Imatinib mesylate reduces endoplasmic reticulum stress and induces remission of diabetes in db/db mice.
Imatinib mesylate reduces endoplasmic reticulum stress and induces remission of diabetes in db/db mice.
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DOI：
10.2337/db08-0080
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发表时间：
2009-02
期刊：
影响因子：
7.7
通讯作者：
Lee, Myung-Shik
中科院分区：
文献类型：
--
作者：
Han, Myoung Sook;Chung, Kun Wook;Cheon, Hyae Gyeong;Dal Rhee, Sang;Yoon, Chang-Hwan;Lee, Moon-Kyu;Kim, Kwang-Won;Lee, Myung-Shik
目的：据报道，伊马替尼可促进慢性白血病患者2型糖尿病的消退。然而，伊马替尼改善糖尿病的机制尚不清楚，也不确定伊马替尼在没有白血病等其他混杂疾病的情况下对2型糖尿病本身是否有效。我们研究了伊马替尼对db/db小鼠糖尿病的影响，并探讨了伊马替尼改善血糖控制的可能机制。研究设计与方法：db/db和C57bl/6小鼠每日腹腔注射伊马替尼25 mg/kg，连续4周后进行糖耐量和胰岛素耐量试验。免疫印迹法检测胰岛素信号转导和内质网应激反应。用末端脱氧核苷酸转移酶介导的dUTP缺口末端标记法和胰岛素免疫组织化学相结合的方法检测β细胞质量和凋亡的β细胞数。用HepG2细胞研究伊马替尼的体外作用。结果：伊马替尼可缓解db/db小鼠的糖尿病，改善胰岛素抵抗。伊马替尼可降低db/db小鼠肝脏和脂肪组织内质网应激标志物的表达，如磷酸化PERK、磷酸化eIF2α、TRB3、CHOP和磷酸化c-jun NH2末端激酶。伊马替尼对胰岛素受体底物-1酪氨酸磷酸化和Akt磷酸化均有改善作用。伊马替尼可降低血清转氨酶水平和肝脏甘油三酯含量。伊马替尼可增加胰腺β-细胞质量，同时伴有TUNEL+β-细胞减少和BrdU+β-细胞数量增加。伊马替尼减轻体外培养的肝癌细胞内质网应激。结论：伊马替尼改善db/db小鼠内质网应激和诱导的糖尿病缓解。伊马替尼或相关化合物可作为治疗2型糖尿病和代谢综合征的药物。
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.
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影响因子：
6
作者：
Hagerkvist, Robert;Jansson, Leif;Welsh, Nils
通讯作者：
Welsh, Nils
影响因子：
4.8
作者：
Hagerkvist, Robert;Sandler, Stellan;Welsh, Nils
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Welsh, Nils
肿瘤坏死因子-α的脂肪表达--在与肥胖相关的胰岛素抵抗中的直接作用
影响因子：
56.9
作者：
HOTAMISLIGIL, GS;SHARGILL, NS;SPIEGELMAN, BM
通讯作者：
SPIEGELMAN, BM
影响因子：
82.9
作者：
Kerkela, Risto;Grazette, Luanda;Force, Thomas
通讯作者：
Force, Thomas
影响因子：
6.5
作者：
Bentley, J;Walker, I;Baldwin, SA
通讯作者：
Baldwin, SA