在临床上，长期使用类皮质糖（glucocorticoid）治疗可发生严重副反应如糖尿病和脂肪肝。而类固醇（steroid）诱发糖尿病的分子机制仍有不同争议。针对此问题，基础所常永生课题组于2019年6月在J.Clinical Investigation （IF 13.685）发表题为”Dexamethasone-induced Kruppel-like factor 9 expression promotes hepatic gluconeogenesis and hyperglycemia”论文，阐明了地塞米松通过诱导Kruppel样因子9（klf9）的表达而促进了肝脏细胞的糖异生并产生高血糖症的机制：在原代肝细胞中klf9的过表达通过其直接结合到Pgc1a基因的启动子而强烈地刺激该基因表达，因而激活糖异生程序。klf9突变后则地塞米松对细胞葡萄糖输出的效应消失；采用腺病毒载体介导klf9在小鼠肝脏中过表达可显著增加血糖水平和葡萄糖耐受低减；相反，全身性klf9突变的小鼠和肝专一性klf9缺失小鼠呈现饥饿性低血糖症；在糖尿病小鼠模型（ob/ob和db/db）中敲低肝klf9明显地降低饥饿性血糖水平；在小鼠模型中，肝klf9缺陷可减轻由长期地塞米松治疗所诱发的高血糖症。以上结果表明，肝脏klf9的诱导作用和klf9对肝葡萄糖代谢的调节作用可作为类皮质糖治疗诱发糖尿病机制的重要鉴定指标。 

     本文研究始于2010年，集成了本实验室10位研究生的相关工作，期间医科院药物所、协和医院和北大医学部等单位的专家参与协作。

【摘要】Chronic glucocorticoid therapy has serious side effects, including diabetes and fatty liver. However, the molecular mechanisms responsible for steroid-induced diabetes remain largely enigmatic. Here, we show that hepatic Krüppel-like factor 9 (Klf9) gene expression is induced by dexamethasone and fasting. The overexpression of Klf9 in primary hepatocytes strongly stimulated Pgc1a gene expression through direct binding to its promoter, thereby activating the gluconeogenic program. However, Klf9 mutation abolished the stimulatory effect of dexamethasone on cellular glucose output. Adenovirusmediated overexpression of KLF9 in the mouse liver markedly increased blood glucose levels and impaired glucose tolerance. Conversely, both global Klf9-mutant mice and liver-specific Klf9-deleted mice displayed fasting hypoglycemia. Moreover, the knockdown of Klf9 in the liver in diabetic mouse models, including ob/ob and db/db mice, markedly lowered fasting blood glucose levels. Notably, hepatic Klf9 deficiency in mice alleviated hyperglycemia induced by chronic dexamethasone treatment. These results suggest a critical role for KLF9 in the regulation of hepatic glucose metabolism and identify hepatic induction of KLF9 as a mechanism underlying glucocorticoid therapy–induced diabe

 图注：Proposed model of GC induction of hepatic gluconeogenesis and hyperglycemia. GCs are diffused into hepatocytes,where GCs bind to GRs in the cytosol. The GC/GR complex translocates into the nucleus to activate Klf9 gene transcription, which in turn promotes Pgc1a expression, thereby activating the hepatic gluconeogenic program and leading to hyperglycemia.