TRPC3 Regulates Islet Beta‐Cell Insulin Secretion
Abstract Insulin release is tightly controlled by glucose‐stimulated calcium (GSCa) through hitherto equivocal pathways. This study investigates TRPC3, a non‐selective cation channel, as a critical regulator of insulin secretion and glucose control. TRPC3's involvement in glucose‐stimulated ins...
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| Format: | Article |
| Language: | English |
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Wiley
2023-02-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202204846 |
| _version_ | 1797895104581599232 |
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| author | Gaëlle Rached Youakim Saliba Dina Maddah Joelle Hajal Viviane Smayra Jules‐Joel Bakhos Klaus Groschner Lutz Birnbaumer Nassim Fares |
| author_facet | Gaëlle Rached Youakim Saliba Dina Maddah Joelle Hajal Viviane Smayra Jules‐Joel Bakhos Klaus Groschner Lutz Birnbaumer Nassim Fares |
| author_sort | Gaëlle Rached |
| collection | DOAJ |
| description | Abstract Insulin release is tightly controlled by glucose‐stimulated calcium (GSCa) through hitherto equivocal pathways. This study investigates TRPC3, a non‐selective cation channel, as a critical regulator of insulin secretion and glucose control. TRPC3's involvement in glucose‐stimulated insulin secretion (GSIS) is studied in human and animal islets. TRPC3‐dependent in vivo insulin secretion is investigated using pharmacological tools and Trpc3−/− mice. TRPC3's involvement in islet glucose uptake and GSCa is explored using fluorescent glucose analogue 2‐[N‐(7‐nitrobenz‐2‐oxa‐1,3‐diazol‐4‐yl) amino]‐2‐deoxy‐D‐glucose and calcium imaging. TRPC3 modulation by a small‐molecule activator, GSK1702934A, is evaluated in type 2 diabetic mice. TRPC3 is functionally expressed in human and mouse islet beta cells. TRPC3‐controlled insulin secretion is KATP‐independent and primarily mediated by diacylglycerol channel regulation of the cytosolic calcium oscillations following glucose stimulation. Conversely, glucose uptake in islets is independent of TRPC3. TRPC3 pharmacologic inhibition and knockout in mice lead to defective insulin secretion and glucose intolerance. Subsequently, TRPC3 activation through targeted small‐molecule enhances insulin secretion and alleviates diabetes hallmarks in animals. This study imputes a function for TRPC3 at the onset of GSIS. These insights strengthen one's knowledge of insulin secretion physiology and set forth the TRPC3 channel as an appealing candidate for drug development in the treatment of diabetes. |
| first_indexed | 2024-04-10T07:21:12Z |
| format | Article |
| id | doaj.art-d2562867f7e34aa88d88b57525e7fc05 |
| institution | Directory Open Access Journal |
| issn | 2198-3844 |
| language | English |
| last_indexed | 2024-04-10T07:21:12Z |
| publishDate | 2023-02-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj.art-d2562867f7e34aa88d88b57525e7fc052023-02-24T12:27:40ZengWileyAdvanced Science2198-38442023-02-01106n/an/a10.1002/advs.202204846TRPC3 Regulates Islet Beta‐Cell Insulin SecretionGaëlle Rached0Youakim Saliba1Dina Maddah2Joelle Hajal3Viviane Smayra4Jules‐Joel Bakhos5Klaus Groschner6Lutz Birnbaumer7Nassim Fares8Physiology and Pathophysiology Research Laboratory Pole of Technology and Health Faculty of Medicine Saint Joseph University of Beirut POBox. 17‐5208 ‐ Mar Mikhaël Beirut 1104 2020 LebanonPhysiology and Pathophysiology Research Laboratory Pole of Technology and Health Faculty of Medicine Saint Joseph University of Beirut POBox. 