ECE2018 Guided Posters Adrenal cortex (10 abstracts)
Effects of replication of the physiological and non-physiological cortisol rhythm on insulin sensitivity in muscle: a molecular in vitro analysis on synchronized muscular cells
Mariarosaria Negri 1 , Gilda Di Gennaro 1 , Claudia Pivonello 1 , Chiara Simeoli 1 , Mary Anna Vennery 2 , Federica Barbagallo 2 , Davide Iacuaniello 1 , Maria Cristina De Martino 1 , Andrea Maria Isidoro 2 , Annamaria Colao 1 & Rosario Pivonello 1
1Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Università Federico II di Napoli, Naples, Italy; 2Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy.
Adrenal insufficiency is a rare endocrine disorder characterized by low levels of cortisol associated with increased mortality, also due to inadequate replacement therapy. The replacement with the thrice-daily immediate release hydrocortisone (IRH), in contrast to the once-daily modified-release hydrocortisone (MRH), more appropriately mimicking the physiological circadian rhythm of cortisol (PCRC), is associated with metabolic disorders, mainly due to the non-physiological peak of cortisol in the evening. The aim of the current in vitro study was to compare the effects of exposure to concentrations achieved in vivo during the different phases of day after IRH and MRH administration, compared to PCRC, on muscle insulin sensitivity. To this purpose, a mouse skeletal muscle cell line (C2C12), has been used and the in vitro oscillation of 24-hour peripheral clock genes expression (BMAL-1, PER-1, PER-2, CRY-2) has been induced by serum shock treatment and analysed by RT-qPCR, allowing to calculate treatment schedules of morning, afternoon and evening exposure (»0800 h, »1300 h and »0600 h), respectively. Simultaneously, the relative expression levels of 84 genes classically involved in muscle insulin sensitivity have been analysed by genomic microarrays and compared between PCRC, IRH and MRH simulated therapies at different times of treatment schedules. In particular, for the evening exposure, microarray analysis showed identical gene expression between IRH treatment and PCRC, whereas MRH caused significant down-regulation of 21 genes relative expression (P<0.05) including insulin receptor (P=0.02), IRS-1 (P=0.02), IRS-2 (P=0.01), PI3KCA (P=0.03), ADIPOR-2 (P=0.02), additionally confirmed by RT-qPCR. Moreover, WB analysis revealed that evening exposure to IRH might reduce intracellular phosphorylated levels of IRS-1 at Tyr608 and of Akt at Ser473 compared to MRH and PCRC treatments suggesting a robust involvement in muscle insulin resistance. In conclusion, these preliminary data demonstrate that, especially for the evening exposure, MRH might preserve the muscle insulin sensitivity otherwise compromised by IRH.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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