Alteration of 11β-hydroxysteroid dehydrogenase type 1 and glucocorticoid receptor by ethanol in rat liver and mouse hepatoma cells.

Alcohol is a potential risk factor of type 2 diabetes, but its underlying mechanism is unclear. To explore this issue, Wistar rats and mouse hepatoma cells (Hepa 1-6) were exposed to ethanol, 8 g·kg(-1) ·d(-1) for 3 months and 100 mM for 48 h, respectively. Glucose and insulin tolerance tests in vivo were performed, and protein levels of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) and glucocorticoid receptor (GR) in liver and Hepa 1-6 cells were measured. Alterations of key enzymes of gluconeogenesis phosphoenolpyruvate carboxykinase (PEPCK) and glucose 6 phosphatase (G6Pase), as well as glycogen synthase kinase 3a (GSK3 α ), were also examined. The results revealed that glucose levels were increased, and insulin sensitivity was impaired accompanied with liver injury in rats exposed to ethanol compared with controls. The 11β-HSD1, GR, PEPCK, G6Pase, and GSK3 α proteins were increased in the liver of rats treated with ethanol compared with controls. Ethanol-exposed Hepa 1-6 cells also showed higher expression of 11β-HSD1, GR, PEPCK, G6Pase, and GSK3 α proteins than control cells. After treatment of Hepa 1-6 cells exposed to ethanol with the GR inhibitor RU486, the expression of 11β-HSD1 and GR was significantly decreased. At the same time the increases in PEPCK, G6Pase, and GSK3 α levels induced by ethanol in Hepa 1-6 cells were also attenuated by RU486. The results indicate that ethanol causes glucose intolerance by increasing hepatic expression of 11β-HSD1 and GR, which leads to increased expression of gluconeogenic and glycogenolytic enzymes.