Metabolomic Assessment Reveals Alteration in Polyols and Branched Chain Amino Acids Associated With Present and Future Renal Impairment in a Discovery Cohort of 637 Persons With Type 1 Diabetes.

Autor:	Tofte N; Steno Diabetes Center Copenhagen, Gentofte, Denmark., Suvitaival T; Steno Diabetes Center Copenhagen, Gentofte, Denmark., Trost K; Steno Diabetes Center Copenhagen, Gentofte, Denmark., Mattila IM; Steno Diabetes Center Copenhagen, Gentofte, Denmark., Theilade S; Steno Diabetes Center Copenhagen, Gentofte, Denmark., Winther SA; Steno Diabetes Center Copenhagen, Gentofte, Denmark.; Novo Nordisk A/S, Måløv, Denmark., Ahluwalia TS; Steno Diabetes Center Copenhagen, Gentofte, Denmark., Frimodt-Møller M; Steno Diabetes Center Copenhagen, Gentofte, Denmark., Legido-Quigley C; Steno Diabetes Center Copenhagen, Gentofte, Denmark.; Institute of Pharmaceutical Science, King's College London, London, United Kingdom., Rossing P; Steno Diabetes Center Copenhagen, Gentofte, Denmark.; Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.
Jazyk:	angličtina
Zdroj:	Frontiers in endocrinology [Front Endocrinol (Lausanne)] 2019 Nov 22; Vol. 10, pp. 818. Date of Electronic Publication: 2019 Nov 22 (Print Publication: 2019).
DOI:	10.3389/fendo.2019.00818
Abstrakt:	Background: Improved understanding of the pathophysiology causing diabetic kidney disease (DKD) is imperative. The aim of this study was to uncover associations between serum metabolites and renal outcomes. Methods: Non-targeted serum metabolomics analyses were performed in samples from 637 persons with type 1 diabetes using two-dimensional gas chromatography coupled to time-of-flight mass-spectrometry. Longitudinal data at follow-up (median 5.5 years) on renal events were obtained from national Danish health registries. A composite renal endpoint ( n = 123) consisted of estimated glomerular filtration rate (eGFR) decline from baseline (≥30%), progression to end-stage renal disease and all-cause mortality. Metabolites with significant associations ( p < 0.05) in any of the cross-sectional analyses with eGFR and albuminuria were analyzed for specific and composite endpoints. Adjustments included traditional cardiovascular risk factors and correction for multiple testing. Results: A data-driven partial correlation analysis revealed a dense fabric of co-regulated metabolites and clinical variables dominated by eGFR. Ribonic acid and myo-inositol were inversely associated with eGFR, positively associated with macroalbuminuria ( p < 0.02) and longitudinally associated with higher risk of eGFR decline ≥30% (HR 2.2-2.7, CI [1.3-4.3], p < 0.001). Ribonic acid was associated with a combined renal endpoint (HR 1.8, CI [1.3-2.3], p = 0.001). The hydroxy butyrate 3,4-dihydroxybutanoic acid was cross-sectionally associated with micro- and macroalbuminuria, urinary albumin excretion rate and inversely associated with eGFR ( p < 0.04) while branched chain amino acids were associated with eGFR and lower risk of the combined renal endpoint ( p < 0.02). Conclusions: Alterations in serum metabolites, particularly polyols and amino acids, were associated with renal endpoints in type 1 diabetes highlighting molecular pathways associated with progression of kidney disease. External validation is needed to further assess their roles and potentials as future therapeutic targets. (Copyright © 2019 Tofte, Suvitaival, Trost, Mattila, Theilade, Winther, Ahluwalia, Frimodt-Møller, Legido-Quigley and Rossing.)
Databáze:	MEDLINE
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