Journal
ACTA PHYSIOLOGICA
Volume 231, Issue 4, Pages -Publisher
WILEY
DOI: 10.1111/apha.13611
Keywords
adenylyl cyclase; exendin-(9-39); glucagon; glucagon-like peptide-1; insulin secretion; pancreatic islets
Categories
Funding
- Leona M. and Harry B. Helmsley Charitable Trust
- Vetenskapsradet [325-2012-6778, 2017-00956]
- Diabetesfonden
- European Foundation for the Study of Diabetes
- Novo Nordisk Fonden
- Insamlingsstiftelsen Diabetes Wellness Network Sverige
- Stiftelsen Familjen Ernfors Fond
- Barndiabetesfonden
- Swedish Research Council [2017-00956] Funding Source: Swedish Research Council
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The study uncovers the crucial role of GLP1 receptors in glucose-induced cAMP signaling in beta-cells, impacting insulin secretion.
Aim: cAMP typically signals downstream of G(s)-coupled receptors and regulates numerous cell functions. In beta-cells, cAMP amplifies Ca2+-triggered exocytosis of insulin granules. Glucose-induced insulin secretion is associated with Ca2+- and metabolism-dependent increases of the sub-plasma-membrane cAMP concentration ([cAMP](pm)) in beta-cells, but potential links to canonical receptor signalling are unclear. The aim of this study was to clarify the role of glucagon-like peptide-1 receptors (GLP1Rs) for glucose-induced cAMP signalling in beta-cells. Methods: Total internal reflection microscopy and fluorescent reporters were used to monitor changes in cAMP, Ca2+ and ATP concentrations as well as insulin secretion in MIN6 cells and mouse and human beta-cells. Insulin release from mouse and human islets was also measured with ELISA. Results: The GLP1R antagonist exendin-(9-39) (ex-9) prevented both GLP1- and glucagon-induced elevations of [cAMP](pm), consistent with GLP1Rs being involved in the action of glucagon. This conclusion was supported by lack of unspecific effects of the antagonist in a reporter cell-line. Ex-9 also suppressed IBMX- and glucose-induced [cAMP](pm) elevations. Depolarization with K+ triggered Ca2+-dependent [cAMP](pm) elevation, an effect that was amplified by high glucose. Ex-9 inhibited both the Ca2+ and glucose-metabolism-dependent actions on [cAMP](pm). The drug remained effective after minimizing paracrine signalling by dispersing the islets and it reduced basal [cAMP](pm) in a cell-line heterologously expressing GLP1Rs, indicating that there is constitutive GLP1R signalling. The ex-9-induced reduction of [cAMP](pm) in glucose-stimulated beta-cells was paralleled by suppression of insulin secretion. Conclusion: Agonist-independent and glucagon-stimulated GLP1R signalling in beta-cells contributes to basal and glucose-induced cAMP production and insulin secretion.
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