Endocrine and metabolic determinants of cardiometabolic risk in mild autonomous cortisol secretion.
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Prete Alessandro, Abdi Lida, Canducci Marco, van den Brandhof Elina L, Albors-Zumel Ariadna, Jenkinson Carl, Gilligan Lorna C, Zhang Yuanqing, Visser Ludger, Chortis Vasileios, Najdekr Lukáš, Jankevics Andris, Lloyd Gavin R, Winder Catherine L, Tsagarakis Stylianos, Lang Katharina, Macech Magdalena, Fell Vanessa, Vodanovic Ivana D, Reimondo Giuseppe, Marina Ljiljana V, Deutschbein Timo, Balomenaki Maria, O'Reilly Michael W, Bednarczuk Tomasz, Dusek Tina, Diamantopoulos Aristidis, Asia Miriam, Kondracka Agnieszka, Yu Kai, Masjkur Jimmy R, Quinkler Marcus, Ueland Grethe Å, Dennedy M Conall, Beuschlein Felix, Tabarin Antoine, Fassnacht Martin, Ivovic Miomira, Terzolo Massimo, Kastelan Darko, Young William F, Manolopoulos Konstantinos N, Ambroziak Urszula, Vassiliadi Dimitra A, Bancos Irina, Sitch Alice J, Taylor Angela E, Tino Peter, Biehl Michael, Dunn Warwick B, Arlt Wiebke, ENSAT EURINE-ACT Investigators
Аннотация
METHODS: In a cross-sectional study, we analysed the 24-h urinary steroid metabolome of 1305 prospectively recruited patients (649 NFAT, 591 MACS, 65 adrenal CS) by tandem mass spectrometry. A sub-group (104 NFAT, 140 MACS, 47 adrenal CS) underwent untargeted serum metabolome analysis by mass spectrometry. Data were analysed using linear regression and supervised machine learning.
FINDINGS: Alongside the expected increase in glucocorticoid excretion from NFAT over MACS to adrenal CS, steroid analysis revealed decreased classic androgen metabolite excretion. By contrast, adrenal-derived 11-oxygenated androgen metabolites remained unchanged. Both glucocorticoid metabolites and the major 11-oxygenated androgen metabolite 11β-hydroxyandrosterone correlated with a higher risk of hypertension and type 2 diabetes. Untargeted metabolome analysis revealed gradual changes towards a lipotoxic phenotype from NFAT over MACS to adrenal CS, with perturbations in glycerophospholipids, lysoglycerophospholipids, triacylglycerides, ceramides, sphingolipids, and acylcarnitines.
INTERPRETATION: MACS represents a metabolic continuum between NFAT and adrenal CS. Increased activity of the adrenal enzyme 11β-hydroxylase (CYP11B1), which catalyses key steps in cortisol and 11-oxygenated androgen biosynthesis, may contribute to steroid excess and cardiometabolic morbidity in MACS. These findings suggest that CYP11B1 may be a potential therapeutic target to ameliorate metabolic dysfunction in MACS.
FUNDING: NIHR Birmingham Biomedical Research Centre; Diabetes UK; Wellcome Trust; European Commission; Medical Research Council.