ECE2018 Guided Posters Adrenal cortex (10 abstracts)
The circadian rhythm of glucocorticoid administration entrains clock-controlled genes in blood mononuclear cells: a DREAM trial ancillary study
Mary Anna Venneri 1 , Valeria Hasenmajer 1 , Daniela Fiore 1 , Emilia Sbardella 1 , Riccardo Pofi 1, , Chiara Graziadio 1 , Daniele Gianfrilli 1 , Claudia Pivonello 3 , Mariarosaria Negri 3 , Fabio Naro 1 , Ashley B Grossman 2 , Andrea Lenzi 1 , Rosario Pivonello 3 & Andrea M Isidori 1
1Sapienza University of Rome, Rome, Italy; 2University of Oxford, Oxford, UK; 3Università Federico II di Napoli, Napoli, Italy.
Introduction: Adrenal insufficiency requires life-long glucocorticoid replacement. Conventional therapies fail to mimic endogenous cortisol circadian rhythm. Clock genes are essential components of the molecular machinery controlling organ’s circadian function and are influenced by glucocorticoids. However, clock genes expression has never been investigated in patients with adrenal insufficiency (AI).
Aim: To evaluate the effect of the timing of glucocorticoid administration on circadian genes expression in peripheral blood mononuclear cells (PBMCs) of AI patients enrolled in the DREAM trial.
Methods: We enrolled 89 AI patients taking conventional glucocorticoid therapy, that were randomly assigned to continue their standard multiple times a day therapy or switch to an equivalent dose of once-daily, modified-release hydrocortisone and 25 healthy matched controls. 83 subjects consented gene expression analysis by realtime qRT-PCR.
Results: Compared to healthy controls, 19 of the 68 genes detected in the PBMC were found differentially expressed in AI patients, at baseline, and 18 restored to control levels 12 week after switching from the standard to once-daily modified-release hydrocortisone, including the core of the clock-machinery: ARNTL[BMAL] (P=0.024), CLOCK (P=0.016), PER3 (P<0.001) and TIMELESS (<0.001); the Creb-related 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) and PRKCB (P=0.006); the transcription factors SP1 (P<0.001) and WEE1 (P<0.001) and the other circadian-related CSNK1A1 (P<0.001), ONP3 (P<0.001) and PRF1 (P<0.001). Changes in gene expression in PBMCs correlated with metabolic and immune findings.
Conclusions: AI patients on standard multiple times a day replacement therapy exhibit a dysregulation of circadian genes in peripheral blood cells. The switch to the once daily modified-release hydrocortisone reconditions peripheral tissue gene expression to an extent that correlates with the clinical outcomes of the DREAM trial [NCT02277587].
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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