Mitochondrial glucose metabolism is essential for stimulated insulin release from pancreatic β-cells. Whether mitofusin gene expression, and hence, mitochondrial network integrity, is important for glucose or incretin signaling has not previously been explored. Here, we generated mice with β-cell–selective, adult-restricted deletion knock-out (dKO) of the mitofusin genes Mfn1 and Mfn2 (βMfn1/2 dKO). βMfn1/2-dKO mice displayed elevated fed and fasted glycemia and a more than fivefold decrease in plasma insulin. Mitochondrial length, glucose-induced polarization, ATP synthesis, and cytosolic and mitochondrial Ca2+ increases were all reduced in dKO islets. In contrast, oral glucose tolerance was more modestly affected in βMfn1/2-dKO mice, and glucagon-like peptide 1 or glucose-dependent insulinotropic peptide receptor agonists largely corrected defective glucose-stimulated insulin secretion through enhanced EPAC-dependent signaling. Correspondingly, cAMP increases in the cytosol, as measured with an Epac-camps–based sensor, were exaggerated in dKO mice. Mitochondrial fusion and fission cycles are thus essential in the β-cell to maintain normal glucose, but not incretin, sensing. These findings broaden our understanding of the roles of mitofusins in β-cells, the potential contributions of altered mitochondrial dynamics to diabetes development, and the impact of incretins on this process.

中文翻译：

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需要 Mitofusins Mfn1 和 Mfn2 来维持葡萄糖而非肠促胰岛素刺激的 β 细胞连接和胰岛素分泌

线粒体葡萄糖代谢对于刺激胰腺 β 细胞释放胰岛素至关重要。mitofusin 基因表达以及因此的线粒体网络完整性是否对葡萄糖或肠促胰岛素信​​号转导很重要以前尚未探索过。在这里，我们生成了具有 β 细胞选择性、成人限制性敲除 (dKO) 的 mitofusin 基因 Mfn1 和 Mfn2 (βMfn1/2 dKO) 的小鼠。βMfn1/2-dKO 小鼠表现出升高的进食和禁食血糖以及血浆胰岛素降低超过五倍。dKO 胰岛中的线粒体长度、葡萄糖诱导的极化、ATP 合成以及细胞溶质和线粒体 Ca2+ 增加均减少。相比之下，口服葡萄糖耐量在 βMfn1/2-dKO 小鼠中受到的影响更为温和，胰高血糖素样肽 1 或葡萄糖依赖性促胰岛素肽受体激动剂通过增强 EPAC 依赖性信号传导在很大程度上纠正了葡萄糖刺激的胰岛素分泌缺陷。相应地，用基于 Epac-camps 的传感器测量的胞质溶胶中的 cAMP 增加在 dKO 小鼠中被夸大了。因此，线粒体融合和裂变周期对于 β 细胞维持正常葡萄糖而非肠降血糖素感知至关重要。这些发现拓宽了我们对 β 细胞中 mitofusins 的作用、改变的线粒体动力学对糖尿病发展的潜在贡献以及肠促胰岛素对该过程的影响的理解。在 dKO 小鼠中被夸大了。因此，线粒体融合和裂变周期对于 β 细胞维持正常葡萄糖而非肠降血糖素感知至关重要。这些发现拓宽了我们对 β 细胞中 mitofusins 的作用、改变的线粒体动力学对糖尿病发展的潜在贡献以及肠促胰岛素对该过程的影响的理解。在 dKO 小鼠中被夸大。因此，线粒体融合和裂变周期对于 β 细胞维持正常葡萄糖而非肠降血糖素感知至关重要。这些发现拓宽了我们对 mitofusins 在 β 细胞中的作用、改变的线粒体动力学对糖尿病发展的潜在贡献以及肠促胰岛素对该过程的影响的理解。