We have examined the metabolic effects of daily administration of
carbenoxolone (CBX), a naturally occurring
11beta-hydroxysteroid dehydrogenase (11beta-HSD1) inhibitor, in mice with high fat diet-induced
insulin resistance and
obesity. Eight-week-old male Swiss TO mice placed on a synthetic high fat diet received daily
intraperitoneal injections of either saline vehicle or CBX over a 16-day period. Daily administration of CBX had no effect on food intake, but significantly lowered
body weight (1.1- to 1.2-fold) compared to saline-treated controls. Non-fasting plasma
glucose levels were significantly decreased (1.6-fold) by CBX treatment on day 4 and remained lower throughout the treatment period. Circulating plasma
corticosterone levels were not significantly altered by CBX treatment. Plasma
glucose concentrations of CBX-treated mice were significantly reduced (1.4-fold) following an intraperitoneal
glucose load compared with saline controls. Similarly, after 16-day treatment with CBX, exogenous
insulin evoked a significantly greater reduction in
glucose concentrations (1.4- to 1.8-fold).
11beta-HSD1 gene expression was significantly down-regulated in liver, whereas
glucocorticoid receptor gene expression was increased in both liver and adipose tissue following CBX treatment. The reduced
body weight and improved metabolic control in mice with high fat diet-induced
obesity upon daily CBX administration highlights the potential value of selective
11beta-HSD1 inhibition as a new route for the treatment of
type 2 diabetes and
obesity.