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.
OBJECTIVE
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
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.
Division of Endocrinology, Metabolism & Molecular Medicine, Charles Drew University of Medicine & Sciences, UCLA School of Medicine, 1731 E 120th St, Los Angeles, CA 90059, USA.
Y
Y
Wang
Y
Y
Nakagawa
L
L
Liu
W
W
Wang
X
X
Ren
A
A
Anghel
K
K
Lutfy
T C
TC
Friedman
Y
Y
Liu
D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D002237:Carbohydrate Dehydrogenases / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009004:Monosaccharide Transport Proteins / Q000235:genetics / Q000378:metabolism*; D016133:Polymerase Chain Reaction
D009004:Monosaccharide Transport Proteins; D002237:Carbohydrate Dehydrogenases; C020552:galactose-6-phosphate dehydrogenase; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1