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Novel roles of mTORC2 in regulation of insulin secretion by actin filament remodeling.
Blandino-Rosano, Manuel; Scheys, Joshua O; Werneck-de-Castro, Joao Pedro; Louzada, Ruy A; Almaça, Joana; Leibowitz, Gil; Rüegg, Markus A; Hall, Michael N; Bernal-Mizrachi, Ernesto.
Afiliación
  • Blandino-Rosano M; Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida.
  • Scheys JO; Medical School, Division of Metabolism, Endocrinology, and Diabetes and Brehm Center for Diabetes Research, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.
  • Werneck-de-Castro JP; Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida.
  • Louzada RA; Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida.
  • Almaça J; Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida.
  • Leibowitz G; Diabetes Unit and Endocrine Service, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
  • Rüegg MA; Biozentrum, University of Basel, Basel, Switzerland.
  • Hall MN; Biozentrum, University of Basel, Basel, Switzerland.
  • Bernal-Mizrachi E; Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida.
Am J Physiol Endocrinol Metab ; 323(2): E133-E144, 2022 08 01.
Article en En | MEDLINE | ID: mdl-35723227
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 ß-cells has been extensively studied, less is known about mTORC2's function in ß-cells. Here, we show that mice with constitutive and inducible ß-cell-specific deletion of RICTOR (ßRicKO and ißRicKO mice, respectively) are glucose intolerant due to impaired insulin secretion when glucose is injected intraperitoneally. Decreased insulin secretion in ßRicKO 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 ßRicKO 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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Actinas / Insulina Límite: Animals Idioma: En Revista: Am J Physiol Endocrinol Metab Asunto de la revista: ENDOCRINOLOGIA / FISIOLOGIA / METABOLISMO Año: 2022 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Actinas / Insulina Límite: Animals Idioma: En Revista: Am J Physiol Endocrinol Metab Asunto de la revista: ENDOCRINOLOGIA / FISIOLOGIA / METABOLISMO Año: 2022 Tipo del documento: Article Pais de publicación: Estados Unidos