The antihyperglycemic effect of estrone sulfate in genetically obese-diabetic (ob/ob) mice is associated with reduced hepatic glucose-6-phosphatase.
Excessive glucose production by the liver contributes significantly to diabetic hyperglycemia. The enzyme system glucose-6-phosphatase plays a key role in regulating hepatic glucose production and therefore its inhibition is a potential therapeutic target for the correction of hyperglycemia. It has previously been shown that sulfated steroids, such as estrone sulfate and dehydroepiandrosterone sulfate, inhibit the glucose-6-phosphatase system in vitro, principally through inhibition of endoplasmic reticulum glucose-6-phosphate transport. We report here that in the obese/diabetic ob/ob mouse model, orally administered estrone sulfate reduces the abnormally elevated hepatic glucose-6-phosphatase enzyme activity and enzyme protein levels that are characteristic in the ob/ob mouse, and that this reduction is associated with normalization of blood glucose levels. Other sulfated and non-sulfated steroids also reduced, to a lesser extent, glucose-6-phosphatase enzyme activity - with the exception of dehydroepiandrosterone sulfate, which had no apparent effect on this system in ob/ob mice. Estrone sulfate is therefore an effective antihyperglycemic agent in ob/ob mice, and the glucose-6-phosphatase system can be successfully targeted for the therapeutic management of hyperglycemia in this animal model of non-insulin-dependent diabetes mellitus.
Borthwick
E B
EB
Department of Obstetrics & Gynecology, University of Dundee, Ninewells Hospital and Medical School, Dundee, Scotland, UK.
Houston
M P
MP
Coughtrie
M W
MW
Burchell
A
A
D000375:Aging; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D019314:Dehydroepiandrosterone Sulfate / Q000494:pharmacology; D003920:Diabetes Mellitus / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology; D004970:Estrone / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D005952:Glucose-6-Phosphatase / Q000378:metabolism*; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D008099:Liver / Q000201:enzymology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D008862:Microsomes, Liver / Q000201:enzymology; D009765:Obesity
D001786:Blood Glucose; D007004:Hypoglycemic Agents; C031555:estradiol sulfate; D004970:Estrone; D004958:Estradiol; D019314:Dehydroepiandrosterone Sulfate; D005952:Glucose-6-Phosphatase; C017296:estrone sulfate