Mitofusins Mfn1 and Mfn2 Are Required to Preserve Glucose- but Not Incretin-Stimulated β-Cell Connectivity and Insulin Secretion

Mitochondrial glucose metabolism is essential for stimulated insulin release from pancreatic beta-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 beta-cell-selective, adult-restricted deletion knock-out (dKO) of the mitofusin genes Mfn1 and Mfn2 (beta Mfn1/2 dKO). beta Mfn1/2-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 beta Mfn1/2-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 beta-cell to maintain normal glucose, but not incretin, sensing. These findings broaden our understanding of the roles of mitofusins in beta-cells, the potential contributions of altered mitochondrial dynamics to diabetes development, and the impact of incretins on this process.

Automated summary

Mitofusin gene expression is essential for maintaining normal glucose metabolism in pancreatic beta-cells, but does not affect incretin signaling. These findings are important for understanding the roles of mitofusins in beta-cells, the potential contributions of altered mitochondrial dynamics to diabetes development, and the impact of incretins on this process.