title: Longitudinal changes in glucocorticoid metabolism are associated with later development of adverse metabolic phenotype.
abstract: OBJECTIVE
  Dysregulation of enzymes that control local tissue steroid metabolism has been implicated in the pathogenesis of obesity and insulin resistance; however, longitudinal changes in glucocorticoid metabolism have not been investigated. This study was performed to evaluate the role of glucocorticoid metabolism in the development of insulin resistance and obesity and to identify biomarkers for future development of metabolic disease.
  
  
  METHODS
  This was a prospective longitudinal observation study conducted over 5 years.
  
  
  METHODS
  A 24-h collection was used to serially analyze urinary glucocorticoid and mineralocorticoid metabolites in 57 obese and overweight patients with no prior diagnosis of diabetes mellitus, recruited from the community.
  
  
  RESULTS
  Baseline higher 5α-reductase (5αR) activity, but not 11β-hydroxysteroid dehydrogenase type 1 activity, was predictive of increased fasting insulin at final visit (11.4 compared with 7.4 mU/l in subjects with lower 5αR activity, P<0.05), area under the curve insulin response to oral glucose tolerance test (176.7 compared with 89.1 mU/l.h, P<0.01), and homeostasis model assessment (HOMA2-IR; 1.3 compared with 0.8, P<0.01). Higher total glucocorticoid production was associated with abnormal glucose tolerance and increased BMI. During this study, systolic blood pressure increased (equivalent to ∼1 mmHg/year), as did plasma sodium levels; this evidence of increased mineralocorticoid activity was associated with increased aldosterone metabolites and decreased 11β-hydroxysteroid dehydrogenase type 2 activity.
  
  
  CONCLUSIONS
  Increased 5αR activity and glucocorticoid secretion rate over time are linked with the development of metabolic disease, and may represent targets for therapeutic intervention, which merits further study.
authors.affiliation: School of Clinical and Experimental MedicineInstitute of Biomedical Research, Centre for Endocrinology, Diabetes and Metabolism, Queen Elizabeth Hospital, University of Birmingham, Birmingham B15 2TT, UKNIHR/Wellcome Trust Clinical Research FacilityQueen Elizabeth Hospital, Birmingham, UK.
authors.forename: Rachel K
authors.initials: RK
authors.lastname: Crowley
authors.affiliation: School of Clinical and Experimental MedicineInstitute of Biomedical Research, Centre for Endocrinology, Diabetes and Metabolism, Queen Elizabeth Hospital, University of Birmingham, Birmingham B15 2TT, UKNIHR/Wellcome Trust Clinical Research FacilityQueen Elizabeth Hospital, Birmingham, UK.
authors.forename: Beverly
authors.initials: B
authors.lastname: Hughes
authors.affiliation: School of Clinical and Experimental MedicineInstitute of Biomedical Research, Centre for Endocrinology, Diabetes and Metabolism, Queen Elizabeth Hospital, University of Birmingham, Birmingham B15 2TT, UKNIHR/Wellcome Trust Clinical Research FacilityQueen Elizabeth Hospital, Birmingham, UK.
authors.forename: Joanna
authors.initials: J
authors.lastname: Gray
authors.affiliation: School of Clinical and Experimental MedicineInstitute of Biomedical Research, Centre for Endocrinology, Diabetes and Metabolism, Queen Elizabeth Hospital, University of Birmingham, Birmingham B15 2TT, UKNIHR/Wellcome Trust Clinical Research FacilityQueen Elizabeth Hospital, Birmingham, UK.
authors.forename: Theresa
authors.initials: T
authors.lastname: McCarthy
authors.affiliation: School of Clinical and Experimental MedicineInstitute of Biomedical Research, Centre for Endocrinology, Diabetes and Metabolism, Queen Elizabeth Hospital, University of Birmingham, Birmingham B15 2TT, UKNIHR/Wellcome Trust Clinical Research FacilityQueen Elizabeth Hospital, Birmingham, UK.
authors.forename: Susan
authors.initials: S
authors.lastname: Hughes
authors.affiliation: School of Clinical and Experimental MedicineInstitute of Biomedical Research, Centre for Endocrinology, Diabetes and Metabolism, Queen Elizabeth Hospital, University of Birmingham, Birmingham B15 2TT, UKNIHR/Wellcome Trust Clinical Research FacilityQueen Elizabeth Hospital, Birmingham, UK.
authors.forename: Cedric H L
authors.initials: CH
authors.lastname: Shackleton
authors.affiliation: School of Clinical and Experimental MedicineInstitute of Biomedical Research, Centre for Endocrinology, Diabetes and Metabolism, Queen Elizabeth Hospital, University of Birmingham, Birmingham B15 2TT, UKNIHR/Wellcome Trust Clinical Research FacilityQueen Elizabeth Hospital, Birmingham, UK.
authors.forename: Nicola
authors.initials: N
authors.lastname: Crabtree
authors.affiliation: School of Clinical and Experimental MedicineInstitute of Biomedical Research, Centre for Endocrinology, Diabetes and Metabolism, Queen Elizabeth Hospital, University of Birmingham, Birmingham B15 2TT, UKNIHR/Wellcome Trust Clinical Research FacilityQueen Elizabeth Hospital, Birmingham, UK.
authors.forename: Peter
authors.initials: P
authors.lastname: Nightingale
authors.affiliation: School of Clinical and Experimental MedicineInstitute of Biomedical Research, Centre for Endocrinology, Diabetes and Metabolism, Queen Elizabeth Hospital, University of Birmingham, Birmingham B15 2TT, UKNIHR/Wellcome Trust Clinical Research FacilityQueen Elizabeth Hospital, Birmingham, UK.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Stewart
authors.affiliation: School of Clinical and Experimental MedicineInstitute of Biomedical Research, Centre for Endocrinology, Diabetes and Metabolism, Queen Elizabeth Hospital, University of Birmingham, Birmingham B15 2TT, UKNIHR/Wellcome Trust Clinical Research FacilityQueen Elizabeth Hospital, Birmingham, UK J.W.Tomlinson@bham.ac.uk.
authors.forename: Jeremy W
authors.initials: JW
authors.lastname: Tomlinson
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000097:blood / Q000652:urine; D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase / Q000378:metabolism* / Q000652:urine; D000328:Adult; D000368:Aged; D001794:Blood Pressure; D005260:Female; D005938:Glucocorticoids / Q000097:blood / Q000378:metabolism* / Q000652:urine; D006801:Humans; D007328:Insulin / Q000097:blood* / Q000378:metabolism; D007333:Insulin Resistance; D016014:Linear Models; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D008901:Mineralocorticoids / Q000378:metabolism; D010641:Phenotype; D011237:Predictive Value of Tests; D011446:Prospective Studies
chemical_list: D005938:Glucocorticoids; D007328:Insulin; D008901:Mineralocorticoids; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase