Impaired Glucose Tolerance and Insulin Resistance Are Associated With Increased Adipose 11β-Hydroxysteroid Dehydrogenase Type 1 Expression and Elevated Hepatic 5α-Reductase Activity

Impaired Glucose Tolerance and Insulin Resistance Are Associated With Increased Adipose 11β-Hydroxysteroid Dehydrogenase Type 1 Expression and Elevated Hepatic 5α-Reductase Activity Jeremy W. Tomlinson 1 , Joanne Finney 2 , Christopher Gay 1 , Beverly A. Hughes 1 , Susan V. Hughes 1 and Paul M. Stewart 1 1 Division of Medical Sciences, Institute of Biomedical Research, University of Birmingham, Queen Elizabeth Hospital, Edgbaston, Birmingham, U.K 2 Wellcome Trust Clinical Research Facility, University Hospitals Birmingham NHS Foundation Trust, Birmingham, U.K Corresponding author: Jeremy W. Tomlinson, j.w.tomlinson{at}bham.ac.uk Abstract OBJECTIVE— The precise molecular mechanisms contributing to the development of insulin resistance, impaired glucose tolerance (IGT), and type 2 diabetes are largely unknown. Altered endogenous glucocorticoid metabolism, including 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), which generates active cortisol from cortisone, and 5α-reductase (5αR), which inactivates cortisol, has been implicated. RESEARCH DESIGN AND METHODS— A total of 101 obese patients (mean age 48 ± 7 years, BMI 34.4 ± 4.3 kg/m 2 , 66 women, 35 men) underwent 75-g oral glucose tolerance testing (OGTT), body composition analysis (dual-energy X-ray absorptiometry), assessment of glucocorticoid metabolism (24-h urine steroid metabolite analysis by gas chromatography/mass spectrometry), and subcutaneous abdominal adipose tissue biopsies. RESULTS— A total of 22.7% of women had IGT compared with 34.2% of men. Two women and five men were diagnosed with type 2 diabetes. In women, adipose 11β-HSD1 expression was increased in patients with IGT and correlated with glucose levels across the OGTT ( R = 0.44, P < 0.001) but was independent of fat mass. Total glucocorticoid secretion was higher in men with and without IGT (normal 13,743 ± 863 vs. 7,453 ± 469 μg/24 h, P < 0.001; IGT 16,871 ± 2,113 vs. 10,133 ± 1,488 μg/24 h, P < 0.05), and in women, it was higher in those with IGT (7,453 ± 469 vs. 10,133 ± 1,488 μg/24 h, P < 0.001). In both sexes, 5αR activity correlated with fasting insulin (men R = 0.53, P = 0.003; women R = 0.33, P = 0.02), insulin secretion across an OGTT (men R = 0.46, P = 0.01; women R = 0.40, P = 0.004), and homeostasis model assessment of insulin resistance (men R = 0.52, P = 0.004; women R = 0.33, P = 0.02). CONCLUSIONS— Increased adipose 11β-HSD1 expression in women may contribute to glucose intolerance. Enhanced 5αR activity in both sexes