Serine phosphorylation of insulin receptor substrate-1: a novel target for the reversal of insulin resistance

Mol Endocrinol. 2001 Nov;15(11):1864-9. doi: 10.1210/mend.15.11.0725.

Abstract

Insulin resistance, the failure to respond to normal circulating concentrations of insulin, is a common state associated with obesity, aging, and a sedentary lifestyle. Compelling evidence implicates TNFalpha as the cause and link between obesity and insulin resistance. Serine phosphorylation of insulin receptor substrate-1 seems prominent among the mechanisms of TNFalpha-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 TNFalpha and insulin signaling pathways. Selective targeting of the molecular scenery whereby this key phosphorylation occurs/operates represents a rich area for the development of rationally designed new antidiabetic drugs. In relation to efficacy and side effects, this prospect should permit a more precise and perhaps individualized approach to therapeutic intervention, allowing clinicians to focus the attack where the problem lies.

Publication types

  • Review

MeSH terms

  • Animals
  • Drug Design
  • Humans
  • Insulin Receptor Substrate Proteins
  • Insulin Resistance / physiology*
  • Phosphoproteins / metabolism*
  • Phosphorylation
  • Serine / metabolism*
  • Signal Transduction*
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • IRS1 protein, human
  • Insulin Receptor Substrate Proteins
  • Phosphoproteins
  • Tumor Necrosis Factor-alpha
  • Serine