Endocrine Abstracts

Inhibiting 11beta-hydroxysteroid dehydrogenase type 1 (11HSD1) has been proposed to prevent local regeneration of cortisol from cortisone, and thus enhance hepatic and adipose insulin sensitivity. In healthy men and patients with type 2 diabetes, the non-selective 11HSD inhibitor carbenoxolone enhances hepatic insulin sensitivity but, paradoxically, does not increase peripheral glucose disposal. In obesity, 11HSD1 activity and mRNA are increased in adipose biopsies. We tested whether regeneration of cortisol by 11HSD1 is increased in adipose in obese men in vivo, and whether, in this context, carbenoxolone inhibits adipose 11HSD1 and enhances glucose uptake.
With ethical approval, 6 lean men (BM1 24.6 plus/minus 1.7) were studied once, and 6 age-matched obese (BMI 36.6 plus/minus 3.8) men participated in a randomised double-blind crossover trial comparing carbenoxolone (100 mg 8 hourly for 7 days) and placebo (phases separated by two weeks). ³H₄-Cortisone was infused into sc abdominal fat using microdialysis, and conversion to ³H₄-cortisol was measured in the effluent. A 2 h euglycaemic (5 mM) hyperinsulinaemic (0.8 mU/kg/min) clamp was then performed.
Conversion of cortisone to cortisol in adipose was higher in obese men (32 plus/minus 18 vs 6 plus/minus 5 % over 1 hour, mean/SD, p<0.01), but carbenoxolone had no effect. Whole body insulin sensitivity was impaired in obese men (M values 13.4 plus/minus 3.7 vs 40.5 plus/minus 12.7 umol/kg/min, p<0.01) but was unaffected by carbenoxolone (13.3 plus/minus 4.5 for carbenoxolone vs 13.4 plus/minus 3.7, p=0.86).
These data show that adipose regeneration of cortisol is enhanced in vivo in human obesity. However, carbenoxolone did not reverse insulin resistance, probably because it failed to inhibit 11HSD1 in adipose. Inhibition of 11HSD1 remains an attractive therapeutic goal in obesity, but novel selective 11HSD1 inhibitors will need to be effective in adipose.