Specific reduction of G6PT may contribute to downregulation of hepatic 11β-HSD1 in diabetic mice

Abstract

Pre-receptor activation of glucocorticoids via 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1 (HSD11B1)) has been identified as an important mediator of the metabolic syndrome. Hexose-6-phosphate dehydrogenase (H6PDH) mediates 11β-HSD1 amplifying tissue glucocorticoid production by driving intracellular NADPH exposure to 11β-HSD1 and requires glucose-6-phosphate transporter (G6PT (SLC37A4)) to maintain its activity. However, the potential effects of G6PT on tissue glucocorticoid production in type 2 diabetes and obesity have not yet been defined. Here, we evaluated the possible role of G6PT antisense oligonucleotides (G6PT ASO) in the pre-receptor metabolism of glucocorticoids as related to glucose homeostasis and insulin tolerance by examining the production of 11β-HSD1 and H6PDH in both maledb/+anddb/dbmouse liver tissue. We observed that G6PT ASO treatment ofdb/dbmice markedly reduced hepatic G6PT mRNA and protein levels and substantially diminished the activation of hepatic 11β-HSD1 and H6PDH. Reduction ofG6ptexpression was correlated with the suppression of both hepatic gluconeogenic enzymes G6Pase and PEPCK and corresponded to the improvement of hyperglycemia and insulin resistance indb/dbmice. Addition of G6PT ASO to mouse hepa1–6 cells led to a dose-dependent decrease in11B-Hsd1production. Knockdown of G6PT with RNA interference also impaired11B-Hsd1expression and showed comparable effects toH6pdhsiRNA on silencing ofH6pdhand11B-Hsd1expression in these intact cells. These findings suggest that G6PT plays an important role in the modulation of pre-receptor activation of glucocorticoids and provides new insights into the role of G6PT in the development of type 2 diabetes.