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Submembrane ATP and Ca2+ kinetics in alpha-cells: unexpected signaling for glucagon secretion
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.
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2015 (English)In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 29, no 8, p. 3379-3388Article in journal (Refereed) Published
Abstract [en]

Cytoplasmic ATP and Ca2+ are implicated in current models of glucose's control of glucagon and insulin secretion from pancreatic alpha- and beta-cells, respectively, but little is known about ATP and its relation to Ca2+ in alpha-cells. We therefore expressed the fluorescent ATP biosensor Perceval in mouse pancreatic islets and loaded them with a Ca2+ indicator. With total internal reflection fluorescence microscopy, we recorded subplasma membrane concentrations of Ca2+ and ATP ([Ca2+](pm); [ATP](pm)) in superficial alpha- and beta-cells of intact islets and related signaling to glucagon and insulin secretion by immunoassay. Consistent with ATP's controlling glucagon and insulin secretion during hypo- and hyperglycemia, respectively, the dose-response relationship for glucoseinduced [ATP](pm) generation was left shifted in alpha-cells compared to beta-cells. Both cell types showed [Ca2+](pm) and [ATP](pm) oscillations in opposite phase, probably reflecting energy-consuming Ca2+ transport. Although pulsatile insulin and glucagon release are in opposite phase, [Ca2+](pm) synchronized in the same phase between alpha- and beta-cells. This paradox can be explained by the overriding of Ca2+ stimulation by paracrine inhibition, because somatostatin receptor blockade potently stimulated glucagon release with little effect on Ca2+. The data indicate that an alpha-cell-intrinsic mechanism controls glucagon in hypoglycemia and that paracrine factors shape pulsatile secretion in hyperglycemia.

Place, publisher, year, edition, pages
2015. Vol. 29, no 8, p. 3379-3388
Keywords [en]
oscillations, islet of Langerhans, signal transduction, paracrine
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy) Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:uu:diva-261252DOI: 10.1096/fj.14-265918ISI: 000358796900025PubMedID: 25911612OAI: oai:DiVA.org:uu-261252DiVA, id: diva2:850314
Funder
Swedish Diabetes AssociationSwedish Research CouncilNovo NordiskAvailable from: 2015-09-01 Created: 2015-08-31 Last updated: 2018-07-31Bibliographically approved
In thesis
1. α-Cell signalling in glucose-regulated glucagon secretion
Open this publication in new window or tab >>α-Cell signalling in glucose-regulated glucagon secretion
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Glucagon is a blood glucose-elevating hormone released from α-cells in the islets of Langerhans during hypoglycaemia. Glucagon is critical for glucose homeostasis and inappropriate regulation of its secretion underlies both impaired counter-regulation of hypoglycaemia and chronic hyperglycaemia in diabetes patients. The mechanisms by which glucose controls glucagon secretion are poorly understood, but have been suggested to involve both direct effects of the sugar on α-cells and indirect effects mediated by paracrine factors released within the islet, including insulin and gamma-hydroxybutyrate (GHB) from β-cells, and somatostatin from δ-cells. This thesis addresses the role of the intracellular messengers ATP, Ca2+ and cAMP in glucose-regulated glucagon secretion. Various fluorescence microscopy techniques were used to monitor changes of these messengers in single, dispersed α-cells and those in situ within intact islets, and glucagon secretion from islets was measured with an immunoassay. Glucose induced elevations of α-cell ATP, which were smaller and showed a left-shifted concentration-dependence compared to those in β-cells, consistent with α-cells being less dependent on oxidative metabolism and optimized for sensing hypoglycaemia. α-Cells showed Ca2+ oscillations with little glucose dependence. Surprisingly, these oscillations became synchronized in phase with Ca2+ oscillations in β-cells at high glucose. Since Ca2+ is a main trigger of exocytosis in both cell types, and since insulin and glucagon secretion is pulsatile in opposite phase, the results indicate that factors other than Ca2+ are more important for shaping glucagon secretion. Consistent with a key role of cAMP for the regulation of glucagon release, the concentration of the messenger was relatively high in α-cells at low glucose concentrations, and elevations of glucose suppressed cAMP in parallel with glucagon secretion. This effect was independent of paracrine signalling from insulin and somatostatin. The glucose-induced suppression of glucagon secretion was prevented by cAMP-elevating agents and mimicked by inhibitors of protein kinase A. GHB lacked effects both on Ca2+, cAMP and glucagon secretion from mouse islets, but tended to stimulate glucagon secretion by a somatostatin-receptor-dependent mechanism in human islets. The data indicate that GHB is not an inhibitor of glucagon secretion and that α-cell-intrinsic glucose sensing involves signalling via cAMP and protein kinase A.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2018. p. 49
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1478
Keywords
Islets, glucagon, insulin, somatostatin, ATP, cAMP, Ca2+, GHB, oscillations, α-cell, β-cell, δ-cell
National Category
Cell and Molecular Biology
Research subject
Medical Cell Biology
Identifiers
urn:nbn:se:uu:diva-356478 (URN)978-91-513-0387-1 (ISBN)
Public defence
2018-09-13, B21, Biomedical Centre, Husargatan 3, Uppsala, 09:15 (English)
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Supervisors
Available from: 2018-08-21 Created: 2018-07-31 Last updated: 2018-08-28

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Li, JiaYu, QianAhooghalandari, ParvinTengholm, AndersGylfe, Erik

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