Journal Article

GLP-1 stimulates insulin secretion by PKC-dependent TRPM4 and TRPM5 activation

Vennekens, Rudi, Ladds, Graham, Rorsman, Patrik, Reinbothe, Thomas, Hastoy, Benoit, Philippaert, Koenraad, Rorsman, Nils, Nikolaev, Viacheslav O., Tarasov, Andrei I., Katsura, Masashi, Zaccolo, Manuela, Salehi, Albert, Kaku, Kohei, Vergari, Elisa, Johnson, Paul R.V., Gorelik, Julia, Weston, Cathryn, Cha, Chae Young, Sones, William R., Chibalina, Margarita V., Ramracheya, Reshma, Shigeto, Makoto, Galione, Antony

2015

Overview

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.

• Publisher: American Society for Clinical Investigation
• Subject: ACTION-POTENTIALS / Animals / B-CELLS / Biomedical research / CATION CHANNEL TRPM4 / Councils / Diabetes / DIABETIC-PATIENTS / Ethics / Experiments / Fysiologi och anatomi / Gastrointestinal hormones / Glucagon-Like Peptide 1 - pharmacology / GLUCAGON-LIKE PEPTIDE-1 / GLUCOSE / Humans / Insulin / Insulin - genetics / Insulin - metabolism / Insulin Secretion / Insulin-Secreting Cells - cytology / Insulin-Secreting Cells - metabolism / Ion Transport - drug effects / Ion Transport - genetics / Medical research / Membrane Potentials - drug effects / Membrane Potentials - genetics / Mice / Mice, Knockout / MOUSE ISLETS / Pancreas / PANCREATIC BETA-CELLS / Physiological aspects / Physiology / Physiology and Anatomy / Properties / Protein Kinase C - genetics / Protein Kinase C - metabolism / PROTEIN-KINASE-C / RAT ISLETS / Rodents / Tetradecanoylphorbol Acetate - pharmacology / TRPM Cation Channels - genetics / TRPM Cation Channels - metabolism / TYPE-2