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Glucose‐induced cAMP elevation in β‐cells involves amplification of constitutive and glucagon‐activated GLP‐1 receptor signalling

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Acta Physiologica

Published online on

Abstract

["\nAbstract\n\nAim\ncAMP typically signals downstream of Gs‐coupled receptors and regulates numerous cell functions. In β‐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 β‐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 β‐cells.\n\n\nMethods\nTotal 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 β‐cells. Insulin release from mouse and human islets was also measured with ELISA.\n\n\nResults\nThe 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 β‐cells was paralleled by suppression of insulin secretion.\n\n\nConclusion\nAgonist‐independent and glucagon‐stimulated GLP1R signalling in β‐cells contributes to basal and glucose‐induced cAMP production and insulin secretion.\n\n", "Acta Physiologica, EarlyView. "]