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

Blandino-Rosano, Manuel and Scheys, Joshua O. and Werneck-de-Castro, Joao Pedro and Louzada, Ruy A. and Almaça, Joana and Leibowitz, Gil and Rüegg, Markus A. and Hall, Michael N. and Bernal-Mizrachi, Ernesto. (2022) Novel roles of mTORC2 in regulation of insulin secretion by actin filament remodeling. American Journal of Physiology, Endocrinology and Metabolism, 323 (2). E133-E144.

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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 (; βRicKO; and i; βRicKO; 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.
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Growth & Development > Biochemistry (Hall)
05 Faculty of Science > Departement Biozentrum > Neurobiology > Pharmacology/Neurobiology (Rüegg)
UniBasel Contributors:Hall, Michael N. and Rüegg, Markus A.
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:American Physiological Society
ISSN:1522-1555
e-ISSN:1522-1555
Note:Publication type according to Uni Basel Research Database: Journal article
Language:English
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edoc DOI:
Last Modified:30 Nov 2022 09:19
Deposited On:14 Nov 2022 09:04

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