Abstract
Insulin resistance, when combined with impaired insulin secretion, contributes to the development of type 2 diabetes. Insulin resistance is characterised by a decrease in insulin effect on glucose transport in muscle and adipose tIssue. Tyrosine phosphorylation of insulin receptor substrate 1 (IRS-1) and its binding to phosphatidylinositol 3-kinase (PI 3-kinase) are critical events in the insulin signalling cascade leading to insulin-stimulated glucose transport. 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 "diabetogenic" factors such as FFA, TNFalpha, hyperinsulinemia and cellular stress, increase the serine phosphorylation of IRS-1 and identified Ser307/612/632 as phosphorylated sites. Moreover, several kinases able to phosphorylate these serine residues have been identified. These exciting results suggest that serine phosphorylation of IRS-1 is a possible hallmark of insulin resistance in biologically insulin responsive cells or tIssues. Identifying the pathways by which "diabetogenic" factors activate IRS-1 kinases and defining the precise role of serine phosphorylation events in IRS-1 regulation represent important goals. Such studies may enable rational drug design to selectively inhibit the activity of the relevant enzymes and generate a novel class of therapeutic agents for type 2 diabetes.
| Originalsprog | Engelsk |
|---|---|
| Tidsskrift | Annales d'Endocrinologie |
| Vol/bind | 65 |
| Udgave nummer | 1 |
| Sider (fra-til) | 43-8 |
| Antal sider | 6 |
| ISSN | 0003-4266 |
| Status | Udgivet - feb. 2004 |
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