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 (gin) 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. (C) 2016 Elsevier B.V. All rights reserved.
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Wolverhampton Univ, Sch Life Sci, Diabet Res Grp, Wolverhampton, EnglandWolverhampton Univ, Sch Life Sci, Diabet Res Grp, Wolverhampton, England
Falobi, A. A.
Ofosu, W. A.
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Univ East, Sch Hlth Sport & Biosci, London, EnglandWolverhampton Univ, Sch Life Sci, Diabet Res Grp, Wolverhampton, England
Ofosu, W. A.
Edeani, J. N.
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Wolverhampton Univ, Sch Life Sci, Diabet Res Grp, Wolverhampton, EnglandWolverhampton Univ, Sch Life Sci, Diabet Res Grp, Wolverhampton, England
Edeani, J. N.
Dunmore, S.
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Wolverhampton Univ, Sch Life Sci, Diabet Res Grp, Wolverhampton, EnglandWolverhampton Univ, Sch Life Sci, Diabet Res Grp, Wolverhampton, England
Dunmore, S.
Smyth, L.
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Univ East, Sch Hlth Sport & Biosci, London, EnglandWolverhampton Univ, Sch Life Sci, Diabet Res Grp, Wolverhampton, England
Smyth, L.
Corcoran, O.
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Wolverhampton Univ, Sch Life Sci, Diabet Res Grp, Wolverhampton, EnglandWolverhampton Univ, Sch Life Sci, Diabet Res Grp, Wolverhampton, England
Corcoran, O.
Ojo, O. O.
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Wolverhampton Univ, Sch Life Sci, Diabet Res Grp, Wolverhampton, England
IRiD Biosci, Stoke On Trent, EnglandWolverhampton Univ, Sch Life Sci, Diabet Res Grp, Wolverhampton, England