Inhibiting cortisol regeneration by 11β-HSD1 is a promising therapy for type two diabetes. In obesity, 11β-HSD1 activity is increased in adipose tissue but decreased in the liver, the latter putatively mediated by hyperinsulinaemia. We tested whether insulin sensitisation with metformin regulates 11β-HSD1 activity in whole body and in liver in obesity.
Five obese men (age 48±5 years, BMI 39.8±3.6 kg/m2) participated in a randomised, double-blinded, crossover study comparing metformin (1 g BD orally for 28 days) with placebo. At the end of each phase, subjects collected a 24 h urine sample and attended twice after overnight fast. On a first visit, 9,11,12,12-[2H]4-cortisol (d4-cortisol) was infused for 4 h, with repeated blood sampling to measure steady state d3-cortisol appearance (whole body 11β-HSD1 activity). On a second visit, subjects took 0.25 mg oral dexamethasone at 2300 h and 25 mg oral cortisone at 0900 h, with repeated blood sampling to measure conversion to cortisol by hepatic 11β-HSD1. Steroids were quantified by RIA (cortisone test) or mass spectrometry (tracer and urinary steroids). Local ethical approval was obtained. Data are mean±S.E.M.
Fasting glucose (5.3±0.3 vs 6.0±0.9 mmol/l) and insulin (11.4±3.5 vs 21.0±7.8 mU/l) were non-significantly decreased by metformin. Metformin increased whole body rate of appearance of d3-cortisol (48±6 vs 39±5 nmol/min, P=0.01), but did not alter the rate of conversion of oral cortisone to cortisol (area under curve 29 951±11 207 vs 34 128±3741, P=0.7) or urinary cortisol metabolites (15.9±4.0 vs 18.3±4.2 mg/day).
Metformin increases whole body 11β-HSD1 activity in euglycaemic obese men. However, whether this is mediated in the liver by reversal of hyperinsulinaemia remains unproven. There has been concern that 11β-HSD1 inhibitors will be less effective in the presence of metformin, given their shared mechanism of suppressing hepatic gluconeogenesis. These data suggest, however, that metformin may increase the local regeneration of cortisol by 11β-HSD1 and provide a bigger target for 11β-HSD1 inhibitors.