Beta cells intrinsically sense and limit their secretory activity via mTORC1-RhoA signaling
Summary: Precise regulation of insulin secretion by pancreatic β cells is essential to prevent excessive insulin release. Here, we show that the nutrient sensor mechanistic Target of Rapamycin Complex 1 (mTORC1) is rapidly activated by glucose in β cells via the insulin secretion machinery, position...
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| Format: | Article |
| Language: | English |
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Elsevier
2025-05-01
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| Series: | Cell Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124725004188 |
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| author | Saar Krell Amit Hamburg Ofer Gover Kfir Molakandov Gil Leibowitz Kfir Sharabi Michael D. Walker Aharon Helman |
| author_facet | Saar Krell Amit Hamburg Ofer Gover Kfir Molakandov Gil Leibowitz Kfir Sharabi Michael D. Walker Aharon Helman |
| author_sort | Saar Krell |
| collection | DOAJ |
| description | Summary: Precise regulation of insulin secretion by pancreatic β cells is essential to prevent excessive insulin release. Here, we show that the nutrient sensor mechanistic Target of Rapamycin Complex 1 (mTORC1) is rapidly activated by glucose in β cells via the insulin secretion machinery, positioning mTORC1 as a sensor of β cell activity. Acute pharmacological inhibition of mTORC1 during glucose stimulation enhances insulin release, suggesting that mTORC1 acts as an intrinsic feedback regulator that restrains insulin secretion. Phosphoproteomic profiling reveals that mTORC1 modulates the phosphorylation of proteins involved in actin remodeling and vesicle trafficking, with a prominent role in the RhoA-GTPase pathway. Mechanistically, mTORC1 promotes RhoA activation and F-actin polymerization, limiting vesicle movement and dampening the second phase of insulin secretion. These findings identify a glucose–mTORC1–RhoA signaling axis that forms an autonomous feedback loop to constrain insulin exocytosis, providing insight into how β cells prevent excessive insulin release and maintain metabolic balance. |
| format | Article |
| id | doaj-art-74cd17df0abb45b89fb65f627d5ab9d4 |
| institution | Kabale University |
| issn | 2211-1247 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj-art-74cd17df0abb45b89fb65f627d5ab9d42025-08-20T03:52:52ZengElsevierCell Reports2211-12472025-05-0144511564710.1016/j.celrep.2025.115647Beta cells intrinsically sense and limit their secretory activity via mTORC1-RhoA signalingSaar Krell0Amit Hamburg1Ofer Gover2Kfir Molakandov3Gil Leibowitz4Kfir Sharabi5Michael D. Walker6Aharon Helman7Department of Biochemistry, Food Science and Nutrition, Robert H. Smith Faculty of Agriculture, Food and Environment, Hebrew University of Jerusalem, Rehovot, Israel; Corresponding authorDepartment of Biochemistry, Food Science and Nutrition, Robert H. Smith Faculty of Agriculture, Food and Environment, Hebrew University of Jerusalem, Rehovot, IsraelDepartment of Biochemistry, Food Science and Nutrition, Robert H. Smith Faculty of Agriculture, Food and Environment, Hebrew University of Jerusalem, Rehovot, IsraelKadimastem Ltd., Weizmann Science Park, Ness Ziona, IsraelDiabetes Unit, Department of Endocrinology and Metabolism, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, IsraelDepartment of Biochemistry, Food Science and Nutrition, Robert H. Smith Faculty of Agriculture, Food and Environment, Hebrew University of Jerusalem, Rehovot, IsraelDepartment of Biomolecular Sciences, Weizmann Institute of Science, Rehovot, IsraelDepartment of Biochemistry, Food Science and Nutrition, Robert H. Smith Faculty of Agriculture, Food and Environment, Hebrew University of Jerusalem, Rehovot, Israel; Corresponding authorSummary: Precise regulation of insulin secretion by pancreatic β cells is essential to prevent excessive insulin release. Here, we show that the nutrient sensor mechanistic Target of Rapamycin Complex 1 (mTORC1) is rapidly activated by glucose in β cells via the insulin secretion machinery, positioning mTORC1 as a sensor of β cell activity. Acute pharmacological inhibition of mTORC1 during glucose stimulation enhances insulin release, suggesting that mTORC1 acts as an intrinsic feedback regulator that restrains insulin secretion. Phosphoproteomic profiling reveals that mTORC1 modulates the phosphorylation of proteins involved in actin remodeling and vesicle trafficking, with a prominent role in the RhoA-GTPase pathway. Mechanistically, mTORC1 promotes RhoA activation and F-actin polymerization, limiting vesicle movement and dampening the second phase of insulin secretion. These findings identify a glucose–mTORC1–RhoA signaling axis that forms an autonomous feedback loop to constrain insulin exocytosis, providing insight into how β cells prevent excessive insulin release and maintain metabolic balance.http://www.sciencedirect.com/science/article/pii/S2211124725004188CP: MetabolismCP: Molecular biology |
| spellingShingle | Saar Krell Amit Hamburg Ofer Gover Kfir Molakandov Gil Leibowitz Kfir Sharabi Michael D. Walker Aharon Helman Beta cells intrinsically sense and limit their secretory activity via mTORC1-RhoA signaling Cell Reports CP: Metabolism CP: Molecular biology |
| title | Beta cells intrinsically sense and limit their secretory activity via mTORC1-RhoA signaling |
| title_full | Beta cells intrinsically sense and limit their secretory activity via mTORC1-RhoA signaling |
| title_fullStr | Beta cells intrinsically sense and limit their secretory activity via mTORC1-RhoA signaling |
| title_full_unstemmed | Beta cells intrinsically sense and limit their secretory activity via mTORC1-RhoA signaling |
| title_short | Beta cells intrinsically sense and limit their secretory activity via mTORC1-RhoA signaling |
| title_sort | beta cells intrinsically sense and limit their secretory activity via mtorc1 rhoa signaling |
| topic | CP: Metabolism CP: Molecular biology |
| url | http://www.sciencedirect.com/science/article/pii/S2211124725004188 |
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