The DOI matches its Crossref record; 64 of the 66 references it cites were found in a registry or an index.
GLP-1 stimulates insulin secretion by PKC-dependent TRPM4 and TRPM5 activation
Open accessAbstract
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.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“As in mouse islets, glucose and sulfonylureas (618) are true initiators of electrical activity in human β-cells.”
From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [618]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“The fact that removal of extracellular Na+ does not prevent glucose-induced depolarization (549, 618) argues that the current cannot be Na+-dependent.”
From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [618]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“which suggests two-pore channels may not play an important role in glucose-induced electrical activity, at least in mouse β-cells.”
From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [618]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“However, GIIS is little affected in Tpcn1/Tpcn2 double knockout mice (618), which suggests two-pore channels may not play an important role in glucose-induced electrical activity, at least in mouse β-cells.”
From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [618]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“Amino acids (arginine and glycine)(744), neurotransmitters (like adenine nucleotides, GABA and acetylcholine) (89, 92, 347, 568) and hormones (618) can also stimulate electrical activity and insulin release but only in the presence of a ‘permissive’ concentration of glucose.”
From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [618]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Danaei, G., Finucane, M. M., Lu, Y., Singh, G. M., Cowan, M. J., Paciorek, C. J., Lin, J. K., Farzadfar, F., Khang, Y.-H., Stevens, G. A., et al. (2011) · The Lancet · doi:10.1016/s0140-6736(11)60679-x · Cited by 3,568
The Physiology of Glucagon-like Peptide 1
Holst, J. J. (2007) · Physiological Reviews · doi:10.1152/physrev.00034.2006 · Cited by 3,371
Automated Method for Isolation of Human Pancreatic Islets
Ricordi, C., Lacy, P. E., FINKE, E. H., Olack, B. J., & Scharp, D. W. (1988) · Diabetes · doi:10.2337/diab.37.4.413 · Cited by 1,321
Triggering and amplifying pathways of regulation of insulin secretion by glucose.
Henquin, J. C. (2000) · Diabetes · doi:10.2337/diabetes.49.11.1751 · Cited by 1,201
Determinants of the impaired secretion of glucagon-like peptide-1 in type 2 diabetic patients
Toft-Nielsen, M.-B., Damholt, M. B., Madsbad, S., Hilsted, L. M., Hughes, T. E., Michelsen, B. K., & Holst, J. J. (2001) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.86.8.7750 · Cited by 869
Göke, R., Fehmann, H. C., Linn, T., Schmidt, H., Krause, M., Eng, J., & Göke, B. (1993) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)36565-2 · Cited by 837
NAADP mobilizes calcium from acidic organelles through two-pore channels
Calcraft, P. J., Ruas, M., Pan, Z., Cheng, X., Arredouani, A., Hao, X., Tang, J., Rietdorf, K., Teboul, L., Chuang, K.-T., et al. (2009) · Nature · doi:10.1038/nature08030 · Cited by 760
Self-citationKnudsen, L. B., Nielsen, P. F., Huusfeldt, P. O., Johansen, N. L., Madsen, K., Pedersen, F. Z., Thøgersen, H., Wilken, M., & Agersø, H. (2000) · Journal of Medicinal Chemistry · doi:10.1021/jm9909645 · Cited by 711
Mechanisms of action of glucagon-like peptide 1 in the pancreas
Doyle, M. E., & Egan, J. M. (2006) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2006.11.007 · Cited by 702
Novel Single Chain cAMP Sensors for Receptor-induced Signal Propagation
Nikolaev, V. O., Bünemann, M., Hein, L., Hannawacker, A., & Lohse, M. J. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.c400302200 · Cited by 688
Self-citation
Cited by
Sorted by citations
Glucagon-like peptide 1 (GLP-1)
Müller, T. D., Finan, B., Bloom, S. R., D'Alessio, D., Drucker, D. J., Flatt, P. R., Fritsche, A., Gribble, F., Grill, H. J., Habener, J. F., et al. (2019) · Molecular Metabolism · doi:10.1016/j.molmet.2019.09.010 · Cited by 1,868
“Membrane depolarization by GLP-1 was mimicked by the PKC activator phorbol myristate acetate (PMA) and was not affected by treatment with either the PKA inhibitor myr-PKI, the KATP channel blocker tolbutamide, or the L-type Ca2þ channel inhibitor isradipine [514].”
BackgroundPancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men
Rorsman, P., & Ashcroft, F. M. (2018) · Physiological Reviews · doi:10.1152/physrev.00008.2017 · Cited by 793
Self-citationRevisiting the Complexity of GLP-1 Action from Sites of Synthesis to Receptor Activation
McLean, B. A., Wong, C. K., Campbell, J. E., Hodson, D. J., Trapp, S., & Drucker, D. J. (2021) · Endocrine Reviews · doi:10.1210/endrev/bnaa032 · Cited by 289
“Activation of GLP-1R by picomolar concentrations of GLP-1 has been demonstrated in mouse and human β-cells (63, 64).”
BackgroundThe Role of Pancreatic Preproglucagon in Glucose Homeostasis in Mice
Chambers, A. P., Sorrell, J. E., Haller, A. M., Roelofs, K. J., Hutch, C. R., Kim, K., Gutiérrez‐Aguilar, R., Li, B., Drucker, D. J., D’Alessio, D. A., et al. (2017) · Cell Metabolism · doi:10.1016/j.cmet.2017.02.008 · Cited by 248
“Moreover, it seems likely that levels of intact GLP-1 achieved in the islet interstitium are sufficient to potentiate glucose-stimulated insulin secretion (Shigeto et al., 2015).”
cAMP signalling in insulin and glucagon secretion
Tengholm, A., & Gylfe, E. (2017) · Diabetes Obesity and Metabolism · doi:10.1111/dom.12993 · Cited by 231
“The GLP-1 receptor also appears to couple via Gαq to stimulate phospholipase C, which generates Ca-mobilizing inositol-1,4,5 trisphosphate (IP3) and protein kinase C (PKC)-activating diacylglycerol.(53) PKC in turn depolarizes the β-cells by activating Na influx through TRPM4 and TRPM5 channels to promote voltage-depe…”
Background
Metadata
- Authors
- Shigeto, M., Ramracheya, R., Tarasov, A. I., Cha, C. Y., Chibalina, M. V., Hastoy, B., Philippaert, K., Reinbothe, T., Rorsman, N., Salehi, A., Sones, W. R., Vergari, E., Weston, C., Gorelik, J., Katsura, M., Nikolaev, V. O., Vennekens, R., Zaccolo, M., Galione, A., Johnson, P. R. V., Kaku, K., Ladds, G., & Rorsman, P.
- Affiliations
- Kawasaki Medical School (JP)
- Churchill Hospital (GB)
- KU Leuven (BE)
- University of Gothenburg (SE)
- University of Warwick (GB)
- Imperial College London (GB)
- Universität Hamburg (DE)
- University of Oxford (GB)
- University of Cambridge (GB)
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2015-11-16
- Volume
- 125
- Issue
- 12
- Pages
- 4714-4728
- ISSN
- 0021-9738 (ISSN-L)
- 1558-8238
- PMC
- PMC4665783
- OpenAlex
- W2178272961
- Cited by
- 189
- References
- 66
- Citations by year
- 2026: 10 · 2025: 18 · 2024: 21 · 2023: 8 · 2022: 15 · 2021: 26 · 2020: 23 · 2019: 14 · 2018: 16 · 2017: 26 · 2016: 10 · 2015: 1
- FWCI
- 17.81
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- University of Hertfordshire Research Archive (University of Hertfordshire) (acceptedVersion)
- University of Hertfordshire Research Archive (University of Hertfordshire) (submittedVersion)
- Lirias (submittedVersion)
- Spiral (Imperial College London) (submittedVersion)
- Apollo (University of Cambridge) (submittedVersion)
- Funders
- Impact Fund
- Wellcome Trust (102828, 084655, 095531/Z/11/Z, 102828/Z/13/Z, 095531)
- British Heart Foundation (RG/12/3/29423)
- Diabetes UK
- University of Warwick
- University of Oxford
- KU Leuven
- Knut och Alice Wallenbergs Stiftelse
- Vetenskapsrådet
- Kawasaki Medical School
- Directorate for Biological Sciences
- Medical Research Council
- Biotechnology and Biological Sciences Research Council (BB/M00015X/1, BB/M00015X/2)
- Japan Society for the Promotion of Science (25460113)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Pancreatic function and diabetes
- Life Sciences › Neuroscience › Sensory Systems › Ion Channels and Receptors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Calcium signaling and nucleotide metabolism
- Keywords
- glucagon-like peptide-1, insulin secretion, glucose-stimulated insulin secretion, pancreatic beta cells, TRPM4, TRPM5, protein kinase C, diacylglycerol, phospholipase C, membrane depolarization, action potential firing, sodium channels, intracellular calcium stores, incretin-based therapy
- MeSH terms
- Insulin Secretion, Animals, Humans, Insulin, Membrane Potentials, Protein Kinase C, Tetradecanoylphorbol Acetate, Ion Transport, Mice, Knockout, TRPM Cation Channels, Insulin-Secreting Cells, Mice, Glucagon-Like Peptide 1
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
