Glucose-Induced Cyclic AMP Oscillations Regulate Pulsatile Insulin Secretion
Open accessAbstract
Cyclic AMP (cAMP) and Ca(2+) are key regulators of exocytosis in many cells, including insulin-secreting beta cells. Glucose-stimulated insulin secretion from beta cells is pulsatile and involves oscillations of the cytoplasmic Ca(2+) concentration ([Ca(2+)](i)), but little is known about the detailed kinetics of cAMP signaling. Using evanescent-wave fluorescence imaging we found that glucose induces pronounced oscillations of cAMP in the submembrane space of single MIN6 cells and primary mouse beta cells. These oscillations were preceded and enhanced by elevations of [Ca(2+)](i). However, conditions raising cytoplasmic ATP could trigger cAMP elevations without accompanying [Ca(2+)](i) rise, indicating that adenylyl cyclase activity may be controlled also by the substrate concentration. The cAMP oscillations correlated with pulsatile insulin release. Whereas elevation of cAMP enhanced secretion, inhibition of adenylyl cyclases suppressed both cAMP oscillations and pulsatile insulin release. We conclude that cell metabolism directly controls cAMP and that glucose-induced cAMP oscillations regulate the magnitude and kinetics of insulin exocytosis.
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Insulin secretion has been detected in real time using the phosphoinositide biosensor GFP4-Grp1 in conjunction with TIRF microscopy, to measure an increase in plasma membrane PIP3.
“Insulin secretion has also been detected in real time using the phosphoinositide biosensor GFP4-Grp1 in conjunction with TIRF microscopy, to measure an increase in the plasma membrane level of phosphatidylinositol (3,4,5) triphosphate (PIP3) (164).”
From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [164]
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Research works printed but not linked: 4
- [1]1. Abdel-Halim, S.M. ∙ Guenifi, A. ∙ Khan, A. ... Impaired coupling of glucose signal to the exocytotic machinery in diabetic GK rats: a defect ameliorated by cAMP Diabetes. 1996; 45:934-940 Crossref PubMed Google Scholar
- [2]2. Ämmälä, C. ∙ Ashcroft, F.M. ∙ Rorsman, P. Calcium-independent potentiation of insulin release by cyclic AMP in single beta-cells Nature. 1993; 363:356-358 Crossref Scopus (354) PubMed Google Scholar
- [3]3. Berenjian, S. ∙ Akusjärvi, G. Binary AdEasy vector systems designed for Tet-ON or Tet-OFF regulated control of transgene expression Virus Res. 2006; 115:16-23 Crossref Scopus (13) PubMed Google Scholar
- [4]4. Bergsten, P. ∙ Grapengiesser, E. ∙ Gylfe, E. ... Synchronous oscillations of cytoplasmic Ca2+ and insulin release in glucose-stimulated pancreatic islets J. Biol. Chem. 1994; 269:8749-8753
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- Authors
- Dyachok, O., Idevall-Hagren, O., Sågetorp, J., Tian, G., Wuttke, A., Arrieumerlou, C., Akusjärvi, G., Gylfe, E., & Tengholm, A.
- Affiliations
- Uppsala University (SE)
- University of Basel (CH)
- Corresponding author
- Tengholm, Anders
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2008-07
- Volume
- 8
- Issue
- 1
- Pages
- 26-37
- ISSN
- 1550-4131 (ISSN-L)
- OpenAlex
- W2003992236
- Cited by
- 193
- References
- 0
- Citations by year
- 2026: 5 · 2025: 5 · 2024: 6 · 2023: 6 · 2022: 8 · 2021: 9 · 2020: 8 · 2019: 12 · 2018: 7 · 2017: 6 · 2016: 7 · 2015: 12 · 2014: 29 · 2013: 19 · 2012: 20
- FWCI
- 11.48
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Uppsala University Publications (Uppsala University) (submittedVersion, other-oa)
- Funders
- European Foundation for the Study of Diabetes
- Cancerfonden
- Meso Scale Diagnostics
- Vetenskapsrådet
- Stiftelsen Familjen Ernfors Fond
- Novo Nordisk Fonden
- Åke Wiberg Stiftelse
- Harald och Greta Jeanssons Stiftelse
- Topics
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Calcium signaling and nucleotide metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Keywords
- pulsatile insulin secretion, glucose-stimulated insulin secretion, pancreatic beta cells, intracellular calcium, adenylate cyclase, insulin exocytosis, MIN6 cells
- MeSH terms
- Insulin Secretion, Cyclic AMP, Animals, Calcium, Dose-Response Relationship, Drug, Exocytosis, Glucose, Insulin, Kinetics, Microscopy, Fluorescence, Second Messenger Systems, Insulin-Secreting Cells, Mice
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