ArticleThe Journal of clinical investigation2015
GLP-1 stimulates insulin secretion by PKC-dependent TRPM4 and TRPM5 activation.
Article in The Journal of clinical investigation, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 94 papers.
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Who cites it
94 citing papers in PubMed, 182 citations in OpenAlex.
- Allelic variant in the glucagon-like peptide 1 receptor gene associated with greater effect of liraglutide and exenatide on gastric emptying: A pilot pharmacogenetics study.Neurogastroenterology and motility · 2018Trial
- Metabolic state determines the brain and direct islet effects of liraglutide on enhanced insulin secretion.Diabetologia · 2026Article
- Pancreatic α cells are required for nutrient homeostasis by regulating dynamic β cell networks in islets.Science advances · 2026Article
- Evolution in metazoans of the TRPM channel family involves multiple gains and losses of genes and domains.Molecular biology and evolution · 2026Article
- Impaired glucose tolerance and mild diabetes induce β-cell dysfunction in mice.Nature communications · 2026Article
- Enhancement of a nuclear factor of activated T cells (NFAT) reporter for the study of G protein-coupled receptors.Communications biology · 2026Article
- Acute Contractile Effects of Glucagon-like-Peptide-1 Receptor Agonists in the Human Heart.Pharmaceutics · 2026Review
- Structural insights into Phospholipase Cε activity and regulation.The Journal of biological chemistry · 2026Review
- Glycolytic activation of β-cell NaMolecular metabolism · 2026Article
- TRPM4 expression predicts prognosis and modulates the immune microenvironment in pancreatic adenocarcinoma.Scientific reports · 2025Article
- Neurobiological Mechanisms and Therapeutic Potential of Glucagon-like Peptide-1 Receptor Agonists in Binge Eating Disorder: A Narrative Review.International journal of molecular sciences · 2025Review
- GLP-1/GIP/GCG receptor triagonist (IUB447) enhances insulin secretion via GLP-1 receptor and Gαq signalling pathway in mice.Diabetologia · 2025Article
- Receptor activity-modifying protein 3 enhances GLP-1-mediated insulin secretion.The Journal of biological chemistry · 2025Article
- The TRP channels serving as chemical-to-electrical signal converter.Physiological reviews · 2025Review
- GLP-1 and Its Role in Glycogen Production: A Narrative Review.Biomedicines · 2025Review
- Unlocking the multifaceted roles of GLP-1: Physiological functions and therapeutic potential.Toxicology reports · 2025Review
- Pyruvate kinase modulates the link between β-cell fructose metabolism and insulin secretion.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2025Article
- β-Adrenergic Blockers Increase cAMP and Stimulate Insulin Secretion Through a PKA/RYR2/TRPM5 Pathway in Pancreatic β-Cells In Vitro.Pharmacology research & perspectives · 2025Article
- The impact of sulfonylureas on diverse ion channels: an alternative explanation for the antidiabetic actions.Frontiers in cell and developmental biology · 2025Review
- TRPM3, TRPM4, and TRPM5 as thermo-sensitive channels.The journal of physiological sciences : JPS · 2024Review
34 more citing papers are in PubMed but not listed here.
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Authors and funding
23 authors at 9 institutions in 5 countries.
Funding
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 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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.