Endocrine Abstracts

The seminal studies of Harvey Cushing informed us of the deleterious consequences of circulating cortisol excess – hypertension, osteoporosis and obesity that contributes to diabetes and premature mortality. As such Cushing’s syndrome offers an excellent paradigm for the metabolic syndrome. However circulating cortisol concentrations are invariably normal in patients with metabolic syndrome. The tissue-specific generation of cortisol, independent of circulating levels, can be catalysed by 11β-hydroxysteroid dehydrogenase (11β-HSD1) that converts cortisone (E) to cortisol (F). High levels are expressed in liver and omental adipose tissue where the enzyme amplifies glucocorticoid-mediated hepatic glucose output and adipocyte differentiation and obesity. The former effect occurs through induction of hepatic gluconeogenesis (GNG); recombinant mice with global deletion of 11β-HSD1 or liver-specific deletion of the GR demonstrate reduced GNG. Conversely over expression of 11β-HSD1 in both liver and fat reproduce features of the metabolic syndrome. The pivotal oxo-reductase activity of 11β-HSD1 is dependant upon the generation of NADPH within the endoplasmic reticulum from an accessory enzyme hexose-6-phosphate dehydrogenase (H6PDH). Recombinant mice lacking H6PDH are unable to regenerate active glucocorticoid and have reduced body weight and glucose concentrations compared to WT litter mates. In humans, however Metabolic syndrome is not associated with increases in 11β-HSD1 expression and/or activity; in simple 11β-HSD1 is reduced by about 10-20% compared to lean controls. However no reduction in enzyme activity is observed in obese patients with type 2 diabetes mellitus suggesting that a reduction in hepatic and possibly adipose 11β-HSD1 activity with increasing obesity might protect against the deleterious metabolic consequences of the syndrome. It is also likely, either via an autocrine mechanism within the liver, or an endocrine level through the adipose contribution via portal vein, that 11β-HSD1 expression is involved in the pathogenesis of hepatic steatosis.

Selective 11β-HSD1 inhibitors have been developed by Pharma that, in vitro and in animal models lower blood glucose, improve insulin sensitivity and cause weight loss in animal models. Biomarkers have been validated to confirm target inhibition in human studies and the results of Phase II efficacy studies are eagerly awaited. Modulation of glucocorticoid hormone action selectively within liver and/or fat represents a novel therapeutic advance to treat the global epidemic of Metabolic Syndrome.