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

Manuel Blandino-Rosano, Joshua O. Scheys, Joao Pedro Werneck-De-Castro, Ruy A. Louzada, Joana Almaça, Gil Leibowitz, Markus A. Rüegg, Michael N. Hall, Ernesto Bernal-Mizrachi*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

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 (β RicKO and iβ RicKO 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 β RicKO 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.

Original languageAmerican English
Pages (from-to)E133-E144
JournalAmerican Journal of Physiology - Endocrinology and Metabolism
Volume323
Issue number2
DOIs
StatePublished - 1 Aug 2022
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2022 American Physiological Society. All rights reserved.

Keywords

  • GLP-1
  • RICTOR
  • actin remodeling
  • insulin secretion
  • mTORC2

Fingerprint

Dive into the research topics of 'Novel roles of mTORC2 in regulation of insulin secretion by actin filament remodeling'. Together they form a unique fingerprint.

Cite this