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Title: Cortisol metabolism in type 2 diabetes mellitus
Author: Andrews, Robert
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2004
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In chapter 2, I describe my first study, which determined whether individuals with DMA or impaired glucose tolerance (IGT) exhibit abnormalities in cortisol activity. An integrated assessment of cortisol secretion, metabolism and action was carried out in 25 un-medicated lean male patients with hyperglycaemia (20 DM and 5 IGT) and 25 healthy controls carefully matched for body mass index, age and blood pressure. This study demonstrated that patients do exhibit abnormalities in cortisol activity. Chapter 3 describes a study that examined whether altered tissue concentration of the glucocorticoid receptor (GR), of 11β-HSD1 or of 11β-HSD2 could explain the difference in dermal blanching seen between patients with hyperglycaemia and normal healthy controls. Tissue concentrations of GR were found to be no different between patients with hyperglycaemia and normal healthy subjects. In chapter 4, I describe a study, which assessed whether inhibition of local tissue metabolism of cortisol, by carbenoxolone (an inhibitor of both 11β-HSD1 or 11β-HSD2) improved insulin sensitivity. 6 patients with DM and 6 matched controls, participated in a double-blind cross-over comparison of carbenoxolone (100 mg 8 hrly orally for 7 d) and placebo. At the end of each phase glucose kinetics were measured in the fasting state from 0700-0730 h, during a 3 h euglycaemic hyperinsulinaemic clamp and during a 2 h euglycaemic hyperinsulinaemic clamp with a 4-fold increase in glucagon levels. Carbenoxolone reduced total cholesterol in healthy subjects but had no effect on cholesterol in patients with DM. Carbenoxolone did not affect insulin sensitivity, but it did reduce glucose rate during hyperglucagonaemia in patients with DM. In conclusion I have demonstrated that abnormalities in cortisol activity are seen in patients with DM and that drugs specifically targeted at preventing cortisol regeneration in tissues may enhance insulin sensitivity and lead to novel developments in the treatment of DM.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available