SAAD Centre for Pharmacy and Diabetes, Ulster University, Coleraine, United Kingdom.
Wellcome Trust-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom.
Front Endocrinol (Lausanne). 2021 Feb 25;12:633625. doi: 10.3389/fendo.2021.633625. eCollection 2021.
Enzymatically stable and specific neuropeptide Y1 receptor (NPYR1) agonists, such as sea lamprey PYY(1-36) (SL-PYY(1-36)), are believed to improve glucose regulation in diabetes by targeting pancreatic islets. In this study, streptozotocin (STZ) diabetic transgenic ; and ; mouse models have been used to study effects of sustained NPYR1 activation on islet cell composition and alpha- and beta-cell lineage transitioning. STZ induced a particularly severe form of diabetes in ; mice, but twice-daily administration (25 nmol/kg) of SL-PYY(1-36) for 11 days consistently improved metabolic status. Blood glucose was decreased (p < 0.05 - p < 0.001) and both fasted plasma and pancreatic insulin significantly increased by SL-PYY(1-36). In both ; and ; mice, STZ provoked characteristic losses (p < 0.05 - p < 0.001) of islet numbers, beta-cell and pancreatic islet areas together with increases in area and central islet location of alpha-cells. With exception of alpha-cell area, these morphological changes were fully, or partially, returned to non-diabetic control levels by SL-PYY(1-36). Interestingly, STZ apparently triggered decreased (p < 0.001) alpha- to beta-cell transition in ; mice, together with increased loss of beta-cell identity in ; mice, but both effects were significantly (p < 0.001) reversed by SL-PYY(1-36). SL-PYY(1-36) also apparently reduced (p < 0.05) beta- to alpha-cell conversion in ; mice and glucagon expressing alpha-cells in ; mice. These data indicate that islet benefits of prolonged NPY1R activation, and especially restoration of beta-cell mass, are observed irrespective of diabetes status, being linked to cell lineage alterations including transdifferentiation of alpha- to beta-cells.
酶稳定且特异性的神经肽 Y1 受体 (NPYR1) 激动剂，如海七鳃鳗 PYY(1-36)(SL-PYY(1-36))，被认为通过靶向胰岛来改善糖尿病中的葡萄糖调节。在这项研究中，链脲佐菌素 (STZ) 糖尿病转基因 ; 和 ; 小鼠模型已被用于研究持续 NPYR1 激活对胰岛细胞组成和 alpha-和 beta-细胞谱系转化的影响。STZ 在 ; 小鼠中诱导了一种特别严重的糖尿病形式，但每天两次（25 nmol/kg）给予 SL-PYY(1-36)11 天可持续改善代谢状态。血糖降低（p < 0.05-p < 0.001），空腹血浆和胰腺胰岛素均显著增加。在 ; 和 ; 小鼠中，STZ 引起了特征性的胰岛数量损失（p < 0.05-p < 0.001），β细胞和胰腺胰岛面积增加，α细胞的中央胰岛位置增加。除了α细胞面积外，这些形态变化被 SL-PYY(1-36)完全或部分恢复到非糖尿病对照水平。有趣的是，STZ 显然触发了 ; 小鼠中 α-到 β-细胞转化的减少（p < 0.001），以及 ; 小鼠中β细胞特征的丧失增加，但这两种作用均被 SL-PYY(1-36)显著逆转（p < 0.001）。SL-PYY(1-36)还明显减少了 ; 小鼠中β-到 α-细胞的转化和 ; 小鼠中表达胰高血糖素的α细胞。这些数据表明，延长 NPY1R 激活的胰岛益处，特别是β细胞质量的恢复，无论糖尿病状态如何都可以观察到，与包括α-到 β-细胞转化的细胞谱系改变有关。
