Serine phosphorylation of insulin receptor substrate-1: A novel target forthe reversal of insulin resistance

Insulin resistance, the failure to respond to normal circulating concentrat ions of insulin, is a common state associated with obesity, aging, and a se dentary lifestyle. Compelling evidence implicates TNF alpha as the cause an d link between obesity and insulin resistance. Serine phosphorylation of in sulin receptor substrate-1 seems prominent among the mechanisms of TNF alph a -induced insulin resistance. Recent advances indicate that serine kinases may phosphorylate and thus inhibit the tyrosine phosphorylation of insulin receptor substrate-1, revealing an integration point of TNF alpha and insu lin signaling pathways. Selective targeting of the molecular scenery whereb y this key phosphorylation occurs/operates represents a rich area for the d evelopment of rationally designed new antidiabetic drugs. In relation to ef ficacy and side effects, this prospect should permit a more precise and per haps individualized approach to therapeutic intervention, allowing clinicia ns to focus the attack where the problem lies.