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Glucose controls glucagon secretion by directly modulating cAMP in alpha cells
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.ORCID iD: 0000-0002-8414-2107
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2019 (English)In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 62, no 7, p. 1212-1224Article in journal (Refereed) Published
Abstract [en]

Aims/hypothesis

Glucagon is critical for normal glucose homeostasis and aberrant secretion of the hormone aggravates dysregulated glucose control in diabetes. However, the mechanisms by which glucose controls glucagon secretion from pancreatic alpha cells remain elusive. The aim of this study was to investigate the role of the intracellular messenger cAMP in alpha-cell-intrinsic glucose regulation of glucagon release.

Methods

Subplasmalemmal cAMP and Ca2+ concentrations were recorded in isolated and islet-located alpha cells using fluorescent reporters and total internal reflection microscopy. Glucagon secretion from mouse islets was measured using ELISA.

Results

Glucose induced Ca2+-independent alterations of the subplasmalemmal cAMP concentration in alpha cells that correlated with changes in glucagon release. Glucose-lowering-induced stimulation of glucagon secretion thus corresponded to an elevation in cAMP that was independent of paracrine signalling from insulin or somatostatin. Imposed cAMP elevations stimulated glucagon secretion and abolished inhibition by glucose elevation, while protein kinase A inhibition mimicked glucose suppression of glucagon release.

Conclusions/interpretation

Glucose concentrations in the hypoglycaemic range control glucagon secretion by directly modulating the cAMP concentration in alpha cells independently of paracrine influences. These findings define a novel mechanism for glucose regulation of glucagon release that underlies recovery from hypoglycaemia and may be disturbed in diabetes.

Place, publisher, year, edition, pages
2019. Vol. 62, no 7, p. 1212-1224
Keywords [en]
Ca2+, Cyclic AMP, Glucagon release, Hypoglycaemia, Insulin, Pancreatic alpha cell, Protein kinase A, Somatostatin
National Category
Endocrinology and Diabetes
Identifiers
URN: urn:nbn:se:uu:diva-388762DOI: 10.1007/s00125-019-4857-6ISI: 000471176200012PubMedID: 30953108OAI: oai:DiVA.org:uu-388762DiVA, id: diva2:1342452
Funder
Swedish Research CouncilErnfors FoundationNovo NordiskSwedish Diabetes AssociationEXODIAB - Excellence of Diabetes Research in SwedenAvailable from: 2019-08-13 Created: 2019-08-13 Last updated: 2019-08-14Bibliographically approved

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Yu, QianShuai, HongyanAhooghalandari, ParvinGylfe, ErikTengholm, Anders

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