Novel roles of mTORC2 in regulation of insulin secretion by actin filament remodeling

Am J Physiol Endocrinol Metab. 2022 Aug 1;323(2):E133-E144. doi: 10.1152/ajpendo.00076.2022. Epub 2022 Jun 20.


Mammalian target of rapamycin (mTOR) kinase is an essential hub where nutrients and growth factors converge to control cellular metabolism. mTOR interacts with different accessory proteins to form complexes 1 and 2 (mTORC), and each complex has different intracellular targets. Although mTORC1's role in β-cells has been extensively studied, less is known about mTORC2's function in β-cells. Here, we show that mice with constitutive and inducible β-cell-specific deletion of RICTOR (βRicKO and iβRicKO mice, respectively) are glucose intolerant due to impaired insulin secretion when glucose is injected intraperitoneally. Decreased insulin secretion in βRicKO islets was caused by abnormal actin polymerization. Interestingly, when glucose was administered orally, no difference in glucose homeostasis and insulin secretion were observed, suggesting that incretins are counteracting the mTORC2 deficiency. Mechanistically, glucagon-like peptide-1 (GLP-1), but not gastric inhibitory polypeptide (GIP), rescued insulin secretion in vivo and in vitro by improving actin polymerization in βRicKO islets. In conclusion, mTORC2 regulates glucose-stimulated insulin secretion by promoting actin filament remodeling.NEW & NOTEWORTHY The current studies uncover a novel mechanism linking mTORC2 signaling to glucose-stimulated insulin secretion by modulation of the actin filaments. This work also underscores the important role of GLP-1 in rescuing defects in insulin secretion by modulating actin polymerization and suggests that this effect is independent of mTORC2 signaling.

Keywords: GLP-1; RICTOR; actin remodeling; insulin secretion; mTORC2.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Actin Cytoskeleton / metabolism
  • Actins* / metabolism
  • Animals
  • Glucagon-Like Peptide 1 / metabolism
  • Glucose / metabolism
  • Glucose / pharmacology
  • Insulin Secretion
  • Insulin* / metabolism
  • Mammals / metabolism
  • Mechanistic Target of Rapamycin Complex 2
  • Mice
  • TOR Serine-Threonine Kinases / metabolism


  • Actins
  • Insulin
  • Glucagon-Like Peptide 1
  • Mechanistic Target of Rapamycin Complex 2
  • TOR Serine-Threonine Kinases
  • Glucose

Associated data

  • figshare/10.6084/m9.figshare.19419896.v2