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
| Authors | Parthsarathy, 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. |
| Keywords | glucose homeostasis; gut; insulin; diabetes |
| Year | 2016 |
| Journal | Biochimica et Biophysica Acta |
| Journal citation | 1860 (4), pp. 757-764 |
| Publisher | Elsevier |
| ISSN | 0304-4165 |
| 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 status | Published |
| Publication dates | 21 Jan 2016 |
| Publication process dates | |
| Deposited | 16 Aug 2018 |
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