Endocrine Abstracts

The role of endogenous glucocorticoid (GC) production and metabolism in the pathogenesis of obesity, insulin resistance and type 2 diabetes remains unclear. Patients with Cushing’s syndrome develop central obesity, insulin resistance and in some cases type 2 diabetes (T2DM), yet circulating cortisol levels are not elevated in simple obesity. Alterations in GC metabolism, including 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) that generates active cortisol from cortisone, and 5α-reductase (5αR) that inactivates cortisol to its tetrahydro-metabolites have been postulated not only to impact upon metabolic phenotype, but also to drive alterations in HPA axis activity.

One hundred and one obese patients were recruited (mean age 48±7 years, BMI 34.4±0.4 kg/m², 65 women, 36 men) and underwent 75 g oral glucose tolerance testing (OGTT) with insulin measurements, body composition analysis (DEXA), assessment of GC metabolism using 24 h urine steroid metabolite analysed by gas chromatography/mass spectroscopy.

About 22.7% of women had impaired glucose tolerance (IGT) compared with 39.4% of men. Two women and 5 men were diagnosed with T2DM. IGT was not associated with changes in body composition on DEXA scanning in men or women. In women only, IGT was associated with increased waist circumference (103±1 vs 111±2 cm, P<0.002). Total GC production rate was significantly higher in men compared to women (Normal: 13 743±863 vs 7453±469 μg/24 h, P<0.001; IGT: 16 871±2113 vs 10 133±1488 μg/24 h, P<0.05) and in women only was higher in patients with IGT (7453±469 vs 10 133±1488 μg/24 h, P<0.001). Using linear regression in both men and women, 5αR activity correlated positively 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). Weaker relationships were observed with regional and total, fat and lean mass in men only. Importantly, after correcting for total fat mass, HOMA-R was still associated with increasing 5αR activity in both men and women (P<0.05). 11β-HSD1 activity correlated positively with HOMA-R (R=0.38, P=0.04), and fasting insulin (R=0.37, P=0.05) in men only.

In women, GC production rates are elevated in IGT, changes that are unrelated to body composition. It remains plausible that this ‘subclinical Cushing’s’ may contribute to their phenotype. In addition, we have shown that increasing 5αR activity is more closely related to insulin resistance and secretion than to body composition. Enhanced 5αR activity may drive HPA axis activation via enhanced cortisol inactivation.