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

Diabetes. 2022 Jul 1;71(7):1472-1489. doi: 10.2337/db21-0800.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • GTP Phosphohydrolases* / genetics
  • Glucose* / metabolism
  • Glucose* / pharmacology
  • Guanine Nucleotide Exchange Factors / metabolism
  • Incretins* / metabolism
  • Incretins* / pharmacology
  • Insulin / metabolism
  • Insulin Secretion
  • Insulin-Secreting Cells* / metabolism
  • Mice
  • Mice, Knockout


  • Guanine Nucleotide Exchange Factors
  • Incretins
  • Insulin
  • GTP Phosphohydrolases
  • Mfn1 protein, mouse
  • Mfn2 protein, mouse
  • Glucose

Associated data

  • figshare/10.2337/figshare.19607232