AIMS/HYPOTHESIS Sodium-glucose cotransporter 2 (SGLT2) inhibitors, which prevent the renal reabsorption of glucose, decrease blood glucose levels in an insulin-independent manner. We previously reported creating a mouse model of systemic inhibition of target receptors for both insulin and IGF-1 by treating animals with OSI-906, a dual insulin/IGF-1 receptor inhibitor, for 7 days. The OSI-906-treated mice exhibited an increased beta cell mass, hepatic steatosis and adipose tissue atrophy, accompanied by hyperglycaemia and hyperinsulinaemia. In the present study, we investigated the effects of an SGLT2 inhibitor, luseogliflozin, on these changes in OSI-906-treated mice. METHODS We treated C57BL/6J male mice either with vehicle, luseogliflozin, OSI-906 or OSI-906 plus luseogliflozin for 7 days, and phenotyping was performed to determine beta cell mass and proliferation. Subsequently, we tested whether serum-derived factors have an effect on beta cell proliferation in genetically engineered beta cells, mouse islets or human islets. RESULTS SGLT2 inhibition with luseogliflozin significantly ameliorated hyperglycaemia, but not hyperinsulinaemia, in the OSI-906-treated mice. Liver steatosis and adipose tissue atrophy induced by OSI-906 were not altered by treatment with luseogliflozin. Beta cell mass and proliferation were further increased by SGLT2 inhibition with luseogliflozin in the OSI-906-treated mice. Luseogliflozin upregulated gene expression related to the forkhead box M1 (FoxM1)/polo-like kinase 1 (PLK1)/centromere protein A (CENP-A) pathway in the islets of OSI-906-treated mice. The increase in beta cell proliferation was recapitulated in a co-culture of Irs2 knockout and Insr/IR knockout (βIRKO) beta cells with serum from both luseogliflozin- and OSI-906-treated mice, but not after SGLT2 inhibition in beta cells. Circulating factors in both luseogliflozin- and OSI-906-treated mice promoted beta cell proliferation in both mouse islets and cadaveric human islets. CONCLUSIONS/INTERPRETATION These results suggest that luseogliflozin can increase beta cell proliferation through the activation of the FoxM1/PLK1/CENP-A pathway via humoral factors that act in an insulin/IGF-1 receptor-independent manner.

中文翻译：

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Luseogliflozin通过激活胰岛素受体和IGF-1受体独立途径的体液因子增加β细胞增殖。

目的/假设：钠葡萄糖共转运蛋白2（SGLT2）抑制剂可防止肾脏对葡萄糖的重吸收，并以不依赖胰岛素​​的方式降低血糖水平。我们以前报道过通过用OSI-906（一种双重胰岛素/ IGF-1受体抑制剂）治疗动物7天来创建对胰岛素和IGF-1靶受体均具有全身抑制作用的小鼠模型。OSI-906处理的小鼠表现出增加的β细胞质量，肝脂肪变性和脂肪组织萎缩，并伴有高血糖和高胰岛素血症。在本研究中，我们研究了SGLT2抑制剂luseogliflozin对OSI-906处理的小鼠中这些变化的影响。方法我们用媒介物，葡糖胺磷，OSI-906或OSI-906加葡糖胺磷对C57BL / 6J雄性小鼠进行了7天的处理，并进行表型测定以确定β细胞量和增殖。随后，我们测试了血清衍生因子是否对基因改造的β细胞，小鼠胰岛或人类胰岛中的β细胞增殖产生影响。结果在OSI-906处理的小鼠中，卢格列净对SGLT2的抑制作用明显改善了高血糖症，但没有改善高胰岛素血症。OSI-906诱导的肝脂肪变性和脂肪组织萎缩未通过luseogliflozin治疗改变。在OSI-906处理的小鼠中，通过葡糖胺净对SGLT2的抑制，β细胞的数量和增殖进一步增加。Luseogliflozin在OSI-906处理的小鼠的胰岛中上调了与叉头盒M1（FoxM1）/ polo样激酶1（PLK1）/着丝粒蛋白A（CENP-A）通路相关的基因表达。在将Irs2敲除和Insr / IR敲除（βIRKO）β细胞与接受luseogliflozin和OSI-906处理的小鼠的血清共培养时，β细胞增殖的增加得以概括，但在SGLT2抑制β细胞后却没有。luseogliflozin和OSI-906处理的小鼠中的循环因子均促进了小鼠胰岛和尸体人胰岛中β细胞的增殖。结论/解释这些结果表明，葡格列净可以通过以胰岛素/ IGF-1受体非依赖性方式起作用的体液因子激活FoxM1 / PLK1 / CENP-A途径来增加β细胞的增殖。luseogliflozin和OSI-906处理的小鼠中的循环因子均促进了小鼠胰岛和尸体人胰岛中β细胞的增殖。结论/解释这些结果表明，葡格列净可以通过以胰岛素/ IGF-1受体非依赖性方式起作用的体液因子激活FoxM1 / PLK1 / CENP-A途径来增加β细胞的增殖。luseogliflozin和OSI-906处理的小鼠中的循环因子均促进了小鼠胰岛和尸体人胰岛中β细胞的增殖。结论/解释这些结果表明，葡格列净可以通过以胰岛素/ IGF-1受体非依赖性方式起作用的体液因子激活FoxM1 / PLK1 / CENP-A途径来增加β细胞的增殖。