Interleukin-1beta-induced insulin resistance in adipocytes through down-regulation of insulin receptor substrate-1 expression

Endocrinology. 2007 Jan;148(1):241-51. doi: 10.1210/en.2006-0692. Epub 2006 Oct 12.


Inflammation is associated with obesity and insulin resistance. Proinflammatory cytokines produced by adipose tissue in obesity could alter insulin signaling and action. Recent studies have shown a relationship between IL-1beta level and metabolic syndrome or type 2 diabetes. However, the ability of IL-1beta to alter insulin signaling and action remains to be explored. We demonstrated that IL-1beta slightly increased Glut 1 translocation and basal glucose uptake in 3T3-L1 adipocytes. Importantly, we found that prolonged IL-1beta treatment reduced the insulin-induced glucose uptake, whereas an acute treatment had no effect. Chronic treatment with IL-1beta slightly decreased the expression of Glut 4 and markedly inhibited its translocation to the plasma membrane in response to insulin. This inhibitory effect was due to a decrease in the amount of insulin receptor substrate (IRS)-1 but not IRS-2 expression in both 3T3-L1 and human adipocytes. The decrease in IRS-1 amount resulted in a reduction in its tyrosine phosphorylation and the alteration of insulin-induced protein kinase B activation and AS160 phosphorylation. Pharmacological inhibition of ERK totally inhibited IL-1beta-induced down-regulation of IRS-1 mRNA. Moreover, IRS-1 protein expression and insulin-induced protein kinase B activation, AS160 phosphorylation, and Glut 4 translocation were partially recovered after treatment with the ERK inhibitor. These results demonstrate that IL-1beta reduces IRS-1 expression at a transcriptional level through a mechanism that is ERK dependent and at a posttranscriptional level independently of ERK activation. By targeting IRS-1, IL-1beta is capable of impairing insulin signaling and action, and could thus participate in concert with other cytokines, in the development of insulin resistance in adipocytes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3-L1 Cells
  • Adipocytes / drug effects*
  • Adipocytes / immunology*
  • Adipocytes / metabolism
  • Animals
  • Down-Regulation / drug effects
  • Down-Regulation / immunology
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • GTPase-Activating Proteins / metabolism
  • Gene Expression / drug effects
  • Gene Expression / immunology
  • Glucose / metabolism
  • Glucose Transporter Type 1 / genetics
  • Glucose Transporter Type 1 / metabolism
  • Glucose Transporter Type 4 / genetics
  • Glucose Transporter Type 4 / metabolism
  • Inflammation / immunology
  • Inflammation / metabolism
  • Insulin Receptor Substrate Proteins
  • Insulin Resistance / immunology*
  • Interleukin-1beta / immunology*
  • Interleukin-1beta / pharmacology*
  • Interleukin-6 / pharmacology
  • MAP Kinase Signaling System / drug effects
  • MAP Kinase Signaling System / immunology
  • Mice
  • Mice, Obese
  • Phosphoproteins / genetics*
  • Phosphorylation / drug effects
  • Proto-Oncogene Proteins c-akt / metabolism
  • Tyrosine / metabolism


  • GTPase-Activating Proteins
  • Glucose Transporter Type 1
  • Glucose Transporter Type 4
  • IRS1 protein, human
  • Insulin Receptor Substrate Proteins
  • Interleukin-1beta
  • Interleukin-6
  • Irs1 protein, mouse
  • Phosphoproteins
  • Slc2a1 protein, mouse
  • Slc2a4 protein, mouse
  • Tbc1d4 protein, mouse
  • Tyrosine
  • Proto-Oncogene Proteins c-akt
  • Extracellular Signal-Regulated MAP Kinases
  • Glucose