microRNAs (miRNAs) are a new class of regulatory molecules implicated in type 2 diabetes which is characterized by insulin resistance and hepatic glucose overproduction. Here, we show that microRNA-451 (miR-451) is elevated in the liver tissues of dietary and genetic mouse models of diabetes. Through adenovirus mediated gain- and loss- of function study, we find that miR-451 negatively regulates hepatic gluconeogenesis and blood glucose levels in normal mice, and identify glycerol kinase (Gyk) as a direct target of miR-51. We demonstrate that miR-451 and Gyk regulate hepatic glucose production, glycerol gluconeogenesis axis, and AKT-FOXO1-PEPCK/G6Pase pathway in an opposite manner; Gyk could reverse the effect of miR-451 on hepatic gluconeogenesis and AKT-FOXO1-PEPCK/G6Pase pathway. Moreover, overexpression of miR-451 or knockdown of Gyk in diabetic mice significantly inhibits hepatic gluconeogenesis, alleviates hyperglycemia, and improves glucose tolerance. Further studies show that miR-451 is upregulated by glucose and insulin in hepatocytes, elevation of hepatic miR-451 in diabetic mice may contribute to inhibiting Gyk expression. Our study provides the first evidence that miR-451 and Gyk regulate AKT-FOXO1-PEPCK/G6Pase pathway, and play critical roles in hepatic gluconeogenesis and glucose homeostasis, and identifies miR-451 and Gyk as potential therapeutic targets against hyperglycemia in diabetes.
- Received February 3, 2016.
- Accepted July 18, 2016.
- © 2016 by the American Diabetes Association.