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GLP-1 stimulates insulin secretion by PKC-dependent Trpm4 and Trpm5 activation

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Publication Date: 2015-11-16

Journal Title: The Journal of Clinical Investigation

Publisher: American Society for Clinical Investigation

Volume: 125

Issue: 12

Pages: 4714-4728

Language: English

Type: Article

Metadata: Show full item record

Citation: Shigeto, M., Ramracheya, R., Cha, C. Y., Chibalina, M. V., Tarasov, A. I., Hastoy, B., Philippaert, K., et al. (2015). GLP-1 stimulates insulin secretion by PKC-dependent Trpm4 and Trpm5 activation. The Journal of Clinical Investigation, 125 (12), 4714-4728.

Description: This is the final version of the article. It was first available from the American Society for Clinical Investigation via

Abstract: 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 K_ATP channel blocker tolbutamide, and the L-type Ca²⁺ 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 Ca²⁺ from thapsigargin-sensitive Ca²⁺ 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.

Sponsorship: We thank David Wiggins for excellent technical assistance. This work was supported by the Medical Research Council, Diabetes UK (to R. Ramracheya ), Oxford Biomedical Research Centre (to A. Tarasov), the Wellcome Trust (Senior Investigator Awards to A. Galione and P. Rorsman), the Warwick Impact Fund (to C. Weston and G. Ladds), the Biotechnology and Biological Sciences Research Council (to G. Ladds), the Knut and Alice Wallenberg Foundation (to P. Rorsman), and the Swedish Research Council (to P. Rorsman). The initial stages of M. Shigeto’s stay in Oxford were supported by a fellowship from Kawasaki Medical School.


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Autor: Shigeto, MakotoRamracheya, ReshmaCha, Chae YoungChibalina, Margarita V.Tarasov, Andrei I.Hastoy, BenoitPhilippaert, KoenraadReinbo



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