Imatinib mesylate reduces endoplasmic reticulum stress and induces remission of diabetes in db/db mice.
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.
Han
Myoung Sook
MS
Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
Chung
Kun Wook
KW
Cheon
Hyae Gyeong
HG
Rhee
Sang Dal
SD
Yoon
Chang-Hwan
CH
Lee
Moon-Kyu
MK
Kim
Kwang-Won
KW
Lee
Myung-Shik
MS
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
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