Rapamycin partially prevents insulin resistance induced by chronic insulin treatment

Biochem Biophys Res Commun. 2002 May 10;293(3):1021-7. doi: 10.1016/S0006-291X(02)00333-9.


Chronic insulin exposure induces serine/threonine phosphorylation and degradation of IRS-1 through a rapamycin-sensitive pathway, which results in a down-regulation of insulin action. In this study, to investigate whether rapamycin (an mTOR inhibitor) could prevent insulin resistance induced by hyperinsulinemia, 3T3-L1 adipocytes were incubated chronically in the presence of insulin with or without the addition of rapamycin. Subsequently, the cells were washed and re-stimulated acutely with insulin. Chronic insulin stimulation caused a reduction of GLUT-4 and IRS-1 proteins with a correlated decrease in acute insulin-induced PKB and MAPK phosphorylations as well as a reduction in insulin-stimulated glucose transport. Rapamycin prevented the reduction of IRS-1 protein levels and insulin-induced PKB Ser-473 phosphorylation with a partial normalization of insulin-induced glucose transport. In contrast, rapamycin had no effect on the decrease in insulin-induced MAPK phosphorylation or GLUT-4 protein levels. These results suggest that chronic insulin exposure leads to a down-regulation of PKB and MAPK pathways through different mechanisms in adipocytes.

MeSH terms

  • Adipocytes / drug effects
  • Adipocytes / metabolism*
  • Animals
  • Biological Transport
  • Cell Line
  • Glucose / metabolism
  • Insulin / administration & dosage
  • Insulin / pharmacology*
  • Insulin Antagonists / pharmacology*
  • Insulin Resistance
  • Mitogen-Activated Protein Kinases / metabolism
  • Phosphorylation
  • Phosphoserine / metabolism
  • Phosphothreonine / metabolism
  • Protein-Serine-Threonine Kinases*
  • Proto-Oncogene Proteins / chemistry
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-akt
  • Sirolimus / pharmacology*
  • Time Factors


  • Insulin
  • Insulin Antagonists
  • Proto-Oncogene Proteins
  • Phosphothreonine
  • Phosphoserine
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Mitogen-Activated Protein Kinases
  • Glucose
  • Sirolimus