Journal
BEST PRACTICE & RESEARCH CLINICAL ENDOCRINOLOGY & METABOLISM
Volume 21, Issue 4, Pages 607-619Publisher
BAILLIERE TINDALL
DOI: 10.1016/j.beem.2007.07.003
Keywords
obesity; glucocorticoid; 11 beta-hyclroxysteroid dehydrogenase type 1; glucocorticoid; receptor; type-2 diabetes.
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Funding
- Medical Research Council [G0502165] Funding Source: researchfish
- MRC [G0502165] Funding Source: UKRI
- Medical Research Council [G0502165] Funding Source: Medline
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The global epidemic of obesity and type-2 diabetes has heightened the need to understand the mechanisms that contribute to its pathogenesis and also to design and trial novel treatments. Patients with glucocorticoid (GC) excess - 'Cushing's syndrome' - are phenotypically similar to patients with simple obesity. As such, much research has focused on the manipulation of local GC action as a therapeutic strategy. The majority of the classical actions of GCs are mediated via activation of the glucocorticoid receptor (GR). 11 beta-Hydroxysteroid dehydrogerase type 1 (11 beta-HSD1) converts inactive cortisone to cortisol and therefore amplifies local GC action. There is now a wealth of data from rodent and clinical studies implicating this conversion in the pathogenesis of obesity, type-2 diabetes, and the metabolic syndrome. Selective 11 beta-HSD1 inhibitors (selective in that they block the activity of 11 beta-HSD1 and not 11 beta-HSD2 which inactivates cortisone to cortisol in mineralocorticoid target tissues) are currently in development although not yet available for use in clinical studies. Rodent studies utilizing these compounds have shown dramatic improvements in insulin sensitivity as well as improvements in lipid profiles and atherogenesis. A further experimental approach has been to design drugs that antagonize GR activation, and again these compounds appear to improve insulin sensitivity and lower glucose production rates. The key test for both of these research strategies is whether they will translate into clinical studies, and results from these trials are now eagerly awaited.
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