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1.
Clin Endocrinol (Oxf) ; 91(1): 72-81, 2019 07.
Article in English | MEDLINE | ID: mdl-30667079

ABSTRACT

OBJECTIVE AND CONTEXT: Increasing adiposity, ageing and tissue-specific regeneration of cortisol through the activity of 11ß-hydroxysteroid dehydrogenase type 1 have been associated with deterioration in glucose tolerance. We undertook a longitudinal, prospective clinical study to determine if alterations in local glucocorticoid metabolism track with changes in glucose tolerance. DESIGN, PATIENTS, AND MEASUREMENTS: Sixty-five overweight/obese individuals (mean age 50.3 ± 7.3 years) underwent oral glucose tolerance testing, body composition assessment, subcutaneous adipose tissue biopsy and urinary steroid metabolite analysis annually for up to 5 years. Participants were categorized into those in whom glucose tolerance deteriorated ("deteriorators") or improved ("improvers"). RESULTS: Deteriorating glucose tolerance was associated with increasing total and trunk fat mass and increased subcutaneous adipose tissue expression of lipogenic genes. Subcutaneous adipose tissue 11ß-HSD1 gene expression decreased in deteriorators, and at study completion, it was highest in the improvers. There was a significant negative correlation between change in area under the curve glucose and 11ß-HSD1 expression. Global 11ß-HSD1 activity did not change and was not different between deteriorators and improvers at baseline or follow-up. CONCLUSION: Longitudinal deterioration in metabolic phenotype is not associated with increased 11ß-HSD1 activity, but decreased subcutaneous adipose tissue gene expression. These changes may represent a compensatory mechanism to decrease local glucocorticoid exposure in the face of an adverse metabolic phenotype.


Subject(s)
11-beta-Hydroxysteroid Dehydrogenase Type 1/metabolism , Adiposity/physiology , Subcutaneous Fat/metabolism , Adiposity/genetics , Adrenal Cortex Hormones/metabolism , Adrenal Cortex Hormones/urine , Adult , Female , Glucocorticoids/metabolism , Glucocorticoids/urine , Humans , Longitudinal Studies , Male , Middle Aged , Prospective Studies , Real-Time Polymerase Chain Reaction
2.
Eur J Endocrinol ; 171(4): 433-42, 2014 Oct.
Article in English | MEDLINE | ID: mdl-24986533

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. DESIGN: 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 11ß-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 11ß-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.


Subject(s)
3-Oxo-5-alpha-Steroid 4-Dehydrogenase/metabolism , Glucocorticoids/metabolism , Insulin/blood , 11-beta-Hydroxysteroid Dehydrogenase Type 1/blood , 11-beta-Hydroxysteroid Dehydrogenase Type 1/urine , 3-Oxo-5-alpha-Steroid 4-Dehydrogenase/urine , Adult , Aged , Blood Pressure , Female , Glucocorticoids/blood , Glucocorticoids/urine , Humans , Insulin/metabolism , Insulin Resistance , Linear Models , Longitudinal Studies , Male , Middle Aged , Mineralocorticoids/metabolism , Phenotype , Predictive Value of Tests , Prospective Studies
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