Glucocorticoids in type 2 diabetes mellitus and the metabolic syndrome

While glucocorticoids were originally named for their role in glucose metabolism, their role in many aspects of resting and stress-related homeostasis has been elucidated. An accumulation of evidence linking abnormal glucocorticoid metabolism to both type 2 diabetes and metabolic syndrome has led to a search for therapeutic agents that lower levels of cortisol, the principal active glucocorticoid in humans, and/or that block the effects of cortisol excess. Several promising approaches are currently under investigation and some compounds have reached early stage clinical development. A popular approach is the inhibition of the enzyme 11 beta-hydroxysteroid dehydrogenase type 1 (11 beta-HSD1), which regenerates the active cortisol from cortisone, its inactive form. This approach still awaits clinical proof of concept. Other therapeutic approaches include blockade at the level of the glucocorticoid receptor and inhibition of adrenal cortisol synthesis. Ketoconazole and metyrapone, inhibitors of 110 hydroxylase, the terminal step in adrenal cortisol synthesis, are frequently used to effect pharmacologic adrenalectomy in patients with Cushing's syndrome, a disorder caused by a marked elevation in levels of cortisol. The 2S,4R enantiomer of ketoconazole, which may be safer than racemic ketoconazole, is currently being tested in a phase-2 clinical trial in patients with type 2 diabetes, many of whom have one or more co-morbidities frequently associated with the metabolic syndrome. Given the central role that cortisol appears to play in the development of the metabolic syndrome, it is likely that a single agent may treat multiple components of this syndrome.