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Constitutive GLP-1-receptor signaling contributes to basal and glucose-stimulated cAMP formation in β-cells: Constitutive GLP-1 receptor signaling in β-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.
(English)In: Article in journal (Other (popular science, discussion, etc.)) Submitted
National Category
Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:uu:diva-368723OAI: oai:DiVA.org:uu-368723DiVA, id: diva2:1269605
Available from: 2018-12-11 Created: 2018-12-11 Last updated: 2018-12-11
In thesis
1. Studies of cAMP and Ca2+ signaling in pancreatic islet cells
Open this publication in new window or tab >>Studies of cAMP and Ca2+ signaling in pancreatic islet cells
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The blood glucose-lowering and -elevating hormones insulin and glucagon are released from the pancreatic islet β- and α-cells, respectively. The intracellular messengers Ca2+ and cAMP have central roles in controlling the secretion of both hormones, but the underlying mechanisms are incompletely understood. A powerful approach to gain further insight is to study the messengers in individual cells within pancreatic islets, provided that each cell can be identified. To facilitate such studies, adenoviral vectors were generated for expression of fluorescent proteins controlled by the insulin and preproglucagon promoters, as well as the somatostatin and pancreatic polypeptide promoters that identify the other two major islet cell types, δ- and PP-cells. Recordings of cAMP and Ca2+ concentration changes with fluorescent reporters demonstrated that cells expressing identification markers responded as expected to well-known stimuli and modulators of the two messengers. Glucose-induced Ca2+ oscillations in β-cells were found to be synchronized with those in δ-cells, and two subpopulations of α-cells with different Ca2+ regulation by glucose were identified. Mouse and human β-cells responded to the insulinotropic hormones glucagon, GIP and GLP-1 with elevations of cAMP. Most α-cells reacted similarly to GIP, whereas only a subpopulation – larger among human than mouse α-cells - responded to glucagon and GLP-1. The GLP-1-receptor antagonist exendin-(9-39) suppressed both GLP-1- and glucagon-induced cAMP elevations in β-cells. Since exendin-(9-39) did not antagonize glucagon receptors, glucagon apparently activates GLP-1 receptors in β-cells. Even in the absence of glucagon/GLP-1, exendin-(9-39) reduced cAMP increases obtained by glucose stimulation or elevation of Ca2+. This effect was attributable to constitutive GLP-1-receptor activity rather than paracrine effects. Exendin-(9-39) also inhibited glucose-induced insulin release, highlighting the importance of cAMP formation in nutrient-stimulated secretion. Simultaneous recordings of cAMP and Ca2+ showed a complex and variable interrelationship between the messengers and the cAMP precursor ATP in β-cells. Depolarization-induced Ca2+ increases inhibited forskolin-, IBMX- and GLP-1-induced cAMP elevations. This cAMP lowering in part reflected suppression of the Ca2+-sensitive activity of adenylyl cyclases AC5 and 6, but also autocrine signaling induced by Ca2+-triggered exocytosis of insulin and adenine nucleotides, whose receptors activate phosphodiesterases and inhibit adenylyl cyclases, respectively.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2018. p. 53
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1521
Keywords
pancreatic islet, insulin, glucagon, somatostatin, pancreatic polypeptide, exendin-(9-39), GLP-1, GIP, ATP, adenosine, cAMP, Ca2+, β-cell, α-cell, δ-cell, PP-cell
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-368612 (URN)978-91-513-0526-4 (ISBN)
Public defence
2019-02-12, B41, Biomedical Centre, Husargatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Note

Ca2+ in the keywords is Ca2+, please help me to change it. Thanks!

Available from: 2019-01-16 Created: 2018-12-11 Last updated: 2019-01-21

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Shuai, HongyanTengholm, Anders

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