Specific amino acids are now known to acutely and chronically regulate insulin secretion from pancreatic β-cells in vivo and in vitro. Understanding the molecular mechanisms by which amino acids regulate insulin secretion may identify novel targets for future diabetes therapies. Mitochondrial metabolism is crucial for the coupling of amino acid and glucose recognition to the exocytosis of the insulin granules. This is illustrated by in vitro and in vivo observations discussed in the present review. Mitochondria generate ATP, which is the main coupling factor in insulin secretion; however, the subsequent Ca2+ signal in the cytosol is necessary, but not sufficient, for full development of sustained insulin secretion. Hence mitochondria generate ATP and other coupling factors serving as fuel sensors for the control of the exocytotic process. Numerous studies have sought to identify the factors that mediate the amplifying pathway over the Ca2+ signal in nutrient-stimulated insulin secretion. Predominantly, these factors are nucleotides (GTP, ATP, cAMP and NADPH), although metabolites have also been proposed, such as long-chain acyl-CoA derivatives and the key amino acid glutamate. This scenario highlights further the importance of the key enzymes or transporters, glutamate dehydrogenase, the aspartate and alanine aminotransferases and the malate/aspartate shuttle, in the control of insulin secretion. Therefore amino acids may play a direct or indirect (via generation of putative messengers of mitochondrial origin) role in insulin secretion.
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March 2005
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Review Article|
February 18 2005
New insights into amino acid metabolism, β-cell function and diabetes
Philip NEWSHOLME;
*Department of Biochemistry, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin 4, Ireland
Correspondence: Dr Philip Newsholme (email [email protected]).
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Lorraine BRENNAN;
Lorraine BRENNAN
*Department of Biochemistry, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin 4, Ireland
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Blanca RUBI;
Blanca RUBI
†Department of Cell Physiology and Metabolism, University Medical Centre, rue Michel-Servet 1, CH-1211 Geneva 4, Switzerland
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Pierre MAECHLER
Pierre MAECHLER
†Department of Cell Physiology and Metabolism, University Medical Centre, rue Michel-Servet 1, CH-1211 Geneva 4, Switzerland
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Publisher: Portland Press Ltd
Received:
October 05 2004
Revision Received:
November 10 2004
Accepted:
November 15 2004
Accepted Manuscript online:
November 15 2004
Online ISSN: 1470-8736
Print ISSN: 0143-5221
The Biochemical Society
2005
Clin Sci (Lond) (2005) 108 (3): 185–194.
Article history
Received:
October 05 2004
Revision Received:
November 10 2004
Accepted:
November 15 2004
Accepted Manuscript online:
November 15 2004
Citation
Philip NEWSHOLME, Lorraine BRENNAN, Blanca RUBI, Pierre MAECHLER; New insights into amino acid metabolism, β-cell function and diabetes. Clin Sci (Lond) 1 March 2005; 108 (3): 185–194. doi: https://doi.org/10.1042/CS20040290
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