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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 male db/+ and db/db mouse liver tissue. We observed that G6PT ASO treatment of db/db mice markedly reduced hepatic G6PT mRNA and protein levels and substantially diminished the activation of hepatic 11β-HSD1 and H6PDH. Reduction of G6pt expression was correlated with the suppression of both hepatic gluconeogenic enzymes G6Pase and PEPCK and corresponded to the improvement of hyperglycemia and insulin resistance in db/db mice. Addition of G6PT ASO to mouse hepa1-6 cells led to a dose-dependent decrease in 11B-Hsd1 production. Knockdown of G6PT with RNA interference also impaired 11B-Hsd1 expression and showed comparable effects to H6pdh siRNA on silencing of H6pdh and 11B-Hsd1 expression 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.

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