GLP-1 stimulates insulin secretion by PKC-dependent TRPM4 and TRPM5 activation
| Autor: | Makoto Shigeto, Manuela Zaccolo, Reshma Ramracheya, Antony Galione, William Sones, Thomas Reinbothe, Benoit Hastoy, Rudi Vennekens, Elisa Vergari, Cathryn Weston, Graham Ladds, Viacheslav O. Nikolaev, Chae Young Cha, Masashi Katsura, Nils J.G. Rorsman, Andrei I. Tarasov, Patrik Rorsman, Paul Johnson, Julia Gorelik, Koenraad Philippaert, Margarita V. Chibalina, Albert Salehi, Kohei Kaku |
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| Přispěvatelé: | Ladds, Graham [0000-0001-7320-9612], Apollo - University of Cambridge Repository |
| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
MOUSE ISLETS
endocrine system medicine.medical_specialty medicine.medical_treatment Immunology TYPE-2 DIABETIC-PATIENTS TRPM Cation Channels Research & Experimental Medicine Biology GLUCOSE Membrane Potentials Mice Tolbutamide Glucagon-Like Peptide 1 Insulin-Secreting Cells Internal medicine Insulin Secretion medicine Animals Humans Insulin Channel blocker PROTEIN-KINASE-C Protein Kinase C Protein kinase C Mice Knockout Science & Technology GLUCAGON-LIKE PEPTIDE-1 Ion Transport Isradipine Pancreatic islets digestive oral and skin physiology Depolarization 11 Medical And Health Sciences General Medicine CATION CHANNEL TRPM4 Insulin oscillation Endocrinology medicine.anatomical_structure Medicine Research & Experimental RAT ISLETS B-CELLS PANCREATIC BETA-CELLS Tetradecanoylphorbol Acetate Life Sciences & Biomedicine hormones hormone substitutes and hormone antagonists ACTION-POTENTIALS medicine.drug |
| Popis: | Strategies aimed at mimicking or enhancing the action of the incretin hormone glucagon-like peptide 1 (GLP-1) therapeutically improve glucose-stimulated insulin secretion (GSIS); however, it is not clear whether GLP-1 directly drives insulin secretion in pancreatic islets. Here, we examined the mechanisms by which GLP-1 stimulates insulin secretion in mouse and human islets. We found that GLP-1 enhances GSIS at a half-maximal effective concentration of 0.4 pM. Moreover, we determined that GLP-1 activates PLC, which increases submembrane diacylglycerol and thereby activates PKC, resulting in membrane depolarization and increased action potential firing and subsequent stimulation of insulin secretion. The depolarizing effect of GLP-1 on electrical activity was mimicked by the PKC activator PMA, occurred without activation of PKA, and persisted in the presence of PKA inhibitors, the KATP channel blocker tolbutamide, and the L-type Ca(2+) channel blocker isradipine; however, depolarization was abolished by lowering extracellular Na(+). The PKC-dependent effect of GLP-1 on membrane potential and electrical activity was mediated by activation of Na(+)-permeable TRPM4 and TRPM5 channels by mobilization of intracellular Ca(2+) from thapsigargin-sensitive Ca(2+) stores. Concordantly, GLP-1 effects were negligible in Trpm4 or Trpm5 KO islets. These data provide important insight into the therapeutic action of GLP-1 and suggest that circulating levels of this hormone directly stimulate insulin secretion by β cells. |
| Databáze: | OpenAIRE |
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