Altered secretion of insulin as well as glucagon has been implicated in the pathogenesis of Type 2 diabetes (T2D), but the mechanisms controlling glucagon secretion from α-cells largely remain unresolved. Therefore, we studied the regulation of glucagon secretion from αTC1-6 (αTC1 clone 6) cells and compared it with insulin release from INS-1 832/13 cells. We found that INS-1 832/13 and αTC1-6 cells respectively secreted insulin and glucagon concentration-dependently in response to glucose. In contrast, tight coupling of glycolytic and mitochondrial metabolism was observed only in INS-1 832/13 cells. Although glycolytic metabolism was similar in the two cell lines, TCA (tricarboxylic acid) cycle metabolism, respiration and ATP levels were less glucose-responsive in αTC1-6 cells. Inhibition of the malate–aspartate shuttle, using phenyl succinate (PhS), abolished glucose-provoked ATP production and hormone secretion from αTC1-6 but not INS-1 832/13 cells. Blocking the malate–aspartate shuttle increased levels of glycerol 3-phosphate only in INS-1 832/13 cells. Accordingly, relative expression of constituents in the glycerol phosphate shuttle compared with malate–aspartate shuttle was lower in αTC1-6 cells. Our data suggest that the glycerol phosphate shuttle augments the malate–aspartate shuttle in INS-1 832/13 but not αTC1-6 cells. These results were confirmed in mouse islets, where PhS abrogated secretion of glucagon but not insulin. Furthermore, expression of the rate-limiting enzyme of the glycerol phosphate shuttle was higher in sorted primary β- than in α-cells. Thus, suppressed glycerol phosphate shuttle activity in the α-cell may prevent a high rate of glycolysis and consequently glucagon secretion in response to glucose. Accordingly, pyruvate- and lactate-elicited glucagon secretion remains unaffected since their signalling is independent of mitochondrial shuttles.
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Research Article|
May 05 2015
Inhibition of the malate–aspartate shuttle in mouse pancreatic islets abolishes glucagon secretion without affecting insulin secretion
Jelena A. Stamenkovic;
Jelena A. Stamenkovic
*Unit of Molecular Metabolism, Department of Clinical Sciences in Malmö, Lund University Diabetes Centre, CRC, Lund University, Skåne University Hospital, Malmö 205 02, Sweden
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Lotta E. Andersson;
Lotta E. Andersson
*Unit of Molecular Metabolism, Department of Clinical Sciences in Malmö, Lund University Diabetes Centre, CRC, Lund University, Skåne University Hospital, Malmö 205 02, Sweden
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Alice E. Adriaenssens;
Alice E. Adriaenssens
†MRC Metabolic Diseases Unit, Wellcome Trust-MRC Institute of Metabolic Sciences, Addenbrooke's Hospital, Cambridge CB2 0XY, U.K.
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Annika Bagge;
Annika Bagge
*Unit of Molecular Metabolism, Department of Clinical Sciences in Malmö, Lund University Diabetes Centre, CRC, Lund University, Skåne University Hospital, Malmö 205 02, Sweden
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Vladimir V. Sharoyko;
Vladimir V. Sharoyko
*Unit of Molecular Metabolism, Department of Clinical Sciences in Malmö, Lund University Diabetes Centre, CRC, Lund University, Skåne University Hospital, Malmö 205 02, Sweden
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Fiona Gribble;
Fiona Gribble
†MRC Metabolic Diseases Unit, Wellcome Trust-MRC Institute of Metabolic Sciences, Addenbrooke's Hospital, Cambridge CB2 0XY, U.K.
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Frank Reimann;
Frank Reimann
†MRC Metabolic Diseases Unit, Wellcome Trust-MRC Institute of Metabolic Sciences, Addenbrooke's Hospital, Cambridge CB2 0XY, U.K.
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Claes B. Wollheim;
Claes B. Wollheim
#x2021;Department of Clinical Sciences in Malmö, Lund University Diabetes Centre, CRC, Lund University, Skåne University Hospital, Malmö 205 02, Sweden
§Department of Cell Physiology and Metabolism, University Medical Centre, 1 rue Michel-Servet, Geneva 4 1211, Switzerland
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Hindrik Mulder;
Hindrik Mulder
*Unit of Molecular Metabolism, Department of Clinical Sciences in Malmö, Lund University Diabetes Centre, CRC, Lund University, Skåne University Hospital, Malmö 205 02, Sweden
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Peter Spégel
Peter Spégel
1
*Unit of Molecular Metabolism, Department of Clinical Sciences in Malmö, Lund University Diabetes Centre, CRC, Lund University, Skåne University Hospital, Malmö 205 02, Sweden
1To whom correspondence should be addressed (email peter.spegel@med.lu.se).
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Publisher: Portland Press Ltd
Received:
June 23 2014
Revision Received:
February 19 2015
Accepted:
March 03 2015
Accepted Manuscript online:
March 03 2015
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2015 Biochemical Society
2015
Biochem J (2015) 468 (1): 49–63.
Article history
Received:
June 23 2014
Revision Received:
February 19 2015
Accepted:
March 03 2015
Accepted Manuscript online:
March 03 2015
Citation
Jelena A. Stamenkovic, Lotta E. Andersson, Alice E. Adriaenssens, Annika Bagge, Vladimir V. Sharoyko, Fiona Gribble, Frank Reimann, Claes B. Wollheim, Hindrik Mulder, Peter Spégel; Inhibition of the malate–aspartate shuttle in mouse pancreatic islets abolishes glucagon secretion without affecting insulin secretion. Biochem J 15 May 2015; 468 (1): 49–63. doi: https://doi.org/10.1042/BJ20140697
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