11-b-hydroxysteroid dehydrogenase (11b-HSD) is a microsomal short chain dehydrogenase/reductase (SDR) which catalyzes the inter-conversion of biologically active glucocorticoid (cortisol in human and corticosterone in rats and mice) and inactive glucocorticoid (cortisone and 11-dehydrocorticosterone). Two tissue specific isoforms (11beta-HSD1 and 11beta-HSD2) of 11b-HSD with two different functions regarding glucocorticoid availability, have been identified. The decreased 11b-hydroxy oxidation of cortisol results in Apparent Mineralocorticoid Excess (AME) disorder which is manifested by hypertension, hypokalemia, low plasma renin activity, and responsiveness to spironolactone. AME is principally a disorder of juveniles and children with this condition oxidize cortisol to cortisone poorly but carry out the reverse process unimpaired. AME arises from mutations in the 11beta-HSD2 gene. The glucocorticoids can also be produced locally by 11b-HSD1 and increased visceral accumulation of glucocorticoids results in visceral obesity, insulin resistant diabetes, hyperlipidemia and hyperphagia. 11betaHSD-2 (rat 400-aa, mouse 396-aa, human 405-aa) is a ~41kD glycosylated membrane-protein present in the endoplasmic reticulum (ER). The N-terminal and C-terminal (catalytic domain) of 11b-HSD2 are in the lumen and cytoplasm of ER, respectively. 11b-HSD2 irreversibly catalyzes the dehydrogenation of active 11b-hydroxycorticoids before they occupy mineralocorticoid receptors (MR) and thus confers aldosterone selectivity for inherently nonselective MR. The enzyme is expressed in a wide array of tissues, with highest level mineralocorticoid target cells such as the renal and outer medullary collecting ducts.