Harvey Cushings work informed us of the deleterious consequences of circulating cortisol excess hypertension, osteoporosis and obesity that contributes to diabetes and premature mortality. Conversely, Hench, Kendall and Reichstein were Nobel Laureates in Physiology 1950 for the discovery of cortisone and demonstrating efficacy in patients with Rheumatoid Arthritis in effect the birth of the anti-inflammatory actions of glucocorticoids.
The tissue-specific generation of cortisol, independent of circulating levels, is 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. 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.
Selective 11β-HSD1 inhibitors lower blood glucose, improve insulin sensitivity and cause weight loss in animal models. Biomarkers have been validated to confirm target inhibition in primate and human studies. Recent clinical trials show reduction in HbA1c and blood pressure in obese patients with diabetes mellitus who have failed on metformin therapy. Potentially the therapy offers a magic bullet for patients with Metabolic syndrome with reduced blood glucose accompanying improved insulin sensitivity, lower lipids and blood pressure and reversal of hepatic steatosis secondary to reduced autocrine generation of cortisol in liver, adipose tissue, pancreas and muscle. Liabilities include activation of the HPA axis secondary to increased cortisol clearance with hyperandrogenism, though the extent and significance of this is debated. Perhaps of more concern is the potential impact upon the inflammatory process since 11β-HSD1 expression is significantly induced at the site of inflammation.
Modulation of glucocorticoid hormone action via selective 11β-HSD1 inhibitors represents a novel therapeutic advance to treat the global epidemic of metabolic syndrome.