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ATP Dynamics in Pancreatic α- and β-cells
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. (Anders Tengholm and Erik Gylfe)
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Glucose metabolism in pancreatic α- and β-cells is believed to regulate secretion of glucagon and insulin, respectively. In β-cells, ATP links glucose metabolism to electrical activity and insulin secretion. In α-cells, ATP has been attributed various roles in glucose-regulated glucagon release, but the underlying mechanisms are poorly understood. Despite its importance in insulin and glucagon secretion little is known about ATP kinetics in α- and β-cells. In this thesis, the novel fluorescent ATP biosensor Perceval was used to monitor physiologically relevant ATP concentrations with little influence of ADP. Glucose stimulation of β-cells within mouse and human pancreatic islets induced pronounced rise of ATP with superimposed oscillations. Simultaneous measurements of the sub-plasma membrane ATP and Ca2+ concentrations revealed glucose-induced oscillations in opposite phase. ATP increased further and the oscillations ceased when voltage-dependent Ca2+ influx was prevented. In contrast, ATP promptly decreased in response to K+-depolarization-induced elevation of Ca2+. Also mobilization of Ca2+ from intracellular stores lowered ATP, but the negative effect was not due to increased ATP consumption by the sarco/endoplasmic reticulum Ca2+-ATPase. Store-operated Ca2+ entry alone had little effect but markedly elevated ATP when combined with muscarinic receptor activation. When comparing ATP and Ca2+ responses in α- and β-cells within the same islet, glucose-induced ATP generation was much less pronounced and the dose-response relationship left-shifted in the α-cells. At basal glucose, individual α-cells showed Ca2+ and concomitant ATP oscillations in opposite-phase with variable frequency. These oscillations largely cancelled out when averaging data from several α-cells. At high glucose, the Ca2+ and ATP oscillations in α-cells tended to synchronize with the corresponding β-cell oscillations. Since β-cell Ca2+ oscillations drive pulsatile insulin secretion, which is antiparallel to pulsatile glucagon secretion, there seems to be an inverse relationship between changes in α-cell Ca2+ and glucagon release. This paradox is attributed to paracrine inhibition overriding Ca2+ stimulation, since somatostatin receptor blockade potently stimulated glucagon release with little effect on α-cell Ca2+ signalling. The data indicate that complex ATP-Ca2+ interactions in α- and β-cells underlie cell-intrinsic regulation of glucagon and insulin secretion and that paracrine inhibition of glucagon release becomes important in hyperglycaemia.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2014. , 53 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1044
Keyword [en]
ATP, Ca2+, β-cell, α-cell, SERCA, SOCE, muscarinic receptor, insulin secretion, glucagon secretion
National Category
Cell Biology
Research subject
Medical Cell Biology
Identifiers
URN: urn:nbn:se:uu:diva-234345ISBN: 978-91-554-9079-9 (print)OAI: oai:DiVA.org:uu-234345DiVA: diva2:756771
Public defence
2014-12-04, B22, Husargatan 3, BMC, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2014-11-13 Created: 2014-10-16 Last updated: 2015-02-03Bibliographically approved
List of papers
1. Oscillations of sub-membrane ATP in glucose-stimulated beta cells depend on negative feedback from Ca2+
Open this publication in new window or tab >>Oscillations of sub-membrane ATP in glucose-stimulated beta cells depend on negative feedback from Ca2+
2013 (English)In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 56, no 7, 1577-1586 p.Article in journal (Refereed) Published
Abstract [en]

ATP links changes in glucose metabolism to electrical activity, Ca2+ signalling and insulin secretion in pancreatic beta cells. There is evidence that beta cell metabolism oscillates, but little is known about ATP dynamics at the plasma membrane, where regulation of ion channels and exocytosis occur. The sub-plasma-membrane ATP concentration ([ATP](pm)) was recorded in beta cells in intact mouse and human islets using total internal reflection microscopy and the fluorescent reporter Perceval. Glucose dose-dependently increased [ATP](pm) with half-maximal and maximal effects at 5.2 and 9 mmol/l, respectively. Additional elevations of glucose to 11 to 20 mmol/l promoted pronounced [ATP](pm) oscillations that were synchronised between neighbouring beta cells. [ATP](pm) increased further and the oscillations disappeared when voltage-dependent Ca2+ influx was prevented. In contrast, K+-depolarisation induced prompt lowering of [ATP](pm). Simultaneous recordings of [ATP](pm) and the sub-plasma-membrane Ca2+ concentration ([Ca2+](pm)) during the early glucose-induced response revealed that the initial [ATP](pm) elevation preceded, and was temporarily interrupted by the rise of [Ca2+](pm). During subsequent glucose-induced oscillations, the increases of [Ca2+](pm) correlated with lowering of [ATP](pm). In beta cells, glucose promotes pronounced oscillations of [ATP](pm), which depend on negative feedback from Ca2+ (.) The bidirectional interplay between these messengers in the sub-membrane space generates the metabolic and ionic oscillations that underlie pulsatile insulin secretion.

Keyword
ATP, Ca2+, Human islets, Mouse islets, Oscillations, Pancreatic beta cell, Perceval, Plasma membrane
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-203521 (URN)10.1007/s00125-013-2894-0 (DOI)000319881300015 ()
Available from: 2013-07-16 Created: 2013-07-15 Last updated: 2017-12-06Bibliographically approved
2. Dual effects of muscarinic receptor activation on intracellular ATP in pancreatic ß-cells
Open this publication in new window or tab >>Dual effects of muscarinic receptor activation on intracellular ATP in pancreatic ß-cells
(English)Manuscript (preprint) (Other academic)
National Category
Cell and Molecular Biology
Research subject
Medical Cell Biology
Identifiers
urn:nbn:se:uu:diva-234963 (URN)
Available from: 2014-10-27 Created: 2014-10-27 Last updated: 2015-02-03
3. Sub-membrane ATP and Ca2+ kinetics in α-cells – unexpectedsignalling for glucagon secretion
Open this publication in new window or tab >>Sub-membrane ATP and Ca2+ kinetics in α-cells – unexpectedsignalling for glucagon secretion
Show others...
(English)Manuscript (preprint) (Other (popular science, discussion, etc.))
National Category
Cell and Molecular Biology
Research subject
Medical Cell Biology
Identifiers
urn:nbn:se:uu:diva-234826 (URN)
Available from: 2014-10-23 Created: 2014-10-23 Last updated: 2015-02-03

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