Insulin resistance, when combined with impaired insulin secretion, contributes to the development of type 2 diabetes. Insulin resistance is characterized by a decrease in the insulin effect on glucose transport in muscle and adipose tissue. Tyrosine phosphorylation of IRS-1 (insulin receptor substrate 1) and its binding to PI 3-kinase (phosphoinositide 3-kinase) are critical events in the insulin signalling cascade leading to insulin-stimulated glucose transport. Various studies have implicated lipids as a cause of insulin resistance in muscle. Elevated plasma fatty acid concentrations are associated with reduced insulin-stimulated glucose transport activity as a consequence of altered insulin signalling through PI 3-kinase. Modification of IRS-1 by serine phosphorylation could be one of the mechanisms leading to a decrease in IRS-1 tyrosine phosphorylation, PI 3-kinase activity and glucose transport. Recent findings demonstrate that non-esterified fatty acids, as well as other factors such as tumour necrosis factor α, hyperinsulinaemia and cellular stress, increase the serine phosphorylation of IRS-1 and identified Ser307 as one of the phosphorylated sites. Moreover, several kinases able to phosphorylate this serine residue have been identified. These exciting results suggest that Ser307 phosphorylation is a possible hallmark of insulin resistance in biologically insulin-responsive cells or tissues. Identification of IRS-1 kinases could enable rational drug design in order to selectively inhibit the activity of the relevant enzymes and generate a novel class of therapeutic agents for type 2 diabetes.
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December 2003
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Conference Article|
December 01 2003
Fatty acid-induced insulin resistance: role of insulin receptor substrate 1 serine phosphorylation in the retroregulation of insulin signalling
Y. Le Marchand-Brustel;
Y. Le Marchand-Brustel
1
INSERM Unité U 568, Faculty of Medicine, Avenue de Valombrose, 06107 Nice Cedex 02, France
1To whom correspondence should be addressed (e-mail lemarcha@unice.fr).
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P. Gual;
P. Gual
INSERM Unité U 568, Faculty of Medicine, Avenue de Valombrose, 06107 Nice Cedex 02, France
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T. Grémeaux;
T. Grémeaux
INSERM Unité U 568, Faculty of Medicine, Avenue de Valombrose, 06107 Nice Cedex 02, France
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T. Gonzalez;
T. Gonzalez
INSERM Unité U 568, Faculty of Medicine, Avenue de Valombrose, 06107 Nice Cedex 02, France
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R. Barrès;
R. Barrès
INSERM Unité U 568, Faculty of Medicine, Avenue de Valombrose, 06107 Nice Cedex 02, France
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J.-F Tanti
J.-F Tanti
INSERM Unité U 568, Faculty of Medicine, Avenue de Valombrose, 06107 Nice Cedex 02, France
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Publisher: Portland Press Ltd
Online ISSN: 1470-8752
Print ISSN: 0300-5127
© 2003 Biochemical Society
2003
Biochem Soc Trans (2003) 31 (6): 1152–1156.
Citation
Y. Le Marchand-Brustel, P. Gual, T. Grémeaux, T. Gonzalez, R. Barrès, J.-F Tanti; Fatty acid-induced insulin resistance: role of insulin receptor substrate 1 serine phosphorylation in the retroregulation of insulin signalling. Biochem Soc Trans 1 December 2003; 31 (6): 1152–1156. doi: https://doi.org/10.1042/bst0311152
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