Kim Kyoung Min, Lee Kuy-Sook, Lee Gha Young, Jin Hyunjin, Durrance Eunice Sung, Park Ho Seon, Choi Sung Hee, Park Kyong Soo, Kim Young-Bum, Jang Hak Chul, Lim Soo
Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea.
Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea; Biomedical Research Institute, Seoul National University Bundang Hospital, Seongnam, Republic of Korea.
Mol Cell Endocrinol. 2015 Jul 5;409:1-10. doi: 10.1016/j.mce.2015.03.011. Epub 2015 Mar 20.
Selective inhibition of glycogen synthase kinase-3 (GSK3) has been targeted as a novel therapeutic strategy for diabetes mellitus. We investigated the anti-diabetic efficacy and molecular mechanisms of KICG1338 (2-(4-fluoro-phenyl)-3H-imidazo[4,5-b]pyridine-7-carboxylic acid(4-methyl-pyridin-3-yl)-amide), a GSK3β inhibitor, in three animal models: Otsuka Long-Evans Tokushima Fatty (OLETF) rats, leptin receptors-deficient db/db mice, and diet-induced obese (DIO) mice. Biochemical parameters including glucose tolerance tests and gene expressions associated with glucose metabolism were investigated. Glucose excursion decreased significantly by KICG1338-treated OLETF rats, accompanied by increase in insulin receptor substrate-1 and glucose transporter (GLUT)-4 expressions in muscle and decreased GLUT-2 expression in liver. Glucose-lowering effects were similarly observed in KICG1338-treated db/db and DIO mice. KICG1338 treatment increased adiponectin levels and decreased TNF-α levels. KICG1338 therapy also led to greater β-cell preservation and less hepatic fat infiltration with decreased expressions of genes involved in inflammation and endoplasmic reticulum stress. These data demonstrate anti-diabetic efficacy of KICG1338, a novel GSK3β inhibitor.
糖原合酶激酶-3（GSK3）的选择性抑制已被作为糖尿病的一种新型治疗策略。我们在三种动物模型中研究了GSK3β抑制剂KICG1338（2-（4-氟苯基）-3H-咪唑并[4,5-b]吡啶-7-羧酸（4-甲基吡啶-3-基）酰胺）的抗糖尿病疗效和分子机制：大冢长-艾氏-德岛肥胖（OLETF）大鼠、瘦素受体缺陷的db/db小鼠和饮食诱导肥胖（DIO）小鼠。研究了包括葡萄糖耐量试验在内的生化参数以及与葡萄糖代谢相关的基因表达。KICG1338处理的OLETF大鼠的血糖波动显著降低，同时肌肉中胰岛素受体底物-1和葡萄糖转运蛋白（GLUT）-4的表达增加，肝脏中GLUT-2的表达降低。在KICG1338处理的db/db小鼠和DIO小鼠中也观察到了降糖作用。KICG1338处理增加了脂联素水平，降低了TNF-α水平。KICG1338治疗还导致更好的β细胞保护和更少的肝脏脂肪浸润，炎症和内质网应激相关基因的表达降低。这些数据证明了新型GSK3β抑制剂KICG1338的抗糖尿病疗效。
