CARBENOXOLONE INCREASES HEPATIC INSULIN SENSITIVITY IN MAN - A NOVEL ROLE FOR 11-OXOSTEROID REDUCTASE IN ENHANCING GLUCOCORTICOID RECEPTOR ACTIVATION

In the kidney, conversion of cortisol to cortisone by the enzyme 11 be ta-hydroxysteroid dehydrogenase protects mineralocorticoid receptors f rom cortisol. In the liver, a different isoform of the enzyme favors 1 1 beta-reductase conversion of cortisone to cortisol. We have tested t he hypothesis that hepatic 11 beta-reductase enhances glucocorticoid r eceptor activation in the liver by inhibiting the enzyme with carbenox olone and observing effects on insulin sensitivity. Seven healthy male s took part in a double blind randomized cross-over study in which ora l carbenoxolone (100 mg every 8 h) or placebo was administered for 7 d ays. Euglycemic hyperinsulinemic clamp studies were then performed, in cluding measurement of forearm glucose uptake. Carbenoxolone increased whole body insulin sensitivity (M values for dextrose infusion rates, 41.1 +/- 2.4 mu mol/kg min for placebo us. 44.6 +/- 2.3 for carbenoxo lone; P < 0.03), but had no effect on forearm insulin sensitivity. We infer that carbenoxolone, by inhibiting hepatic 11 beta-reductase and reducing intrahepatic cortisol concentration, increases hepatic insuli n sensitivity and decreases glucose production. Thus, plasma cortisone provides an inactive pool that can be converted to active glucocortic oids at sites where 11 beta-reductase is expressed, abnormal hepatic 1 1 beta-reductase activity might be important in syndromes of insulin r esistance, and manipulation of hepatic 11 beta-reductase may be useful in treating insulin resistance.