11β-hydroxysteroid dehydrogenase 2 activity is elevated in extreme obese subjects and negatively associated with insulin sensitivity
1Division of Endocrinology, Diabetes, Angiology, Nephrology, and Clinical Chemistry, Department of Internal Medicine, University Hospital of Tübingen, Tübingen, Germany; 2Department of Nutrition and Health, Research Institute of Child Nutrition, Dortmund, Germany; 3Nutritonal and Preventive Medicine, Department of Internal Medicine, University Hospital of Tübingen, Tübingen, Germany; 4Steroid Laboratory, Department of Pharmacology, University of Heidelberg, Heidelberg, Germany.
Objectives: Alterations in glucocorticoid (GC) metabolism may contribute to the development of obesity and insulin resistance. We aimed to study the role of 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) in human adiposity, paying special attention to the association between altered GC metabolism and insulin sensitivity.
Design: In 24-h urine samples of 72 extremely obese (mean BMI 45.5±1.1 kg/m2), but otherwise healthy patients urinary free cortisol (UFF) and cortisone (UFE), tetrahydrocortisol, 5α-tetrahydrocortisol, and tetrahydrocortisone were quantified by RIA. The sum of the three major tetrahydrometabolites is an estimate for daily GC secretion, and the sum of UFF and UFE represents potentially-bioactive-free-GCs. Thirty healthy lean subjects (BMI 22.3±0.3 kg/m2) served as controls.
Results: In obese subjects, absolute daily GC secretion and the potentially-bioactive-free-GCs were significantly (P<0.005) higher than in lean controls (11.8±0.7 vs 8.0±0.6 mg/d; and 171.8±11.2 vs 117.6±9.2 μg/d, respectively). However, when these values were corrected for body surface area (BSA), significant differences were no longer detectable. While enzyme activity indices for 5α-reductase and 11β-HSD1 were similar in lean and obese subjects, 11β-HSD2 was markedly elevated in adiposity (3.7±0.2 vs 2.1±0.1; P<0.0001). This increase was accompanied by a significant reduction of UFF excretion corrected for BSA (16.5±1.2 vs 21.7±2.0 μg/d per m2; P=0.0222). Besides, 11β-HSD2 activity was significantly correlated with insulin sensitivity (P=0.0262).
Conclusions: When body size is accounted for, both adrenal GC secretion and potentially-bioactive-free-GCs are indistinguishable between lean and extremely obese subjects. However, in obesity the kidney appears to intensify its supply of the direct substrate cortisone for extra-renal 11β-HSD1 which may fuel visceral adiposity and insulin resistance.
Endocrine Abstracts (2008) 16 P21