Holter Marlena M, Phuong Daryl J, Lee Isaac, Saikia Mridusmita, Weikert Lisa, Fountain Samantha, Anderson Elizabeth T, Fu Qin, Zhang Sheng, Sloop Kyle W, Cummings Bethany P
Department of Biomedical Sciences, Cornell University, College of Veterinary Medicine, Ithaca, NY, USA.
Nancy E. and Peter C. Meinig School of Biomedical Engineering, Ithaca, NY, USA.
Sci Adv. 2022 Jul 22;8(29):eabn3773. doi: 10.1126/sciadv.abn3773.
Recent studies demonstrate that α cells contribute to glucose-stimulated insulin secretion (GSIS). Glucagon-like peptide-1 receptor (GLP-1R) agonists potently potentiate GSIS, making these drugs useful for diabetes treatment. However, the role of α and β cell paracrine interactions in the effects of GLP-1R agonists is undefined. We previously found that increased β cell GLP-1R signaling activates α cell GLP-1 expression. Here, we characterized the bidirectional paracrine cross-talk by which α and β cells communicate to mediate the effects of the GLP-1R agonist, liraglutide. We find that the effect of liraglutide to enhance GSIS is blunted by α cell ablation in male mice. Furthermore, the effect of β cell GLP-1R signaling to activate α cell GLP-1 is mediated by a secreted protein factor that is regulated by the signaling protein, 14-3-3-zeta, in mouse and human islets. These data refine our understanding of GLP-1 pharmacology and identify 14-3-3-zeta as a potential target to enhance α cell GLP-1 production.
最近的研究表明，α细胞有助于葡萄糖刺激的胰岛素分泌（GSIS）。胰高血糖素样肽-1受体（GLP-1R）激动剂能有效增强GSIS，使这些药物可用于糖尿病治疗。然而，α细胞与β细胞旁分泌相互作用在GLP-1R激动剂作用中的作用尚不清楚。我们之前发现，β细胞GLP-1R信号增强会激活α细胞GLP-1表达。在此，我们对α细胞与β细胞之间双向旁分泌串扰进行了表征，通过这种串扰，α细胞与β细胞相互沟通以介导GLP-1R激动剂利拉鲁肽的作用。我们发现，在雄性小鼠中，α细胞消融会减弱利拉鲁肽增强GSIS的作用。此外，β细胞GLP-1R信号激活α细胞GLP-1的作用是由一种分泌蛋白因子介导的，该因子在小鼠和人类胰岛中受信号蛋白14-3-3-ζ调节。这些数据完善了我们对GLP-1药理学的理解，并确定14-3-3-ζ是增强α细胞GLP-1生成的潜在靶点。
