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 -Hydroxysteroid Dehydrogenase Type 1 and Metabolic Disease
a University of Edinburgh, Centre for Cardiovascular Science, Edinburgh EH16 4TJ, Scotland, United Kingdom
Key Words: 11  -hydroxysteroid dehydrogenases • glucocorticoids • obesity • type 2 diabetes • metabolic syndrome • cardiovascular disease
Address for correspondence: Brian R. Walker, Endocrinology Unit, Centre for Cardiovascular Sciences, Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, Scotland, United Kingdom. Voice: +44-0-131-242-6770; fax:+44-0-131-242-6779. e-mail: B.Walker{at}ed.ac.uk
Activation of intracellular glucocorticoid receptors is determined not only by the plasma concentrations of cortisol, under the influence of the hypothalamic-pituitary-adrenal (HPA) axis, but also by 11HSD enzymes within the target cell which interconvert cortisol with its inert metabolite cortisone. Data from cells in culture, isolated tissues, and transgenic mouse models have established that 11HSD type 1 regenerates glucocorticoids and amplifies glucocorticoid receptor activation. In humans, the rate of cortisol regeneration in peripheral tissues is of similar magnitude to adrenal secretion of cortisol at most times of day, and occurs principally in the splanchnic circulation. Approximately two-thirds of the splanchnic activity appears to reside in visceral adipose tissue, sufficient to allow visceral adipose tissue to "deliver" cortisol to the liver via the portal vein. In obesity, 11HSD1 activity in subcutaneous adipose tissue is increased, putatively explaining the link between obesity and other features of the metabolic syndrome. The regulation of 11HSD1, and the basis for its upregulation in obesity, are now being explored. Against this background, inhibition of 11HSD1 has become a major therapeutic target in metabolic syndrome. Preclinical results with novel selective 11HSD1 inhibitors are encouraging, and clinical proof of principle has been achieved with the nonselective inhibitor carbenoxolone. Although the parallels between metabolic syndrome and Cushing's syndrome were originally drawn with reference to patients with elevated plasma cortisol concentrations, it now appears that manipulating tissue concentrations of cortisol will allow the subtle level of control required for long-term therapy to reduce the risks of cardiovascular disease.
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