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. 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 5a-reductase (5aR) activity, but not 11b-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 5aR 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 w1 mmHg/year), as did plasma sodium levels; this evidence of increased mineralocorticoid activity was associated with increased aldosterone metabolites and decreased 11b-hydroxysteroid dehydrogenase type 2 activity. Conclusions: Increased 5aR 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.

Effect of Age, Season, Body Condition, and Endocrine Status on Serum Free Cortisol Fraction and Insulin Concentration in Horses

“…Alternatively, obesity itself might be the primary stimulus for either global overactivation of the HPA axis resulting in increased circulating cortisol concentrations, or increases in cortisol availability or activity at the level of the target tissues, or both. Chronically increased glucocorticoid production and increased hair cortisol (consistent with chronic free cortisol excess) have been associated with obesity in several studies in people,38, 39, 40, 41 and are consistent with long‐standing over‐activity of the HPA axis in obese states. Tissue cortisol metabolism also appears to be altered in obesity.…”

THERAPY OF ENDOCRINE DISEASE: Improvement of cardiovascular risk factors after adrenalectomy in patients with adrenal tumors and subclinical Cushing’s syndrome: a systematic review and meta-analysis

“…One of the likely explanations for this observation could be a potential misclassification of patients; for example, one study described that a significant proportion of patients with NF adrenal tumors developed adrenal insufficiency after surgery, clearly suggesting that autonomous glucocorticoid production was not recognized preoperatively (47). Overall glucocorticoid production has been linked to HTN, abnormal glucose tolerance and increased BMI (50). Thus, it is also possible that a temporary reduction of the overall glucocorticoid load caused by unilateral adrenalectomy could have contributed to a short-term BP improvement described in patients with NF adrenal tumors.…”

Glucocorticoids and non-alcoholic fatty liver disease

“…Activity increases with BMI and decreases with weight loss and in addition predicts the future development of an adverse metabolic phenotype (123)(124)(125). Specifically in the context of NAFLD, 5αR activity is generally reported as increased (113) and isotope clearance studies using liquid chromatography tandem mass spectrometry have demonstrated increased cortisol clearance (126) .Differences in activity according to stage of disease have also been proposed with increased 5αR activity in patients with NASH and not simple steatosis.…”