Fatty acid-induced insulin resistance: role of insulin receptor substrate 1 serine phosphorylation in the retroregulation of insulin signalling

• Published in: Biochemical Society transactions Vol. 31; no. Pt 6; p. 1152
• Main Authors: Le Marchand-Brustel, Y, Gual, P, Grémeaux, T, Gonzalez, T, Barrès, R, Tanti, J-F
• Format: Journal Article
• Language: English
• Published: England 01-12-2003
• Subjects: Animals; Fatty Acids - physiology; Glucose - metabolism; Insulin - metabolism; Insulin Receptor Substrate Proteins; Insulin Resistance; Osmotic Pressure; Phosphoproteins - chemistry; Phosphoproteins - metabolism; Serine - metabolism; Signal Transduction; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 0300-5127
• DOI: 10.1042/bst0311152

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 alpha, hyperinsulinaemia and cellular stress, increase the serine phosphorylation of IRS-1 and identified Ser(307) as one of the phosphorylated sites. Moreover, several kinases able to phosphorylate this serine residue have been identified. These exciting results suggest that Ser(307) 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.