Excessive hepatic glucose production (HGP) is a key factor promoting hyperglycemia in diabetes. Hepatic cryptochrome 1 (CRY1) plays an important role in maintaining glucose homeostasis by suppressing forkhead box O1 (FOXO1)-mediated HGP. Although downregulation of hepatic CRY1 appears to be associated with increased HGP, the mechanism(s) by which hepatic CRY1 dysregulation confers hyperglycemia in subjects with diabetes is largely unknown. In this study, we demonstrate that a reduction in hepatic CRY1 protein is stimulated by elevated E3 ligase F-box and leucine-rich repeat protein 3 (FBXL3)-dependent proteasomal degradation in diabetic mice. In addition, we found that GSK3β-induced CRY1 phosphorylation potentiates FBXL3-dependent CRY1 degradation in the liver. Accordingly, in diabetic mice, GSK3β inhibitors effectively decreased HGP by facilitating the effect of CRY1-mediated FOXO1 degradation on glucose metabolism. Collectively, these data suggest that tight regulation of hepatic CRY1 protein stability is crucial for maintaining systemic glucose homeostasis.

中文翻译：

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肝脏 GSK3β 依赖性 CRY1 降解导致糖尿病性高血糖。

过量的肝葡萄糖产生（HGP）是促进糖尿病高血糖的关键因素。肝脏隐花色素 1 (CRY1) 通过抑制叉头盒 O1 (FOXO1) 介导的 HGP 在维持葡萄糖稳态中起重要作用。尽管肝脏 CRY1 的下调似乎与 HGP 增加有关，但肝脏 CRY1 失调导致糖尿病患者出现高血糖的机制在很大程度上是未知的。在这项研究中，我们证明了糖尿病小鼠中 E3 连接酶 F-box 和富含亮氨酸重复蛋白 3 (FBXL3) 依赖性蛋白酶体降解的升高会刺激肝脏 CRY1 蛋白的减少。此外，我们发现 GSK3β 诱导的 CRY1 磷酸化增强了肝脏中 FBXL3 依赖性 CRY1 的降解。因此，在糖尿病小鼠中，GSK3β 抑制剂通过促进 CRY1 介导的 FOXO1 降解对葡萄糖代谢的影响而有效降低 HGP。总的来说，这些数据表明对肝脏 CRY1 蛋白稳定性的严格调节对于维持全身葡萄糖稳态至关重要。