Insulin resistance is a hallmark of diabetes and an unmet clinical need. Insulin inhibits hepatic glucose production and promotes lipogenesis by suppressing FOXO1-dependent activation of G6pase and inhibition of glucokinase, respectively. The tight coupling of these events poses a dual conundrum: mechanistically, as the FOXO1 corepressor of glucokinase is unknown, and clinically, as inhibition of glucose production is predicted to increase lipogenesis. Here, we report that SIN3A is the insulin-sensitive FOXO1 corepressor of glucokinase. Genetic ablation of SIN3A abolishes nutrient regulation of glucokinase without affecting other FOXO1 target genes and lowers glycemia without concurrent steatosis. To extend this work, we executed a small-molecule screen and discovered selective inhibitors of FOXO-dependent glucose production devoid of lipogenic activity in hepatocytes. In addition to identifying a novel mode of insulin action, these data raise the possibility of developing selective modulators of unliganded transcription factors to dial out adverse effects of insulin sensitizers.

中文翻译：

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对FOXO1激活物/阻遏物平衡的选择性抑制可调节肝葡萄糖的处理。

胰岛素抵抗是糖尿病的标志，也是未满足的临床需求。胰岛素分别通过抑制G6pase的FOXO1依赖性激活和葡萄糖激酶的抑制来抑制肝葡萄糖的产生并促进脂肪生成。这些事件的紧密耦合构成了一个双重难题：在机械上，因为葡萄糖激酶的FOXO1核心抑制剂是未知的，而在临床上，由于对葡萄糖生成的抑制预计会增加脂肪生成。在这里，我们报告SIN3A是葡萄糖激酶的胰岛素敏感性FOXO1核心加压因子。SIN3A的基因消融取消了葡萄糖激酶的营养调节，而又不影响其他FOXO1靶基因，并降低了血糖，而没有并发脂肪变性。为了扩展这项工作，我们进行了一个小分子筛选，发现了肝细胞中没有脂肪生成活性的FOXO依赖性葡萄糖生成的选择性抑制剂。除了确定胰岛素作用的新模式外，这些数据还提出了开发未配体转录因子选择性调节剂以消除胰岛素敏化剂不良反应的可能性。