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

被引:23
|
作者
Parthsarathy, Vadivel [1 ]
Irwin, Nigel [1 ]
Hasib, Annie [1 ]
Martin, Christine M. [1 ]
McClean, Stephen [1 ]
Bhat, Vikas K. [1 ]
Ng, Ming T. [1 ]
Flatt, Peter R. [1 ]
Gault, Victor A. [1 ]
机构
[1] Univ Ulster, Sch Biomed Sci, SAAD Ctr Pharm & Diabet, Coleraine BT52 1SA, Londonderry, North Ireland
来源
关键词
Glucose homeostasis; Gut hormone; Insulin secretion; Type; 2; diabetes; Xenin-25; GASTRIC-INHIBITORY POLYPEPTIDE; GLUCAGON-LIKE PEPTIDE-1; SECRETION; DEGRADATION; MICE; INTOLERANCE; FRAGMENT; CHICKS;
D O I
10.1016/j.bbagen.2016.01.015
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:757 / 764
页数:8
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