一种新型的化学修饰的胃泌酸调节素-25类似物具有改善的降血糖和胰岛素释放特性。
A novel chemically modified analogue of xenin-25 exhibits improved glucose-lowering and insulin-releasing properties.
作者信息
Parthsarathy Vadivel, Irwin Nigel, Hasib Annie, Martin Christine M, McClean Stephen, Bhat Vikas K, Ng Ming T, Flatt Peter R, Gault Victor A
机构信息
SAAD Centre for Pharmacy and Diabetes, School of Biomedical Sciences, University of Ulster, Coleraine BT52 1SA, Northern Ireland, UK.
SAAD Centre for Pharmacy and Diabetes, School of Biomedical Sciences, University of Ulster, Coleraine BT52 1SA, Northern Ireland, UK.
出版信息
Biochim Biophys Acta. 2016 Apr;1860(4):757-64. doi: 10.1016/j.bbagen.2016.01.015. Epub 2016 Jan 21.
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.
GENERAL SIGNIFICANCE
Glutamine (gln)-modified analogues of xenin may represent an attractive therapeutic approach for type 2 diabetes.
背景
Xenin-25是一种K细胞衍生的具有胰岛素释放活性的肠道肽，释放到循环系统后会迅速降解。我们推测，将所有天然存在的赖氨酸（Lys）和精氨酸（Arg）残基替换为谷氨酰胺（Gln）会导致酶抗性延长并增强生物学效应。
方法
使用小鼠血浆评估肽的稳定性，在BRIN-BD11细胞中评估体外胰岛素释放作用，并在高脂喂养小鼠中检测急性降糖和胰岛素释放作用。对于亚慢性研究，在高脂喂养小鼠中评估一系列代谢参数和胰腺组织学，这些小鼠每天接受两次生理盐水或xenin-25（gln），持续21天。
结果
与天然xenin-25不同，xenin-25（gln）对血浆介导的降解具有抗性，并在BRIN-BD11细胞中显著刺激胰岛素分泌。在高脂喂养小鼠中急性给予xenin-25（gln）可显著降低血糖并增加血浆胰岛素浓度。在高脂喂养小鼠中每天两次给予xenin-25（gln）不影响食物摄入量、体重或循环胰岛素浓度，但从第9天起显著降低血糖。此外，在接受xenin-25（gln）治疗的小鼠中，葡萄糖耐量、葡萄糖介导的胰岛素分泌、胰岛素敏感性和GIP刺激的胰岛素释放均显著增强。胰腺免疫组织化学显示，在接受xenin-25（gln）治疗的小鼠中，α细胞面积减少，β细胞面积增加，β/α细胞比率增加。此外，xenin-25（gln）在ob/ob小鼠中也发挥了类似的有益作用，表现为血糖降低、更好的血糖反应和葡萄糖介导的胰岛素释放。
结论
Xenin-25（gln）对血浆介导的降解具有抗性，并在高脂喂养和ob/ob小鼠中发挥持续有益的代谢作用。
普遍意义
谷氨酰胺（gln）修饰的xenin类似物可能是治疗2型糖尿病的一种有吸引力的治疗方法。
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