Circadian rhythm of glucocorticoid administration entrains clock genes in immune cells: a DREAM trial ancillary study

Circadian rhythm of glucocorticoid administration entrains clock genes in immune cells: a DREAM... Abstract Context Adrenal insufficiency (AI) requires life-long glucocorticoid replacement. Conventional therapies fail to mimic the endogenous cortisol circadian rhythm. Clock genes are essential components of the molecular machinery controlling an organ’s circadian function and are influenced by glucocorticoids. However, clock gene expression has never been investigated in AI patients. Objective To evaluate the effect of the timing of glucocorticoid administration on circadian gene expression in peripheral blood mononuclear cells (PBMCs) of AI patients from the DREAM trial. Design Outcome assessors blinded, randomized, active comparator clinical trial. Participants and Intervention Eighty-nine AI patients taking glucocorticoids were randomly assigned to continue their multiple daily doses, or switch to an equivalent dose of once-daily modified-release hydrocortisone, and compared to 25 healthy controls: 65 AI patients and 18 controls consented gene expression analysis by real-time qRT-PCR. Results Compared to healthy controls, 19 of the 68 genes were found differentially expressed in AI patients at baseline, 18 of which were restored to control levels 12 week after switching therapy, comprising: ARNTL[BMAL] (P=0.024), CLOCK (P=0.016), PER3 (P<0.001), TIMELESS (<0.001), AANAT (p=0.021), CAMK2D (p<0.001), CREB1 (p=0.010), CREB3 (p=0.037), MAPK1 (p<0.001), MAT2A (p=0.013), PRKAR1A (p=0.006), PRKAR2A (p=0.006), PRKCB (p=0.006); SP1 (p<0.001), WEE1 (p<0.001), CSNK1A1 (p<0.001), ONP3 (p<0.001) and PRF1 (p<0.001). Changes in WEE1, PRF1 and PER3 expression correlated with glycated hemoglobin, inflammatory monocytes and CD16+ NK cells. Conclusions AI patients on standard therapy exhibit a dysregulation of circadian genes in PBMCs. The once-daily administration reconditions peripheral tissue gene expression to levels close to healthy controls, paralleling the clinical outcomes of the DREAM trial [NCT02277587]. Copyright © 2018 Endocrine Society http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Clinical Endocrinology and Metabolism Oxford University Press

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Publisher
Endocrine Society
Copyright
Copyright © 2018 Endocrine Society
ISSN
0021-972X
eISSN
1945-7197
D.O.I.
10.1210/jc.2018-00346
Publisher site
See Article on Publisher Site

Abstract

Abstract Context Adrenal insufficiency (AI) requires life-long glucocorticoid replacement. Conventional therapies fail to mimic the endogenous cortisol circadian rhythm. Clock genes are essential components of the molecular machinery controlling an organ’s circadian function and are influenced by glucocorticoids. However, clock gene expression has never been investigated in AI patients. Objective To evaluate the effect of the timing of glucocorticoid administration on circadian gene expression in peripheral blood mononuclear cells (PBMCs) of AI patients from the DREAM trial. Design Outcome assessors blinded, randomized, active comparator clinical trial. Participants and Intervention Eighty-nine AI patients taking glucocorticoids were randomly assigned to continue their multiple daily doses, or switch to an equivalent dose of once-daily modified-release hydrocortisone, and compared to 25 healthy controls: 65 AI patients and 18 controls consented gene expression analysis by real-time qRT-PCR. Results Compared to healthy controls, 19 of the 68 genes were found differentially expressed in AI patients at baseline, 18 of which were restored to control levels 12 week after switching therapy, comprising: ARNTL[BMAL] (P=0.024), CLOCK (P=0.016), PER3 (P<0.001), TIMELESS (<0.001), AANAT (p=0.021), CAMK2D (p<0.001), CREB1 (p=0.010), CREB3 (p=0.037), MAPK1 (p<0.001), MAT2A (p=0.013), PRKAR1A (p=0.006), PRKAR2A (p=0.006), PRKCB (p=0.006); SP1 (p<0.001), WEE1 (p<0.001), CSNK1A1 (p<0.001), ONP3 (p<0.001) and PRF1 (p<0.001). Changes in WEE1, PRF1 and PER3 expression correlated with glycated hemoglobin, inflammatory monocytes and CD16+ NK cells. Conclusions AI patients on standard therapy exhibit a dysregulation of circadian genes in PBMCs. The once-daily administration reconditions peripheral tissue gene expression to levels close to healthy controls, paralleling the clinical outcomes of the DREAM trial [NCT02277587]. Copyright © 2018 Endocrine Society

Journal

Journal of Clinical Endocrinology and MetabolismOxford University Press

Published: May 25, 2018

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