., Flatt, Peter R. and Gault, Victor A. 2016. A novel chemically modified analogue of xenin-25 exhibits improved glucose-lowering and insulin-releasing properties. Biochimica et Biophysica Acta. 1860 (4), pp. 757-764. https://doi.org/10.1016/j.bbagen.2016.01.015
AuthorsParthsarathy, Vadivel, Irwin, Nigel, Hasib, Annie, Martin, Christine M., McClean, Stephen, Bhat, Vikas K., NG, Ming T., Flatt, Peter R. and Gault, Victor A.
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 21days.

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.

GENERAL SIGNIFICANCE: Glutamine (gln)-modified analogues of xenin may represent an attractive therapeutic approach for type 2 diabetes.

Keywordsglucose homeostasis; gut; insulin; diabetes
Year2016
JournalBiochimica et Biophysica Acta
Journal citation1860 (4), pp. 757-764
PublisherElsevier
ISSN0304-4165
Digital Object Identifier (DOI)https://doi.org/10.1016/j.bbagen.2016.01.015
Web address (URL)http://hdl.handle.net/10545/622908
hdl:10545/622908
http://europepmc.org/article/med/26802310
Output statusPublished
Publication dates21 Jan 2016
Publication process dates
Deposited16 Aug 2018
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