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Scientists reveal novel mechanisms underlying regulation of glucose metabolism and glucose homeostasis by miR-451 and glycerol kinase

Type 2 diabetes (T2D) is characterized by insulin resistance and abnormally elevated hepatic glucose production primarily resulted from sustained gluconeogenesis, but the underlying mechanisms are poorly understood. microRNAs are small endogenous non-coding RNAs that regulate gene expression through degradating target mRNAs or repressing mRNA translation. Recent studies suggest that dysregulation of hepatic miRNAs may lead to T2D. microRNA-451 (miR-451) has been reported to be dysregulated in multiple types of cancers and contribute to tumorigenesis, tumor progression, and metastasis by targeting various molecules. Some target molecules and signaling pathways mediated the effects of miR-451 on cancer cell growth and migration, such as 14-3-3 proteins, CAB39, LKB1/AMPK and PI3K/AKT signaling pathways, are critical regulators of hepatic glucose metabolism and therapeutic targets of T2D. Microarray analysis showed that miR-451 levels were elevated in the livers of diabetic and obese animal models. However, it’s not clear if miR-451 could regulate hepatic glucose metabolism and glucose homeostasis by targeting these molecules under physiological conditions and contribute to T2D.

A research group led by Professor Le Yingying from the Institute for Nutritional Sciences, SIBS, Chinese Academy of Sciences, confirmed that expression of miR-451 was increased in the liver tissues of diet-induced and genetically diabetic mice. Through adenovirus mediated gain- and loss-of-function approaches, they demonstrated 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-451. They found 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 was sufficient to inhibit hepatic gluconeogenesis and improve hyperglycemia and glucose intolerance in diabetic mice. Further studies showed 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. Their 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.

This work was published online in Diabetes on August 5, 2016, as a research article entitled “MicroRNA-451 Negatively Regulates Hepatic Glucose Production and Glucose Homeostasis by Targeting Glycerol Kinase Mediated Gluconeogenesis”.

This study was funded by Ministry of Science and Technology of China, the Science and Technology Commission of Shanghai Municipality and Chinese Academy of Sciences.

Author Contact:
Le Yingying, M.D., Ph.D.
Professor and Principle Investigator
Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
Tel: 86-21-54920901
Fax: 86-21-54920291
Email: yyle@sibs.ac.cn


Regulation of hepatic gluconeogenesis and glucose homeostasis by miR-451 and glycerol kinase
Image by Dr. Le’s lab

Article website: http://diabetes.diabetesjournals.org/content/early/2016/08/04/db16-0166

 
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