The role of 11β-Hydroxysteroid Dehydrogenase type 1 and Hepatic Glucocorticoid Metabolism in the Metabolic Syndrome

Abstract

The metabolic syndrome represents a state of insulin resistance, which has drawn great attention due to its public health importance. A quarter of the world’s adult population are considered to have the metabolic syndrome (Moadab et al. 2009). Despite having a striking phenotypic similarity with patients with Cushing’s syndrome, those with the metabolic syndrome have normal circulating cortisol levels. It has been proposed that these patients have dysregulated cortisol metabolism with either increased glucocorticoid activation or reduced inactivation at a tissue level. Since this may be amenable to therapeutic manipulation there has been an intense focus on the microsomal enzyme 11$\beta$-hydroxysteroid dehydrogenase type 1 (11$\beta$-HSD1) which activates cortisone to cortisol in vivo. Through a series of in vitro and detailed translational studies, this thesis attempts to investigate hepatic glucocorticoid metabolism with relevance to the pathophysiology of the metabolic syndrome. The hepatic zonation and characterization of 11$\beta$-HSD1 was defined. The relation between glucocorticoid metabolism and glucose homeostasis was analysed with relevance to body composition in normal, obese and type 2 diabetic human subjects. Glucose 6 phosphate was identified as a novel direct link between glucose metabolism and the HPA axis. Hepatic glucocorticoid metabolism and its role in the pathogenesis of alcoholic liver disease and non alcoholic fatty liver disease were defined