SAAD Centre for Pharmacy and Diabetes, Ulster University, Coleraine, Northern Ireland, UK.
Diabetes Metab Res Rev. 2021 Mar;37(3):e3384. doi: 10.1002/dmrr.3384. Epub 2020 Aug 18.
The antidiabetic effects of the gut hormone xenin include augmenting insulin secretion and positively affecting pancreatic islet architecture.
The current study has further probed pancreatic effects through sub-chronic administration of the long-acting xenin analogue, xenin-25[Lys PAL], in both high fat fed (HFF) and streptozotocin (STZ)-induced insulin-deficient Ins1 ;Rosa26-eYFP transgenic mice. Parallel effects on metabolic control and pancreatic islet morphology, including islet beta-cell lineage tracing were also assessed.
Xenin-25[Lys PAL] treatment reversed body weight loss induced by STZ, increased plasma insulin and decreased blood glucose levels. There were less obvious effects on these parameters in HFF mice, but all xenin-25[Lys PAL] treated mice exhibited decreased pancreatic alpha-cell areas and circulating glucagon. Xenin-25[Lys PAL] treatment fully, or partially, returned overall islet and beta-cell areas in STZ- and HFF mice to those of lean control animals, respectively, and was consistently associated with decreased beta-cell apoptosis. Interestingly, xenin-25[Lys PAL] also increased beta-cell proliferation and decreased alpha-cell apoptosis in STZ mice, with reduced alpha-cell growth noted in HFF mice. Lineage tracing studies revealed that xenin-25[Lys PAL] reduced the number of insulin positive pancreatic islet cells that lost their beta-cell identity, in keeping with a decreased transition of insulin positive to glucagon positive cells. These beneficial effects on islet cell differentiation were linked to maintained expression of Pdx1 within beta-cells. Xenin-25[Lys PAL] treatment was also associated with increased numbers of smaller sized islets in both models.
Benefits of xenin-25[Lys PAL] on diabetes includes positive modulation of islet cell differentiation, in addition to promoting beta-cell growth and survival.
肠激素 Xenin 的抗糖尿病作用包括增强胰岛素分泌和对胰岛结构产生积极影响。
本研究通过在高脂肪喂养（HFF）和链脲佐菌素（STZ）诱导的胰岛素缺乏 Ins1;Rosa26-eYFP 转基因小鼠中给予长效 Xenin 类似物 Xenin-25[LysPAL]，进一步探讨了其对胰腺的影响。还评估了对代谢控制和胰岛形态的平行影响，包括胰岛β细胞谱系追踪。
Xenin-25[LysPAL]治疗逆转了 STZ 引起的体重减轻，增加了血浆胰岛素并降低了血糖水平。在 HFF 小鼠中，这些参数的影响不太明显，但所有 Xenin-25[LysPAL]治疗的小鼠的胰腺α细胞面积和循环胰高血糖素均减少。Xenin-25[LysPAL]治疗使 STZ 和 HFF 小鼠的总体胰岛和β细胞面积分别完全或部分恢复到瘦对照动物的水平，并且与β细胞凋亡减少相关。有趣的是，Xenin-25[LysPAL]还增加了 STZ 小鼠的β细胞增殖并减少了α细胞凋亡，在 HFF 小鼠中观察到α细胞生长减少。谱系追踪研究表明，Xenin-25[LysPAL]减少了失去β细胞特征的胰岛素阳性胰岛细胞的数量，与胰岛素阳性向胰高血糖素阳性细胞的转变减少相一致。这些对胰岛细胞分化的有益影响与 Pdx1 在β细胞内的维持表达有关。Xenin-25[LysPAL]治疗还与两种模型中较小胰岛数量的增加有关。
Xenin-25[LysPAL]对糖尿病的益处包括对胰岛细胞分化的积极调节，以及促进β细胞的生长和存活。
