Tissue-specific dysregulation of hexose-6-phosphate dehydrogenase and glucose-6-phosphate transporter production in db/db mice as a model of type 2 diabetes.

AIMS/HYPOTHESIS: Tissue-specific amplification of glucocorticoid action through 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) affects the development of the metabolic syndrome. Hexose-6-phosphate dehydrogenase (H6PDH) mediates intracellular NADPH availability for 11β-HSD1 and depends on the glucose-6-phosphate transporter (G6PT). Little is known about the tissue-specific alterations of H6PDH and G6PT and their contributions to local glucocorticoid action in db/db mice.

METHODS

We characterised the role of H6PDH and G6PT in pre-receptor metabolism of glucocorticoids by examining the production of the hepatic 11β-HSD1-H6PDH-G6PT system in db/db mice.

RESULTS

We observed that increased production of hepatic H6PDH in db/db mice was paralleled by upregulation of hepatic G6PT production and responded to elevated circulating levels of corticosterone. Treatment of db/db mice with the glucocorticoid antagonist RU486 markedly reduced production of both H6PDH and 11β-HSD1 and improved hyperglycaemia and insulin resistance. The reduction of H6PDH and 11β-HSD1 production by RU486 was accompanied by RU486-induced suppression of hepatic G6pt (also known as Slc37a4) mRNA. Incubation of mouse primary hepatocytes with corticosterone enhanced G6PT and H6PDH production with corresponding activation of 11β-HSD1 and PEPCK: effects that were blocked by RU486. Knockdown of H6pd by small interfering RNA showed effects comparable with those of RU486 for attenuating the corticosterone-induced H6PDH production and 11ß-HSD1 reductase activity in these intact cells. Addition of the G6PT inhibitor chlorogenic acid to primary hepatocytes suppressed H6PDH production.

CONCLUSIONS/INTERPRETATION: These findings suggest that increased hepatic H6PDH and G6PT production contribute to 11β-HSD1 upregulation of local glucocorticoid action that may be related to the development of type 2 diabetes.