Cellular mechanisms of insulin resistance: role of stress-regulated serine kinases and insulin receptor substrates (IRS) serine phosphorylation

Curr Opin Pharmacol. 2009 Dec;9(6):753-62. doi: 10.1016/j.coph.2009.07.004. Epub 2009 Aug 13.


Insulin receptor substrates (IRS) serine phosphorylation is a time-controlled physiological feedback mechanism in insulin signaling that is hijacked by metabolic and inflammatory stresses to promote insulin resistance. Kinases, including IKKbeta, JNK, ERK, mTOR, and S6K, activated by the inducers of insulin resistance induce uncontrolled IRS serine phosphorylation. Studies with genetically modified mice reveal that these kinases integrate signals from metabolic and inflammatory stresses in adipose tissue, liver, and hypothalamus leading to peripheral and central insulin resistance. Moreover, IKKbeta/NF-kappaB and JNK1 pathways in myeloid cells represent a core mechanism involved in inflammation linked to obesity. These kinases are thus potential drug targets against insulin resistance and the targeting of the IKKbeta/NF-kappaB or the JNK pathway may evolve into future diabetes medication.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Diabetes Mellitus, Type 2 / drug therapy
  • Drug Delivery Systems / methods
  • Humans
  • I-kappa B Kinase / metabolism
  • Inflammation / physiopathology
  • Insulin Receptor Substrate Proteins / metabolism*
  • Insulin Resistance / genetics
  • Insulin Resistance / physiology*
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Mice
  • Mice, Knockout
  • Models, Biological
  • NF-kappa B / metabolism
  • Phosphorylation / physiology*
  • Protein-Serine-Threonine Kinases / metabolism*
  • Signal Transduction / physiology*
  • TOR Serine-Threonine Kinases


  • Insulin Receptor Substrate Proteins
  • Intracellular Signaling Peptides and Proteins
  • NF-kappa B
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • mTOR protein, mouse
  • Protein-Serine-Threonine Kinases
  • I-kappa B Kinase