Endocrine Abstracts

Glucocorticoid (GC) production rates are elevated in obese, insulin resistant individuals. We and others have demonstrated decreased hepatic cortisol regeneration through reduced 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) activity that converts inactive cortisone to cortisol. In addition, there is enhanced cortisol clearance by A-ring reductases, (notably 5α-reductase). We have argued that these changes drive the hypothalamo-pituitary–adrenal axis and represent a protective mechanism to decrease tissue specific cortisol exposure to preserve metabolic phenotype. On this background, we established the Birmingham Prospective Obesity, Diabetes and Steroid metabolism cohort (BPODS) to prospectively track changes in GC metabolism with metabolic phenotype. Individuals who are unable to decrease tissue specific cortisol exposure may be at greater metabolic risk.

One hundred and fourteen obese patients (75 women, BMI>30 kg/m²) were recruited and underwent anthropometric measurements, fasting blood tests, oral glucose tolerance test (OGTT), DXA body composition and 24 h urine collections for steroid metabolite analysis (GC/MS). All investigations were repeated 12 months after enrolment.

Over the initial 12-month prospective follow-up period, mean change in weight was +1.1±0.6 kg and BMI +0.42±0.22 kg/m². 36.7% of patients lost weight and 62.3% gained weight (unchanged in one patient). Mean change in glucose tolerance (AUC across OGTT) was −0.17±0.28 mmol/l per min (41.4% deterioration, 58.6% improvement). Individuals who decreased 11β-HSD1 activity (urinary GC/MS analysis) lost weight (−2.0±2.5 kg), however, in contrast, those with increased 11β-HSD1 activity gained weight (+1.7±0.6 kg, P<0.05). In addition, baseline 5α-reductase activity in men predicted deterioration in glucose tolerance over the 12-month period (R=0.46, P<0.05). Independently, increasing trunk fat mass (DXA) was associated with worsening glucose tolerance (−1.2±0.5 vs +0.13±0.33 mmol/l per min, P<0.05) and increasing fasting insulin (−3.3±2.2 vs +1.3±0.9 pmol/l, P<0.05).

We have demonstrated that 11β-HSD1 and 5α-reductase activity are able to predict individuals with increasing body weight and worsening glucose tolerance. Furthermore, decreasing 11β-HSD1 activity tacks with improvements in metabolic phenotype and endorses therapeutic inhibition as a valid treatment target.