ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Endocrine Abstracts (2008) 16 P21

11[beta]-hydroxysteroid dehydrogenase 2 activity is elevated in extreme obese subjects and negatively associated with insulin sensitivity

Karsten Müssig1, Thomas Remer2, Axel Haupt1, Baptist Gallwitz1, Andreas Fritsche3, Hans-Ulrich Häring1 & Christiane Maser-Gluth4

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.

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