Li Lianju, Zou Yaoyu, Shen Chongrong, Chen Na, Tong Muye, Liu Ruixin, Wang Jiqiu, Ning Guang
Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Shanghai, 200025, China.
Heliyon. 2024 Aug 22;10(17):e36726. doi: 10.1016/j.heliyon.2024.e36726. eCollection 2024 Sep 15.
Patients with gain-of-function mutations of Dyrk1b have higher fasting blood glucose (FBG) levels. However, the role of Dyrk1b in glucose metabolism is not fully elucidated. Herein, we found that hepatic Dyrk1b overexpression in mice impaired systemic glucose tolerance and hepatic insulin signaling. Dyrk1b overexpression in vitro attenuated insulin signaling in a kinase activity-dependent manner, and its kinase activity was required for its effect on systemic glucose homeostasis and hepatic insulin signaling in vivo. Dyrk1b ablation improved systemic glucose tolerance and hepatic insulin signaling in mice. Quantitative proteomic analyses showed that Dyrk1b downregulated WW domain-binding protein 2 (Wbp2) protein abundance. Mechanistically, Dyrk1b enhanced Wbp2 ubiquitylation and proteasomal degradation. Restoration of hepatic Wbp2 partially rescued the impaired glucose homeostasis in Dyrk1b overexpression mice. In addition, Dyrk1b inhibition with AZ191 moderately improved systemic glucose homeostasis. Our study uncovers that hepatic Dyrk1b impairs systemic glucose homeostasis via its modulation of Wbp2 expression in a kinase activity-dependent manner.
携带Dyrk1b功能获得性突变的患者空腹血糖（FBG）水平较高。然而，Dyrk1b在葡萄糖代谢中的作用尚未完全阐明。在此，我们发现小鼠肝脏中Dyrk1b的过表达损害了全身葡萄糖耐量和肝脏胰岛素信号传导。体外Dyrk1b过表达以激酶活性依赖的方式减弱胰岛素信号传导，其激酶活性是其对体内全身葡萄糖稳态和肝脏胰岛素信号传导产生影响所必需的。Dyrk1b基因敲除改善了小鼠的全身葡萄糖耐量和肝脏胰岛素信号传导。定量蛋白质组学分析表明，Dyrk1b下调了WW结构域结合蛋白2（Wbp2）的蛋白丰度。从机制上讲，Dyrk1b增强了Wbp2的泛素化和蛋白酶体降解。肝脏Wbp2的恢复部分挽救了Dyrk1b过表达小鼠受损的葡萄糖稳态。此外，用AZ191抑制Dyrk1b可适度改善全身葡萄糖稳态。我们的研究发现，肝脏Dyrk1b通过以激酶活性依赖的方式调节Wbp2表达来损害全身葡萄糖稳态。
