Imatinib Mesylate Reduces Endoplasmic Reticulum Stress and Induces Remission of Diabetes indb/dbMice

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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 mechanism9s 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. β-Cell mass and apoptotic β-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-eIF2α, TRB3, CHOP, and phospho–c-Jun NH2-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 β-cell mass was increased by imatinib, accompanied by decreased TUNEL+ β-cell and increased BrdU+ β-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.

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