Endocrine Abstracts

Intracellular cortisol is regulated by 11βHSD1. Although the field has focused on regeneration of cortisol from inert cortisone by 11β-reductase activity of 11βHSD1, we have used stable isotope tracers and arteriovenous sampling to quantify simultaneous dehydrogenase (cortisone generation) and reductase (cortisol regeneration) in human adipose and skeletal muscle. In vitro studies suggest insulin regulates this balance of reductase vs dehydrogenase activity. In obesity, 11βHSD1 expression is increased in adipose. We hypothesised that the directionality of 11βHSD1 in metabolic tissues is regulated by insulin and in obesity recycling between cortisol and cortisone is accelerated.

Ten lean (BMI 23.8±0.4 kg/m²) and ten obese (32.9±0.9 kg/m²) otherwise healthy men participated in a two-phase crossover single-blinded study comparing saline infusion with a hyperinsulinaemic euglycaemic clamp. 9,11,12,12-[²H]₄-cortisol (D4-cortisol, measuring reductase) and 1,2-[²H]₂-cortisone (D2-cortisone, measuring dehydrogenase) were infused, samples obtained of arterialised blood and from veins draining forearm skeletal muscle and abdominal subcutaneous adipose, and blood flow measured by occlusion plethysmography and Xenon washout, respectively. Data are lean vs obese, mean±S.E.M.

Before insulin/saline infusion, whole body 11β-reductase (Rate of appearance (Ra) D3-cortisol 22.66±2.17 vs 26.17±2.15 nmol/min; P=0.27) and 11β-dehydrogenase (Ra cortisone 15.34±3.91 vs 15.82±2.67 nmol/min; P=0.92) did not differ between lean and obese. However, reductase and dehydrogenase activities were only detectable across adipose tissue in obese individuals and across skeletal muscle in lean. Acute hyperinsulinaemia upregulated cortisol regeneration across adipose tissue in obese (insulin vs placebo P=0.006) and tended to upregulate cortisone generation across skeletal muscle in lean (insulin vs placebo P=0.06).

In conclusion, insulin has tissue-specific effects to increase net cortisol regeneration in adipose tissue but not skeletal muscle, potentially amplifying post-prandial lipid storage. Up-regulation of 11βHSD1 in adipose in obesity accelerates recycling between cortisol and cortisone, enhancing the dynamic response to insulin but not necessarily increasing basal intracellular cortisol.