Blockade of glucocorticoid excess at the tissue level: inhibitors of 11beta-hydroxysteroid dehydrogenase type 1 as a therapy for type 2 diabetes.

Glucocorticoids are stress hormones with regulatory effects on carbohydrate, protein, and lipid metabolism. There are two forms of glucocorticoids in humans: the active cortisol (corticosterone in rodents) and inactive cortisone (11-dehydrocorticosterone in rodents). The physiological actions of glucocorticoids are mediated by glucocorticoid receptor (GR) which, upon binding to its natural ligand cortisol, is activated and regulates diverse physiological events. GR is a nuclear receptor ubiquitously expressed in tissues and triggers biological effects through transcriptional activation or suppression of target genes (Figure 1). Cortisol is synthesized in the adrenal glands as part of adrenal steroidogenesis that also involves the production of mineralocorticoids and androgens. Cortisol is secreted in a relatively high level at 10-20 mg/day. Cortisol biosynthesis is tightly controlled by adrenocorticotropic hormone (ACTH), a peptide hormone secreted from the anterior pituitary and is itself regulated by the hypothalamic peptide corticotrophin-releasing hormone (CRH). Circulating cortisol regulates its own biosynthesis by sending negative feedback signals to the pituitary and hypothalamus. Together, this neuroendocrine feedback circuit constitutes the hypothalamic-pituitary-adrenal (HPA) axis. The HPA activity is stimulated by physical or psychological stress and varies throughout the 24 h cycle. As a result, the circulating cortisol undergoes circadian rhythm, reaching its peak concentration of ∼800 nmol/L in the morning and nadir of ∼200 nmol/L at midnight in humans. About 96% of the circulating cortisol is protein-bound with 6% to albumin and 90% to corticosteroid binding globulin (CBG). Circulating CBG levels are approximately 700 nmol/L and regulated by estrogens and disease conditions. Free cortisol dictates glucocorticoid action. It is thought that CBG may serve to restrict access of cortisol to target tissues and regulate its bioavailability and metabolic clearance. CBG may also serve as a carrier for cortisol facilitating transport of cortisol in blood to certain tissues. In contrast, the inactive cortisone is in a free unbound form and its plasma concentration remains steady at approximately 100 nmol/L throughout the day. The metabolism of both cortisol and cortisone occurs in liver involving the A-ring reductases and several other enzymes, and the principal metabolites are tetrahydrocortisone (THE) and 5Rand 5 -tetrahydrocortisol (5Rand 5 -THF) (Figure 2). Another aspect of the regulation of glucocorticoid production involves two 11 -hydroxysteroid dehydrogenase (11 -HSD) isozymes that interconvert cortisone and cortisol (Figure 2). 11 -HSD1 is a reductase in vivo converting cortisone to cortisol and amplifies glucocorticoid action in a tissue-specific manner. In contrast, its isozyme 11 HSD2 acts as a dehydrogenase and catalyzes the opposite reaction, converting cortisol to cortisone. 11 -HSD1 is predominantly expressed in liver, adipose, placenta, and brain. 11 -HSD2 is primarily expressed in kidney and functions as the main source of cortisone production. Together, glucocorticoid homeostasis is maintained by the HPA axis and the activities of the 11 -HSD enzymes. The metabolic syndrome is a cluster of metabolic abnormalities including central obesity, insulin resistance, atherogenic * To whom correspondence should be addressed. Telephone: 805-4475598. Fax: 805-499-0953. E-mail: mwang@amgen.com. † Department of Medicinal Chemistry. ‡ Department of Metabolic Disorders. a Abbreviations: 11 -HSD1 or -2, 11 -hydroxysteroid dehydrogenase type 1 or 2; CBG, corticosteroid binding globulin; CBX, carbenoxolone; CRH, corticotrophin-releasing hormone; GA, glycyrrhetinic acid; GR, glucocorticoid receptor; HPA axis, the hypothalamic-pituitary-adrenal axis; THE, tetrahydrocortisone; THF, tetrahydrocortisol.  Copyright 2008 by the American Chemical Society