Fatty acid-induced insulin resistance: role of insulin receptor substrate 1 serine phosphorylation in the retroregulation of insulin signalling
Research output: Contribution to journal › Journal article › Communication
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.
Original language | English |
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Journal | Biochemical Society Transactions |
Volume | 31 |
Issue number | Pt 6 |
Pages (from-to) | 1152-6 |
Number of pages | 5 |
ISSN | 0300-5127 |
DOIs | |
Publication status | Published - Dec 2003 |
- Animals, Fatty Acids, Glucose, Insulin, Insulin Receptor Substrate Proteins, Insulin Resistance, Osmotic Pressure, Phosphoproteins, Serine, Signal Transduction, Tumor Necrosis Factor-alpha
Research areas
ID: 45577474