Cookies on this website
We use cookies to ensure that we give you the best experience on our website. If you click 'Continue' we'll assume that you are happy to receive all cookies and you won't see this message again. Click 'Find out more' for information on how to change your cookie settings.

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 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1), which generates active cortisol from cortisone, and 5alpha-reductase (5alphaR), 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 11beta-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 microg/24 h, P < 0.001; IGT 16,871 +/- 2,113 vs. 10,133 +/- 1,488 microg/24 h, P < 0.05), and in women, it was higher in those with IGT (7,453 +/- 469 vs. 10,133 +/- 1,488 microg/24 h, P < 0.001). In both sexes, 5alphaR 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 11beta-HSD1 expression in women may contribute to glucose intolerance. Enhanced 5alphaR activity in both sexes is associated with insulin resistance but not body composition. Augmented glucocorticoid inactivation may serve as a compensatory, protective mechanism to preserve insulin sensitivity.

Original publication

DOI

10.2337/db08-0495

Type

Journal article

Journal

Diabetes

Publication Date

10/2008

Volume

57

Pages

2652 - 2660

Keywords

11-beta-Hydroxysteroid Dehydrogenase Type 1, Absorptiometry, Photon, Adipose Tissue, Adult, Body Mass Index, Cholestenone 5 alpha-Reductase, Cortisone, Female, Gas Chromatography-Mass Spectrometry, Glucocorticoids, Glucose Intolerance, Glucose Tolerance Test, Humans, Insulin Resistance, Liver, Male, Middle Aged, Obesity, Regression Analysis, Sex Factors