17‐5208 ‐ Mar Mikhaël Beirut 1104 2020 LebanonPhysiology and Pathophysiology Research Laboratory Pole of Technology and Health Faculty of Medicine Saint Joseph University of Beirut POBox. 17‐5208 ‐ Mar Mikhaël Beirut 1104 2020 LebanonPhysiology and Pathophysiology Research Laboratory Pole of Technology and Health Faculty of Medicine Saint Joseph University of Beirut POBox. 17‐5208 ‐ Mar Mikhaël Beirut 1104 2020 LebanonFaculty of Medicine Saint Joseph University Saint Joseph University of Beirut POBox. 17‐5208 ‐ Mar Mikhaël Beirut 1104 2020 LebanonPhysiology and Pathophysiology Research Laboratory Pole of Technology and Health Faculty of Medicine Saint Joseph University of Beirut POBox. 17‐5208 ‐ Mar Mikhaël Beirut 1104 2020 LebanonGottfried‐Schatz‐Research‐Centre‐Biophysics Medical University of Graz Graz 8010 AustriaSchool of Medical Sciences Institute of Biomedical Research (BIOMED) Catholic University of Argentina Buenos Aires C1107AAZ ArgentinaPhysiology and Pathophysiology Research Laboratory Pole of Technology and Health Faculty of Medicine Saint Joseph University of Beirut POBox. 17‐5208 ‐ Mar Mikhaël Beirut 1104 2020 LebanonAbstract Insulin release is tightly controlled by glucose‐stimulated calcium (GSCa) through hitherto equivocal pathways. This study investigates TRPC3, a non‐selective cation channel, as a critical regulator of insulin secretion and glucose control. TRPC3's involvement in glucose‐stimulated insulin secretion (GSIS) is studied in human and animal islets. TRPC3‐dependent in vivo insulin secretion is investigated using pharmacological tools and Trpc3−/− mice. TRPC3's involvement in islet glucose uptake and GSCa is explored using fluorescent glucose analogue 2‐[N‐(7‐nitrobenz‐2‐oxa‐1,3‐diazol‐4‐yl) amino]‐2‐deoxy‐D‐glucose and calcium imaging. TRPC3 modulation by a small‐molecule activator, GSK1702934A, is evaluated in type 2 diabetic mice. TRPC3 is functionally expressed in human and mouse islet beta cells. TRPC3‐controlled insulin secretion is KATP‐independent and primarily mediated by diacylglycerol channel regulation of the cytosolic calcium oscillations following glucose stimulation. Conversely, glucose uptake in islets is independent of TRPC3. TRPC3 pharmacologic inhibition and knockout in mice lead to defective insulin secretion and glucose intolerance. Subsequently, TRPC3 activation through targeted small‐molecule enhances insulin secretion and alleviates diabetes hallmarks in animals. This study imputes a function for TRPC3 at the onset of GSIS. These insights strengthen one's knowledge of insulin secretion physiology and set forth the TRPC3 channel as an appealing candidate for drug development in the treatment of diabetes.https://doi.org/10.1002/advs.202204846beta cellscalciumdiabetesinsulinTRPC3 |
| spellingShingle | Gaëlle Rached Youakim Saliba Dina Maddah Joelle Hajal Viviane Smayra Jules‐Joel Bakhos Klaus Groschner Lutz Birnbaumer Nassim Fares TRPC3 Regulates Islet Beta‐Cell Insulin Secretion Advanced Science beta cells calcium diabetes insulin TRPC3 |
| title | TRPC3 Regulates Islet Beta‐Cell Insulin Secretion |
| title_full | TRPC3 Regulates Islet Beta‐Cell Insulin Secretion |
| title_fullStr | TRPC3 Regulates Islet Beta‐Cell Insulin Secretion |
| title_full_unstemmed | TRPC3 Regulates Islet Beta‐Cell Insulin Secretion |
| title_short | TRPC3 Regulates Islet Beta‐Cell Insulin Secretion |
| title_sort | trpc3 regulates islet beta cell insulin secretion |
| topic | beta cells calcium diabetes insulin TRPC3 |
| url | https://doi.org/10.1002/advs.202204846 |
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