Imatinib Mesylate Reduces Endoplasmic Reticulum Stress and Induces Remission of Diabetes in db/db Mice
MS Han, KW Chung, HG Cheon, SD Rhee, CH Yoon… - Diabetes, 2009 - Am Diabetes Assoc
MS Han, KW Chung, HG Cheon, SD Rhee, CH Yoon, MK Lee, KW Kim, MS Lee
Diabetes, 2009•Am Diabetes AssocOBJECTIVE—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 …
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 …
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. 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.
Am Diabetes Assoc