Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, University of Wisconsin-Madison, Madison, WI, USA.
Research Service, William S. Middleton Memorial Veterans Hospital, Madison, WI, USA.
Islets. 2023 Dec 31;15(1):2223327. doi: 10.1080/19382014.2023.2223327.
Of the β-cell signaling pathways altered by obesity and insulin resistance, some are adaptive while others contribute to β-cell failure. Two critical second messengers are Ca and cAMP, which control the timing and amplitude of insulin secretion. Previous work has shown the importance of the cAMP-inhibitory Prostaglandin EP3 receptor (EP3) in mediating the β-cell dysfunction of type 2 diabetes (T2D). Here, we used three groups of C57BL/6J mice as a model of the progression from metabolic health to T2D: wildtype, normoglycemic (NGOB), and hyperglycemic (HGOB). Robust increases in β-cell cAMP and insulin secretion were observed in NGOB islets as compared to wildtype controls; an effect lost in HGOB islets, which exhibited reduced β-cell cAMP and insulin secretion despite increased glucose-dependent Ca influx. An EP3 antagonist had no effect on β-cell cAMP or Ca oscillations, demonstrating agonist-independent EP3 signaling. Finally, using sulprostone to hyperactivate EP3 signaling, we found EP3-dependent suppression of β-cell cAMP and Ca duty cycle effectively reduces insulin secretion in HGOB islets, while having no impact insulin secretion on NGOB islets, despite similar and robust effects on cAMP levels and Ca duty cycle. Finally, increased cAMP levels in NGOB islets are consistent with increased recruitment of the small G protein, Rap1GAP, to the plasma membrane, sequestering the EP3 effector, Gɑ, from inhibition of adenylyl cyclase. Taken together, these results suggest that rewiring of EP3 receptor-dependent cAMP signaling contributes to the progressive changes in β cell function observed in the model of diabetes.
在肥胖和胰岛素抵抗改变的β细胞信号通路中，有些是适应性的，而有些则导致β细胞衰竭。两种关键的第二信使是 Ca 和 cAMP，它们控制胰岛素分泌的时间和幅度。先前的工作表明，cAMP 抑制性前列腺素 EP3 受体（EP3）在介导 2 型糖尿病（T2D）的β细胞功能障碍方面非常重要。在这里，我们使用三组 C57BL/6J 小鼠作为从代谢健康到 T2D 进展的模型：野生型、正常血糖（NGOB）和高血糖（HGOB）。与野生型对照相比，NGOB 胰岛中观察到β细胞 cAMP 和胰岛素分泌的显著增加；在 HGOB 胰岛中，尽管葡萄糖依赖性 Ca 内流增加，但β细胞 cAMP 和胰岛素分泌减少，这一作用丧失。EP3 拮抗剂对β细胞 cAMP 或 Ca 振荡没有影响，证明了激动剂独立的 EP3 信号传导。最后，使用舒前列素激活 EP3 信号，我们发现 EP3 依赖性抑制β细胞 cAMP 和 Ca 作用循环可有效减少 HGOB 胰岛中的胰岛素分泌，而对 NGOB 胰岛中的胰岛素分泌没有影响，尽管对 cAMP 水平和 Ca 作用循环有相似且强烈的影响。最后，NGOB 胰岛中 cAMP 水平的增加与小 G 蛋白 Rap1GAP 向质膜的募集增加一致，将 EP3 效应物 Gɑ 隔离，从而抑制腺苷酸环化酶。总之，这些结果表明，EP3 受体依赖性 cAMP 信号转导的重布线导致了糖尿病模型中观察到的β细胞功能进行性变化。
