Imatinib mesylate reduces endoplasmic reticulum stress and induces remission of diabetes in db/db mice

Diabetes. 2009 Feb;58(2):329-36. doi: 10.2337/db08-0080.

Abstract

Objective: Imatinib has been reported to induce regression of type 2 diabetes in chronic leukemia patients. However, the mechanism of diabetes amelioration by imatinib is unknown, and it is uncertain whether imatinib has effects on type 2 diabetes itself without other confounding diseases like leukemia. We studied the effect of imatinib on diabetes in db/db mice and investigated possible mechanism's underlying improved glycemic control by imatinib.

Research design and methods: Glucose tolerance and insulin tolerance tests were done after daily intraperitoneal injection of 25 mg/kg imatinib into db/db and C57BL/6 mice for 4 weeks. Insulin signaling and endoplasmic reticulum stress responses were studied by Western blotting. beta-Cell mass and apoptotic beta-cell number were determined by combined terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) staining and insulin immunohistochemistry. The in vitro effect of imatinib was studied using HepG2 cells.

Results: Imatinib induced remission of diabetes in db/db mice and amelioration of insulin resistance. Expression of endoplasmic reticulum stress markers in the liver and adipose tissues of db/db mice, such as phospho-PERK, phospho-eIF2alpha, TRB3, CHOP, and phospho-c-Jun NH(2)-terminal kinase, was reduced by imatinib. Insulin receptor substrate-1 tyrosine phosphorylation and Akt phosphorylation after insulin administration were improved by imatinib. Serum aminotransferase levels and hepatic triglyceride contents were decreased by imatinib. Pancreatic beta-cell mass was increased by imatinib, accompanied by decreased TUNEL(+) beta-cell and increased BrdU(+) beta-cell numbers. Imatinib attenuated endoplasmic reticulum stress in hepatoma cells in vitro.

Conclusions: Imatinib ameliorated endoplasmic reticulum stress and induced remission of diabetes in db/db mice. Imatinib or related compounds could be used as therapeutic agents against type 2 diabetes and metabolic syndrome.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipose Tissue / drug effects
  • Adipose Tissue / metabolism
  • Animals
  • Benzamides
  • Cell Cycle Proteins / metabolism
  • Cell Line, Tumor
  • Diabetes Mellitus, Type 2 / metabolism
  • Diabetes Mellitus, Type 2 / therapy*
  • Endoplasmic Reticulum / drug effects*
  • Endoplasmic Reticulum / metabolism
  • Eukaryotic Initiation Factor-2 / metabolism
  • Humans
  • Imatinib Mesylate
  • Immunohistochemistry
  • In Situ Nick-End Labeling
  • Insulin Resistance
  • Insulin-Secreting Cells / drug effects
  • Insulin-Secreting Cells / metabolism
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • Liver / drug effects
  • Liver / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Piperazines / pharmacology*
  • Protein Kinase Inhibitors / pharmacology
  • Pyrimidines / pharmacology*
  • Remission Induction
  • Transcription Factor CHOP / metabolism

Substances

  • Benzamides
  • Cell Cycle Proteins
  • Eukaryotic Initiation Factor-2
  • Piperazines
  • Protein Kinase Inhibitors
  • Pyrimidines
  • TRB3 protein, mouse
  • Transcription Factor CHOP
  • Imatinib Mesylate
  • JNK Mitogen-Activated Protein Kinases