Alteration in insulin action:: role of IRS-1 serine phosphorylation in the retroregulation of insulin signalling

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, TNIalpha hyperinsulinemia and cellular stress, increase the serine phosphorylation of IRS-1 and identified Ser(307/612/632) 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.