Diabetologia:Luseogliflozin通过激活胰岛素受体和IGF-1受体独立通路的体液因子促进细胞增殖

2020-04-12 MedSci原创 MedSci原创

钠-葡萄糖共转运体2(SGLT2)抑制剂可阻止肾脏对葡萄糖的重吸收,以胰岛素依赖性的方式降低血糖水平。

钠-葡萄糖共转运体2(SGLT2)抑制剂可阻止肾脏对葡萄糖的重吸收,以胰岛素依赖性的方式降低血糖水平。我们之前报道了通过用胰岛素/IGF-1双受体抑制剂OSI-906治疗动物7天,建立了一个全身性抑制胰岛素和IGF-1靶向受体的小鼠模型。经OSI-906处理的小鼠表现出β细胞质量增加、肝脏脂肪沉积和脂肪组织萎缩,并伴有高胰岛素血症和高胰岛素血症。在本研究中,我们研究了SGLT2抑制剂luseogliflozin对OSI-906处理的小鼠的这些变化的影响。

研究人员使用vehicle、luseogliflozin、OSI-906或OSI-906 plus luseogliflozin对C57BL/6J雄性小鼠进行了7天的处理,并进行了表型分析,以确定细胞的数量和增殖情况。随后,在基因工程细胞、小鼠胰岛或人类胰岛中测试了血清衍生因子是否对细胞增殖有影响。

在经OSI -906处理的小鼠中,用luseogliflozin抑制SGLT2显著地改善了高血糖症,但没有改善高胰岛素血症。用luseogliflozin治疗小鼠的肝脏脱脂和脂肪组织萎缩没有改变。在OSI-906治疗的小鼠中,用luseogliflozin抑制SGLT2进一步增加了β细胞质量和增殖。Luseogliflozin上调了与M1(FoxM1)/polo样激酶1(PLK1)/centromere蛋白A(CENP-A)通路相关的基因表达。在Irs2敲除和Insr/IR敲除(βIRKO)β细胞与来自luseogliflozin-和OSI-906处理的小鼠的血清共培养中,β细胞增殖的增加被重述,但在β细胞中SGLT2抑制后,β细胞中的SGLT2抑制后,β细胞增殖的增加未得到重复。luseogliflozin-和OSI-906处理的小鼠中的循环因子都促进了小鼠肾小球和尸体人肾小球的β细胞增殖。

这些结果表明,luseogliflozin可以通过激活FoxM1/PLK1/CENP-A途径增加细胞增殖,而这种途径是通过一种与胰岛素/IGF-1受体无关的体液因子来实现的。

原始出处:

Kazuki Tajima, Tomoko Okuyama,Luseogliflozin increases beta cell proliferation through humoral factors that activate an insulin receptor- and IGF-1 receptor-independent pathway

本文系梅斯医学(MedSci)原创编译整理,转载需授权!

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    2020-04-14 晓辰