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Impaired glucose tolerance and insulin resistance are associated with increased adipose 11β-hydroxysteroid dehydrogenase type 1 expression and elevated hepatic 5-reductase activity

¹ Division of Medical Sciences, Institute of Biomedical Research, University of Birmingham, Queen Elizabeth Hospital, Edgbaston, Birmingham, UK. B15 2TT
² Wellcome Trust Clinical Research Facility, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK. B15 2TH

Objective: The precise molecular mechanisms contributing to the development of insulin resistance, impaired glucose tolerance (IGT) and type 2 diabetes (T2DM) are largely unknown. Altered endogenous glucocorticoid (GC) metabolism, including 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) that generates active cortisol from cortisone, and 5-reductase (5R) that inactivates cortisol have been implicated.

Research Design and Methods: 101 obese patients (mean age 48±7years, BMI 34.4±4.3kg/m², 66 women, 35 men) underwent 75g oral glucose tolerance testing (OGTT), body composition analysis (DXA), assessment of GC metabolism (24h urine steroid metabolite analysis by GC/MS) and subcutaneous abdominal adipose tissue biopsies.

Results: 22.7% of women had IGT compared with 34.2% of men. 2 women and 5 men were diagnosed with T2DM. 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 GC secretion was higher in men with and without IGT (Normal: 13743±863 vs. 7453±469 µg/24h, p<0.001; IGT: 16871±2113 vs. 10133±1488µg/24h, p<0.05) and in women was higher in patients with IGT (7453±469 vs. 10133±1488µg/24h, p<0.001). In both sexes, 5R 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 HOMA-R (Men: R=0.52, p=0.004; Women: R=0.33, p=0.02).

Conclusion: Increased adipose 11β-HSD1 expression in women may contribute to glucose intolerance. Enhanced 5R activity in both sexes is associated with insulin resistance, but not body composition. Augmented GC inactivation may serve as compensatory, protective mechanism to preserve insulin sensitivity.

Key Words: Obesity • 5-reductase • 11β-hydroxysteroid dehydrogenase • cortisol • insulin sensitivity

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