Cargando…

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

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Tofte, Nete, Suvitaival, Tommi, Trost, Kajetan, Mattila, Ismo Matias, Theilade, Simone, Winther, Signe Abitz, Ahluwalia, Tarunveer Singh, Frimodt-Møller, Marie, Legido-Quigley, Cristina, Rossing, Peter
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6883958/
https://www.ncbi.nlm.nih.gov/pubmed/31824430
http://dx.doi.org/10.3389/fendo.2019.00818
_version_ 1783474479702212608
author Tofte, Nete
Suvitaival, Tommi
Trost, Kajetan
Mattila, Ismo Matias
Theilade, Simone
Winther, Signe Abitz
Ahluwalia, Tarunveer Singh
Frimodt-Møller, Marie
Legido-Quigley, Cristina
Rossing, Peter
author_facet Tofte, Nete
Suvitaival, Tommi
Trost, Kajetan
Mattila, Ismo Matias
Theilade, Simone
Winther, Signe Abitz
Ahluwalia, Tarunveer Singh
Frimodt-Møller, Marie
Legido-Quigley, Cristina
Rossing, Peter
author_sort Tofte, Nete
collection PubMed
description 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.
format Online
Article
Text
id pubmed-6883958
institution National Center for Biotechnology Information
language English
publishDate 2019
publisher Frontiers Media S.A.
record_format MEDLINE/PubMed
spelling pubmed-68839582019-12-10 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 Tofte, Nete Suvitaival, Tommi Trost, Kajetan Mattila, Ismo Matias Theilade, Simone Winther, Signe Abitz Ahluwalia, Tarunveer Singh Frimodt-Møller, Marie Legido-Quigley, Cristina Rossing, Peter Front Endocrinol (Lausanne) Endocrinology 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. Frontiers Media S.A. 2019-11-22 /pmc/articles/PMC6883958/ /pubmed/31824430 http://dx.doi.org/10.3389/fendo.2019.00818 Text en Copyright © 2019 Tofte, Suvitaival, Trost, Mattila, Theilade, Winther, Ahluwalia, Frimodt-Møller, Legido-Quigley and Rossing. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Endocrinology
Tofte, Nete
Suvitaival, Tommi
Trost, Kajetan
Mattila, Ismo Matias
Theilade, Simone
Winther, Signe Abitz
Ahluwalia, Tarunveer Singh
Frimodt-Møller, Marie
Legido-Quigley, Cristina
Rossing, Peter
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
title 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
title_full 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
title_fullStr 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
title_full_unstemmed 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
title_short 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
title_sort 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
topic Endocrinology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6883958/
https://www.ncbi.nlm.nih.gov/pubmed/31824430
http://dx.doi.org/10.3389/fendo.2019.00818
work_keys_str_mv AT toftenete metabolomicassessmentrevealsalterationinpolyolsandbranchedchainaminoacidsassociatedwithpresentandfuturerenalimpairmentinadiscoverycohortof637personswithtype1diabetes
AT suvitaivaltommi metabolomicassessmentrevealsalterationinpolyolsandbranchedchainaminoacidsassociatedwithpresentandfuturerenalimpairmentinadiscoverycohortof637personswithtype1diabetes
AT trostkajetan metabolomicassessmentrevealsalterationinpolyolsandbranchedchainaminoacidsassociatedwithpresentandfuturerenalimpairmentinadiscoverycohortof637personswithtype1diabetes
AT mattilaismomatias metabolomicassessmentrevealsalterationinpolyolsandbranchedchainaminoacidsassociatedwithpresentandfuturerenalimpairmentinadiscoverycohortof637personswithtype1diabetes
AT theiladesimone metabolomicassessmentrevealsalterationinpolyolsandbranchedchainaminoacidsassociatedwithpresentandfuturerenalimpairmentinadiscoverycohortof637personswithtype1diabetes
AT winthersigneabitz metabolomicassessmentrevealsalterationinpolyolsandbranchedchainaminoacidsassociatedwithpresentandfuturerenalimpairmentinadiscoverycohortof637personswithtype1diabetes
AT ahluwaliatarunveersingh metabolomicassessmentrevealsalterationinpolyolsandbranchedchainaminoacidsassociatedwithpresentandfuturerenalimpairmentinadiscoverycohortof637personswithtype1diabetes
AT frimodtmøllermarie metabolomicassessmentrevealsalterationinpolyolsandbranchedchainaminoacidsassociatedwithpresentandfuturerenalimpairmentinadiscoverycohortof637personswithtype1diabetes
AT legidoquigleycristina metabolomicassessmentrevealsalterationinpolyolsandbranchedchainaminoacidsassociatedwithpresentandfuturerenalimpairmentinadiscoverycohortof637personswithtype1diabetes
AT rossingpeter metabolomicassessmentrevealsalterationinpolyolsandbranchedchainaminoacidsassociatedwithpresentandfuturerenalimpairmentinadiscoverycohortof637personswithtype1diabetes