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.
| Original language | English |
|---|---|
| Journal | Annales d'Endocrinologie |
| Volume | 65 |
| Issue number | 1 |
| Pages (from-to) | 43-8 |
| Number of pages | 6 |
| ISSN | 0003-4266 |
| Publication status | Published - Feb 2004 |
Keywords
- Animals
- Diabetes Mellitus, Type 1
- Diabetes Mellitus, Type 2
- Homeostasis
- Humans
- Insulin
- Insulin Receptor Substrate Proteins
- Insulin Resistance
- Phosphoproteins
- Phosphorylation
- Phosphoserine
- Receptor, Insulin
- Signal Transduction
