SFEBES2014 Poster Presentations Obesity, diabetes, metabolism and cardiovascular (80 abstracts)
Longitudinal changes in glucocorticoid metabolism predict the development of metabolic phenotype
Rachel Crowley 1 , Beverly Hughes 1 , Joanna Gray 2 , Theresa McCarthy 2 , Susan Hughes 1 , Cedric Shackleton 3 , Nicola Crabtree 2 , Peter Nightingale 2 , Paul Stewart 1 & Jeremy Tomlinson 1
1Centre for Endocrinology, Diabetes and Metabolism, University of Birmingham, Birmingham, UK; 2NIHR / Wellcome Trust Clinical Research Facility, Queen Elizabeth Hospital, Birmingham, UK; 3Children’s Hospital, Oakland’s Research Institute, Oakland, California , USA.
Dysregulation of the enzymes that control local tissue steroid metabolism has been implicated in the pathogenesis of obesity and insulin resistant states, however longitudinal changes in glucocorticoid metabolism over time have not been investigated. This study was designed to evaluate the role of pre-receptor glucocorticoid metabolism in the development of insulin resistance and obesity. 24 h urinary glucocorticoid and mineralocorticoid metabolites were measured by gas chromatography/mass spectrometry in obese and overweight patients serially over 5 years and analysed in the context of dysglycaemia and hypertension at final visit, in order to identify potential biomarkers for the future development of metabolic disease.
Higher 5α-reductase activity, but not 11β-hydroxysteroid dehydrogenase type 1 activity, at study baseline was predictive of later development of increased fasting insulin (11.4 compared to 7.4 mU/l in subjects with lower 5αR activity, P<0.05), insulin response to oral glucose tolerance test (area under the curve for insulin 176.7 compared to 89. mU/l.h, P<0.01) and insulin resistance (HOMA2-IR 1.3 compared to 0.8, P<0.01) in obese and overweight subjects. Higher total glucocorticoid production was associated with abnormal glucose tolerance and increased BMI. Increased activation of the mineralocorticoid receptor during the study was indicated by increasing systolic blood pressure (equivalent to ~ 1 mmHg/year) and plasma sodium levels over the 5 years of the study; mineralocorticoid activity was associated with increased aldosterone and decreased 11β-hydroxysteroid dehydrogenase type 2 activity.
This is the first longitudinal analysis of corticosteroid secretion and metabolism and its relationship with metabolic phenotype. Increased 5α-reductase activity and glucocorticoid secretion rate over time are linked to the development of metabolic disease, and may represent targets for therapeutic intervention.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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