Bisphenol A impairs hepatic glucose sensing in C57BL/6 male mice.
OBJECTIVE
Glucose sensing (eg. glucokinase activity) becomes impaired in the development of type 2 diabetes, the etiology of which is unclear. Estrogen can stimulate glucokinase activity, whereas the pervasive environmental pollutant bisphenol A (BPA) can inhibit estrogen action, hence we aimed to determine the effect of BPA on glucokinase activity directly.


METHODS
To evaluate a potential acute effect on hepatic glucokinase activity, BPA in water (n = 5) vs. water alone (n = 5) was administered at the EPA's purported "safe dose" (50 µg/kg) by gavage to lean 6-month old male C57BL/6 mice. Two hours later, animals were euthanized and hepatic glucokinase activity measured over glucose levels from 1-20 mmol/l in liver homogenate. To determine the effect of chronic BPA exposure on hepatic glucokinase activity, lean 6-month old male C57BL/6 mice were provided with water (n = 15) or water with 1.75 mM BPA (∼50 µg/kg/day; n = 14) for 2 weeks. Following the 2-week exposure, animals were euthanized and glucokinase activity measured as above.


RESULTS
Hepatic glucokinase activity was signficantly suppressed after 2 hours in animals given an oral BPA bolus compared to those who received only water (p = 0.002-0.029 at glucose 5-20 mmol/l; overall treatment effect p<0.001). Exposure to BPA over 2 weeks also suppressed hepatic glucokinase activity in exposed vs. unexposed mice (overall treatment effect, p = 0.003). In both experiments, the Hill coefficient was higher and Vmax lower in mice treated with BPA.


CONCLUSIONS
Both acute and chronic exposure to BPA significantly impair hepatic glucokinase activity and function. These findings identify a potential mechanism for how BPA may increase risk for diabetes.
Division of Endocrinology, Metabolism and Diabetes, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States of America. leigh.perreault@ucdenver.edu
Leigh
L
Perreault
Carrie
C
McCurdy
Anna A
AA
Kerege
Julie
J
Houck
Kristine
K
Færch
Bryan C
BC
Bergman
D000818:Animals; D001559:Benzhydryl Compounds / Q000633:toxicity*; D005947:Glucose / Q000378:metabolism*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D010636:Phenols / Q000633:toxicity*; D000098826:Bisphenol A Compounds
D001559:Benzhydryl Compounds; D005947:Glucose; D010636:Phenols; C006780:bisphenol A; D000098826:Bisphenol A Compounds