Acute insulin-releasing actions of amino acids have been studied in detail, but comparatively little is known about the β-cell effects of long-term exposure to amino acids. The present study examined the effects of prolonged exposure of β-cells to the metabolizable amino acid L-alanine. Basal insulin release or cellular insulin content were not significantly altered by alanine culture, but acute alanine-induced insulin secretion was suppressed by 74% (P<0.001). Acute stimulation of insulin secretion with glucose, KCl or KIC (2-oxoisocaproic acid) following alanine culture was not affected. Acute alanine exposure evoked strong cellular depolarization after control culture, whereas AUC (area under the curve) analysis revealed significant (P<0.01) suppression of this action after culture with alanine. Compared with control cells, prior exposure to alanine also markedly decreased (P<0.01) the acute elevation of [Ca2+]i (intracellular [Ca2+]) induced by acute alanine exposure. These diminished stimulatory responses were partially restored after 18 h of culture in the absence of alanine, indicating reversible amino-acid-induced desensitization. 13C NMR spectra revealed that alanine culture increased glutamate labelling at position C4 (by 60%; P<0.01), as a result of an increase in the singlet peak, indicating increased flux through pyruvate dehydrogenase. Consistent with this, protein expression of the pyruvate dehydrogenase kinases PDK2 and PDK4 was significantly reduced. This was accompanied by a decrease in cellular ATP (P<0.05), consistent with diminished insulin-releasing actions of this amino acid. Collectively, these results illustrate the phenomenon of β-cell desensitization by amino acids, indicating that prolonged exposure to alanine can induce reversible alterations to metabolic flux, Ca2+ handling and insulin secretion.
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February 2009
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Research Article|
January 15 2009
Prolonged L-alanine exposure induces changes in metabolism, Ca2+ handling and desensitization of insulin secretion in clonal pancreatic β-cells
Neville H. McClenaghan;
Neville H. McClenaghan
*School of Biomedical Sciences, University of Ulster, Coleraine BT52 ISA, U.K.
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Siobhan M. Scullion;
Siobhan M. Scullion
*School of Biomedical Sciences, University of Ulster, Coleraine BT52 ISA, U.K.
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Brian Mion;
Brian Mion
†UCD School of Agriculture, Food Science and Veterinary Medicine, UCD Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland
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Chandralal Hewage;
Chandralal Hewage
‡UCD School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland
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J. Paul G. Malthouse;
J. Paul G. Malthouse
‡UCD School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland
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Peter R. Flatt;
Peter R. Flatt
*School of Biomedical Sciences, University of Ulster, Coleraine BT52 ISA, U.K.
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Philip Newsholme;
Philip Newsholme
‡UCD School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland
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Lorraine Brennan
†UCD School of Agriculture, Food Science and Veterinary Medicine, UCD Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland
Correspondence: Dr Lorraine Brennan (email [email protected]).
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Publisher: Portland Press Ltd
Received:
April 29 2008
Revision Received:
August 13 2008
Accepted:
August 14 2008
Accepted Manuscript online:
August 14 2008
Online ISSN: 1470-8736
Print ISSN: 0143-5221
© The Authors Journal compilation © 2009 Biochemical Society
2009
Clin Sci (Lond) (2009) 116 (4): 341–351.
Article history
Received:
April 29 2008
Revision Received:
August 13 2008
Accepted:
August 14 2008
Accepted Manuscript online:
August 14 2008
Citation
Neville H. McClenaghan, Siobhan M. Scullion, Brian Mion, Chandralal Hewage, J. Paul G. Malthouse, Peter R. Flatt, Philip Newsholme, Lorraine Brennan; Prolonged L-alanine exposure induces changes in metabolism, Ca2+ handling and desensitization of insulin secretion in clonal pancreatic β-cells. Clin Sci (Lond) 1 February 2009; 116 (4): 341–351. doi: https://doi.org/10.1042/CS20080138
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