title: Imatinib mesylate reduces endoplasmic reticulum stress and induces remission of diabetes in db/db mice.
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.
  
  
  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.
authors.affiliation: Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Myoung Sook
authors.initials: MS
authors.lastname: Han
authors.forename: Kun Wook
authors.initials: KW
authors.lastname: Chung
authors.forename: Hyae Gyeong
authors.initials: HG
authors.lastname: Cheon
authors.forename: Sang Dal
authors.initials: SD
authors.lastname: Rhee
authors.forename: Chang-Hwan
authors.initials: CH
authors.lastname: Yoon
authors.forename: Moon-Kyu
authors.initials: MK
authors.lastname: Lee
authors.forename: Kwang-Won
authors.initials: KW
authors.lastname: Kim
authors.forename: Myung-Shik
authors.initials: MS
authors.lastname: Lee
mesh_terms: D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001549:Benzamides; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism / Q000628:therapy*; D004721:Endoplasmic Reticulum / Q000187:drug effects* / Q000378:metabolism; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D006801:Humans; D000068877:Imatinib Mesylate; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D007333:Insulin Resistance; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D010879:Piperazines / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology*; D012074:Remission Induction; D051742:Transcription Factor CHOP / Q000378:metabolism
chemical_list: D001549:Benzamides; D018797:Cell Cycle Proteins; D015852:Eukaryotic Initiation Factor-2; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; C474830:TRB3 protein, mouse; D051742:Transcription Factor CHOP; D000068877:Imatinib Mesylate; D048031:JNK Mitogen-Activated Protein Kinases