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University of Edinburgh, Endocrinology Unit, Department of Medical Sciences, Western General Hospital, Edinburgh EH4 2XU, United Kingdom
Address all correspondence and requests for reprints to: Prof. Brian R. Walker, British Heart Foundation Senior Research Fellow, University of Edinburgh, Endocrinology Unit, Department of Medical Sciences, Western General Hospital, Edinburgh EH4 2XU, United Kingdom. E-mail: B.Walker{at}ed.ac.uk.
Abstract
Recent evidence suggests that increased cortisol secretion, altered cortisol metabolism, and/or increased tissue sensitivity to cortisol may link insulin resistance, hypertension, and obesity. Whether these changes are important in type 2 diabetes mellitus (DM) is unknown.
We performed an integrated assessment of glucocorticoid secretion, metabolism, and action in 25 unmedicated lean male patients with hyperglycemia (20 with type 2 diabetes and 5 with impaired glucose intolerance by World Health Organization criteria) and 25 healthy men, carefully matched for body mass index, age, and blood pressure. Data are mean ± SE. Patients with hyperglycemia (DM) had higher HbA1c (6.9 ± 0.2% vs. 6.0 ± 0.1%, P < 0.0001) and triglycerides. Cortisol secretion was not different, as judged by 0900 h plasma cortisol and 24 h total urinary cortisol metabolites. However, the proportion of cortisol excreted as 5
- and 5ß-reduced metabolites was increased in DM patients. Following an oral dose of cortisone 25 mg, generation of plasma cortisol by hepatic 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD 1) was impaired in DM patients (area under the curve, 3617 ± 281 nM.2 h vs. 4475 ± 228; P < 0.005). In contrast, in sc gluteal fat biopsies from 17 subjects (5 DM and 12 controls) in vitro 11ß-HSD 1 activity was not different (area under the curve, 128 ± 56% conversion.30 h DM vs. 119 ± 21, P = 0.86). Sensitivity to glucocorticoids was increased in DM patients both centrally (0900 h plasma cortisol after overnight 250 µg oral dexamethasone 172 ± 16 nM vs. 238 ± 20 nM, P < 0.01) and peripherally (more intense forearm dermal blanching following overnight topical beclomethasone; 0.56 ± 0.92 ratio to vehicle vs. 0.82 ± 0.69, P < 0.05).
In summary, in patients with glucose intolerance, cortisol secretion, although normal, is inappropriately high given enhanced central and peripheral sensitivity to glucocorticoids. Normal 11ß-HSD 1 activity in adipose tissue with impaired hepatic conversion of cortisone to cortisol suggests that tissue-specific changes in 11ß-HSD 1 activity in hyperglycemia differ from those in primary obesity but may still be susceptible to pharmacological inhibition of the enzyme to reduce intracellular cortisol concentrations. Thus, altered cortisol action occurs not only in obesity and hypertension but also in glucose intolerance, and could therefore contribute to the link between these multiple cardiovascular risk factors.
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