Dexamethasone-induced hyperglycemia in obese Avy/a (viable yellow) female mice entails preferential induction of a hepatic estrogen sulfotransferase.
Sex steroid sulfotransferases (ST) sulfurylate and thus inactivate estrogens or androgens, producing an androgenized or estrogenized state in the liver. The expression of diabetes in a number of animal models is sexually dimorphic and has been associated with steroidal states. Although the viable yellow (Avy) mutation produces an insulin-resistant obesity syndrome in mice of both sexes, only males develop chronic hyperglycemia. Hyperglycemia was rapidly induced in Avy/a females by dexamethasone (dex). This treatment completely suppressed both endogenous plasma corticosterone and hepatic corticosterone-binding globulin (CBG) mRNA within 24 h. Hyperglycemia in dex-implanted Avy/a females was accompanied by aberrant shifts in hepatic androgen/estrogen balance. This was effected by induction of estrogen sulfotransferase (EST) mRNA together with a > 10-fold increase in enzymatic activity. Similar dex-induced increases in androgen ST or phenol ST were not observed. Prior implantation of estrogen prevented development of hyperglycemia. The time-dependent spontaneous reversal of dex-induced hyperglycemia correlated with re-expression of CBG mRNA transcripts and reduced levels of EST transcripts and enzyme activity. Although dex-induced hyperglycemia was limited to Avy/a females, dex elicited hyperinsulinemia in lean a/a control mice of both sexes and exacerbated constitutive hyperinsulinemia in Avy/a males and females. In summary, dex-induced hyperglycemia in Avy/a females was associated with increased catabolism of hepatic estrogens mediated by induction of EST.
Lilly Research Laboratories, Eli Lilly, Indianapolis, Indiana.
A M
AM
Gill
E H
EH
Leiter
J G
JG
Powell
H D
HD
Chapman
T T
TT
Yen
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003345:Corticosterone / Q000097:blood; D003907:Dexamethasone / Q000494:pharmacology*; D004958:Estradiol / Q000494:pharmacology; D005260:Female; D006943:Hyperglycemia / Q000139:chemically induced*; D007328:Insulin / Q000097:blood; D008099:Liver / Q000201:enzymology*; D008297:Male; D051379:Mice; D008820:Mice, Obese; D009765:Obesity / Q000150:complications*; D012333:RNA, Messenger / Q000378:metabolism; D015238:Sulfotransferases / Q000096:biosynthesis*; D014156:Transcortin / Q000235:genetics
D001786:Blood Glucose; D007328:Insulin; D012333:RNA, Messenger; D004958:Estradiol; D003907:Dexamethasone; D014156:Transcortin; D015238:Sulfotransferases; C020122:estrone sulfotransferase; D003345:Corticosterone