It has been shown that chronic hyperglycemia gradually decreases insulin biosynthesis and secretion which is accompanied by reduced expression of very important insulin gene transcription factors MafA and PDX-1. Such phenomena are well known as β-cell glucose toxicity. It has been shown that the downregulation of MafA and/or PDX-1 expression considerably explains the molecular mechanism for glucose toxicity. However, it remained unknown which molecules can enhance MafA and/or PDX-1 expression levels. In this study, we comprehensively searched for G protein-coupled receptor (GPCR) compounds which can enhance MafA and/or PDX-1 expression levels using a small molecule compound library in pancreatic β-cell line MIN6 cells and islets isolated from nondiabetic C57BL/6 J mice and obese type 2 diabetic C57BL/KsJ-db/db mice. We found that fulvestrant and dexmedetomidine hydrochloride increased MafA, PDX-1, or insulin expression levels in MIN6 cells. We confirmed that fulvestrant and dexmedetomidine hydrochloride increased MafA, PDX-1, or insulin expression levels in islets from nondiabetic mice as well. Furthermore, these reagents more clearly enhanced MafA, PDX-1, or insulin expression levels in islets from obese type 2 diabetic db/db mice in which MafA and PDX-1 expression levels are reduced due to glucose toxicity. In conclusion, fulvestrant and dexmedetomidine hydrochloride increased MafA, PDX-1, or insulin expression levels in MIN6 cells and islets from nondiabetic mice and obese type 2 diabetic db/db mice. To the best of our knowledge, this is the first report showing some molecule which can enhance MafA and/or PDX-1 expression levels. Therefore, although further extensive study is necessary, we think that the information in this study could be, at least in part, useful at some point such as in the development of new antidiabetes medicine based on the molecular mechanism of β-cell glucose toxicity in the future.

中文翻译：

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使用小分子化合物库全面搜索可增强 MafA 和/或 PDX-1 表达水平的 GPCR 化合物

研究表明，慢性高血糖会逐渐降低胰岛素的生物合成和分泌，并伴随着非常重要的胰岛素基因转录因子MafA和PDX-1表达的减少。这种现象被称为β细胞葡萄糖毒性。研究表明，MafA 和/或 PDX-1 表达的下调在很大程度上解释了葡萄糖毒性的分子机制。然而，尚不清楚哪些分子可以增强 MafA 和/或 PDX-1 表达水平。在这项研究中，我们使用小分子化合物库在从非糖尿病 C57BL/ 中分离的胰腺β细胞系 MIN6 细胞和胰岛中全面搜索可以增强 MafA 和/或 PDX-1 表达水平的 G 蛋白偶联受体 (GPCR) 化合物。6 J 小鼠和肥胖 2 型糖尿病 C57BL/KsJ-db/db 小鼠。我们发现氟维司群和盐酸右美托咪定增加了 MIN6 细胞中 MafA、PDX-1 或胰岛素的表达水平。我们证实，氟维司群和盐酸右美托咪定也增加了非糖尿病小鼠胰岛中的 MafA、PDX-1 或胰岛素表达水平。此外，这些试剂更明显地增强了肥胖 2 型糖尿病 db/db 小鼠胰岛中的 MafA、PDX-1 或胰岛素表达水平，其中 MafA 和 PDX-1 表达水平由于葡萄糖毒性而降低。总之，氟维司群和盐酸右美托咪定增加了非糖尿病小鼠和肥胖 2 型糖尿病 db/db 小鼠的 MIN6 细胞和胰岛中 MafA、PDX-1 或胰岛素的表达水平。据我们所知，这是第一份显示某些分子可以增强 MafA 和/或 PDX-1 表达水平的报告。因此，虽然需要进一步广泛的研究，但我们认为本研究中的信息在某些方面可能（至少部分）有用，例如基于β细胞葡萄糖毒性的分子机制开发新的抗糖尿病药物。未来。