Endocrine Abstracts

The phenotypic similarities between patients with Cushing’s syndrome and obesity have highlighted the potential pathogenic role of glucocorticoids in obesity / metabolic syndrome. However circulating cortisol levels in these conditions are normal. At a tissue specific level, the enzyme 11β-hydroxysteroid dehydrogenase (11β-HSD) controls cortisol availability to the glucocorticoid receptor (GR). In liver and adipose tissue, the type 1 isoform alone is expressed (11β-HSD1) which inter-converts inactive cortisone (E) and active cortisol (F). The enzyme is bi-directional, however, in vivo, reductase activity (cortisol generation) predominates, permitted by the generation of cofactor (NADPH) within the lumen of the endoplasmic reticulum by hexose-6-phosphate dehydrogenase.

11β-HSD1 is highly expressed in adipose tissue, and it has been hypothesized that intra-abdominal adiposity is caused by increased 11β-HSD1 activity and expression resulting in ‘Cushing’s disease of the omentum’. Whilst transgenic rodent models would seem to endorse this hypothesis, 11β-HSD1 reductase activity is decreased in human obesity, as is expression in omental pre-adipocytes. Therefore, we have hypothesized that this represents a primary protective response rather than a pathogenic mechanism. Indeed, down-regulation of activity is not observed in obese type 2 diabetics and we propose that this may contribute to hyperglycaemia and increased adiposity in this population. Therapeutic selective inhibition of 11β-HSD1 to decrease tissue specific cortisol availability remains an exciting and imminently realistic prospect. Studies in rodent models of type 2 diabetes have suggested that these drugs are potent insulin sensitizers, improve lipid profiles and may cause weight loss. Clinical studies are now eagerly awaited.