Dysregulation of CRY1 Promotes Hyperglycemia in Diabetic Mice

Abstract

Abnormally activated hepatic glucose production (HGP) is one of major factors contributing to hyperglycemia in diabetes. Recently, we have reported that cryptochrome (CRY1) plays a key role in hepatic glucose production. Although decreased hepatic CRY1 is closely associated with type 2 diabetes, the underlying mechanisms of dysregulated protein stability of hepatic CRY1 are largely unknown. Here, we demonstrate that upon overnutrition, elevated phosphorylation of CRY1 plays a role in the regulation of hepatic glucose production through proteasomal degradation in liver. Also, we uncover crucial signaling pathways involved in phosphorylation-mediated degradation of hepatic CRY1 protein in diabetic animals. In diabetic animals, increased CRY1 protein by suppressing CRY1 phosphorylation improved upregulated HGP in a CRY1-FOXO1 dependent manner. Collectively, our data suggest that protein stability of CRY1 would be critical to maintain systemic glucose homeostasis.