Cortisol is regenerated from
cortisone by
11beta-hydroxysteroid dehydrogenase type 1 (11HSD1), amplifying
glucocorticoid action in adipose tissue and liver. 11HSD1 inhibitors are being developed for
type 2 diabetes and may be most effective in
obesity, where adipose 11HSD1 is increased. However, the magnitude of regeneration of
cortisol in different tissues in humans is unknown, hindering understanding of the pathophysiological and therapeutic importance of 11HSD1. In eight healthy men, we infused 9,11,12,12-(2)H4-cortisol and measured tracer enrichment in the hepatic vein as an
indicator of total splanchnic
cortisol generation. Oral
cortisone (25 mg) was then given to measure first-pass hepatic
cortisol generation. In steady state, splanchnic
cortisol production was 45 +/- 11 nmol/min when arterialized plasma
cortisone concentration was 92 +/- 7 nmol/l. Extrapolation from hepatic
cortisol generation after oral
cortisone suggested that, at steady state, the liver contributes 15.2 nmol/min and extrahepatic splanchnic tissue contributes 29.8 nmol/min to the total splanchnic
cortisol production. We conclude that tissues draining into the portal vein, including visceral adipose tissue, contribute substantially to the regeneration of
cortisol. Thus, in addition to
free fatty acids and
adipokines, the portal vein delivers
cortisol to the liver, and inhibition of 11HSD1 in visceral adipose tissue may indeed be valuable in ameliorating
insulin resistance in
obesity.