Insulin receptor substrate 2 expression and involvement in neuronal insulin resistance in diabetic neuropathy

Exp Diabetes Res. 2011:2011:212571. doi: 10.1155/2011/212571. Epub 2011 Jun 15.


Insulin signaling depends on tyrosine phosphorylation of insulin receptor substrates (IRSs) to mediate downstream effects; however, elevated serine phosphorylation of IRS impairs insulin signaling. Here, we investigated IRS protein expression patterns in dorsal root ganglia (DRG) of mice and whether their signaling was affected by diabetes. Both IRS1 and IRS2 are expressed in DRG; however, IRS2 appears to be the prevalent isoform and is expressed by many DRG neuronal subtypes. Phosphorylation of Ser(731)IRS2 was significantly elevated in DRG neurons from type 1 and type 2 diabetic mice. Additionally, Akt activation and neurite outgrowth in response to insulin were significantly decreased in DRG cultures from diabetic ob/ob mice. These results suggest that DRG neurons express IRS proteins that are altered by diabetes similar to other peripheral tissues, and insulin signaling downstream of the insulin receptor may be impaired in sensory neurons and contribute to the pathogenesis of diabetic neuropathy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Diabetes Mellitus, Experimental / chemically induced
  • Diabetes Mellitus, Experimental / complications*
  • Diabetic Neuropathies / metabolism*
  • Diabetic Neuropathies / physiopathology*
  • Disease Models, Animal
  • Ganglia, Spinal / metabolism
  • Insulin / metabolism
  • Insulin / pharmacology
  • Insulin Receptor Substrate Proteins / metabolism*
  • Insulin Resistance / genetics
  • Insulin Resistance / physiology*
  • Leptin / genetics
  • Leptin / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neurites / drug effects
  • Neurons / metabolism*
  • Obesity / genetics
  • Obesity / metabolism
  • Phosphorylation
  • Proto-Oncogene Proteins c-akt / metabolism
  • Signal Transduction / physiology*
  • Streptozocin / adverse effects


  • Insulin
  • Insulin Receptor Substrate Proteins
  • Irs2 protein, mouse
  • Leptin
  • Streptozocin
  • Proto-Oncogene Proteins c-akt