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Title: 11β-hydroxysteroid dehydrogenase type 1 and glucocorticoid metabolism in obesity
Author: Stimson, Roland H.
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2008
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Obese humans have increased 11β-HSD1 messenger RNA levels in subcutaneous adipose tissue but decreased 11β-HSD1 activity in the liver. The in vivo importance of visceral adipose tissue in cortisol generation by 11β-HSD1 is unknown, and we have used selective vein cannulation with tracer glucocorticoid infusions in humans to examine whether increased visceral adipose 11β-HSD1 activity may increase cortisol concentrations reaching the liver with its resultant adverse metabolic effects. The cause of the dysregulation of 11β-HSD1 in obesity is unknown, and we have utilised tracer glucocorticoid infusions and adipose biopsies to determine whether manipulations in dietary macronutrient content in humans and rodents regulate 11β-HSD1. We have also examined the potential benefits of glucocorticoid rodents regulate 11β-HSD1. We have also examined the potential benefit of glucocorticoid inhibition in the treatment of insulin resistance in humans, and whether PPARy-agonists, drugs commonly used in the treatment of type 2 diabetes mellitus, may mediate their beneficial metabolic effects partly through inhibition of 11β-HSD1 in adipose tissue in humans. Our results show that visceral adipose tissue 11β-HSD1 may be important in determining cortisol concentrations reaching the liver in humans, while showing that diet is a potent regulator of liver 11β-HSD1 activity. PPARy-agonists, however, do not acutely regulate 11β-HSD1 in adipose tissue and their insulin-sensitising effects are independent of glucocorticoid action. We have also shown that acute glucoccorticoid inhibition does not improve insulin sensitivity in humans. Inhibition of 11β-HSD1 in adipose tissue may be an important tool in the treatment of metabolic disease.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available