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GDF15 is elevated in conditions of glucocorticoid deficiency and is modulated by glucocorticoid replacement

Lookup NU author(s): Professor Brian Walker

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

Context: GDF15 is a stress-induced hormone acting in the hindbrain that activates neural circuitry involved in establishing aversive responses and reducing food intake and body weight in animal models. Anorexia, weight loss, nausea and vomiting are common manifestations of glucocorticoid deficiency and we hypothesised that glucocorticoid deficiency may be associated with elevated levels of GDF15.Objective: To determine the impact of primary adrenal insufficiency (PAI) and glucocorticoid replacement on circulating GDF15 levels.Methods and Results: We measured circulating concentrations of GDF15 in a cohort of Addison’s disease patients following steroid withdrawal and healthy volunteers. Significantly higher GDF15 (mean±SD) was observed in the Addison’s cohort, 739.1±225.8 pg/ml vs. healthy controls 497.9±167.7 pg/ml (p=0.01). The effect of hydrocortisone replacement on GDF15 was assessed in three independent PAI cohorts with classical congenital adrenal hyperplasia or Addison’s disease; intravenous hydrocortisone replacement reduced GDF15 in all groups. We examined the response of GDF15 to increasing doses of glucocorticoid replacement in healthy volunteers with pharmacologically mediated cortisol deficiency. A dose-dependent difference in GDF15 (mean±SD) was observed between the groups with values of 491.0±157.7 pg/ml, 427.0±152.1 pg/ml and 360±143.1 pg/ml, in the low, medium and high glucocorticoid replacement groups respectively, p <0.0001. Conclusions: GDF15 is increased in states of glucocorticoid deficiency and restored by glucocorticoid replacement. Given the site of action of GDF15 in the hindbrain and its effects on appetite, further study is required to determine the effect of GDF15 in mediating the anorexia and nausea that is a common feature of glucocorticoid deficiency.


Publication metadata

Author(s): Melvin A, Chantzichristos D, Kyle CJ, Mackenzie SD, Walker BR, Johannsson G, Stimson RH, O'Rahilly S

Publication type: Article

Publication status: Published

Journal: The Journal of Clinical Endocrinology and Metabolism

Year: 2020

Volume: 105

Issue: 5

Print publication date: 05/05/2020

Online publication date: 19/12/2019

Acceptance date: 12/12/2019

Date deposited: 16/12/2019

ISSN (print): 0021-972X

ISSN (electronic): 1945-7197

Publisher: Oxford University Press

URL: https://doi.org/10.1210/clinem/dgz277

DOI: 10.1210/clinem/dgz277


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Funding

Funder referenceFunder name
MR/K010271/1
MRC
Wellcome Trust (107049/Z/15/Z)

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