TY - JOUR
T1 - Plasma Metabolomics Identifies Markers of Impaired Renal Function
T2 - A Meta-analysis of 3089 Persons with Type 2 Diabetes
AU - Tofte, Nete
AU - Vogelzangs, Nicole
AU - Mook-Kanamori, Dennis
AU - Brahimaj, Adela
AU - Nano, Jana
AU - Ahmadizar, Fariba
AU - van Dijk, Ko Willems
AU - Frimodt-Moller, Marie
AU - Arts, Ilja
AU - Beulens, Joline W. J.
AU - Rutters, Femke
AU - van der Heijden, Amber A.
AU - Kavousi, Maryam
AU - Stehouwer, Coen D. A.
AU - Nijpels, Giel
AU - van Greevenbroek, Marleen M. J.
AU - van der Kallen, Carla J. H.
AU - Rossing, Peter
AU - Ahluwalia, Tarunveer S.
AU - 't Hart, Leen M.
N1 - Publisher Copyright:
© Endocrine Society 2020. All rights reserved.
PY - 2020/7
Y1 - 2020/7
N2 - Context: There is a need for novel biomarkers and better understanding of the pathophysiology of diabetic kidney disease.Objective: To investigate associations between plasma metabolites and kidney function in people with type 2 diabetes (T2D).Design: 3089 samples from individuals with T2D, collected between 1999 and 2015, from 5 independent Dutch cohort studies were included. Up to 7 years follow-up was available in 1100 individuals from 2 of the cohorts.Main outcome measures: Plasma metabolites (n = 149) were measured by nuclear magnetic resonance spectroscopy. Associations between metabolites and estimated glomerular filtration rate (eGFR), urinary albumin-to-creatinine ratio (UACR), and eGFR slopes were investigated in each study followed by random effect meta-analysis. Adjustments included traditional cardiovascular risk factors and correction for multiple testing.Results: In total, 125 metabolites were significantly associated (P-FDR = 1.5x10(-32) - 0.046; beta = -11.98-2.17) with eGFR. Inverse associations with eGFR were demonstrated for branched-chain and aromatic amino acids (AAAs), glycoprotein acetyls, triglycerides (TGs), lipids in very low-density lipoproteins (VLDL) subclasses, and fatty acids (P-FDR <0.03). We observed positive associations with cholesterol and phospholipids in high-density lipoproteins (HDL) and apolipoprotein A1 (P-FDR <0.05). Albeit some metabolites were associated with UACR levels (P <0.05), significance was lost after correction for multiple testing. Tyrosine and HDL-related metabolites were positively associated with eGFR slopes before adjustment for multiple testing (P-Tyr = 0.003; P-HDLrelated <0.05), but not after.Conclusions: This study identified metabolites associated with impaired kidney function in T2D, implying involvement of lipid and amino acid metabolism in the pathogenesis. Whether these processes precede or are consequences of renal impairment needs further investigation.
AB - Context: There is a need for novel biomarkers and better understanding of the pathophysiology of diabetic kidney disease.Objective: To investigate associations between plasma metabolites and kidney function in people with type 2 diabetes (T2D).Design: 3089 samples from individuals with T2D, collected between 1999 and 2015, from 5 independent Dutch cohort studies were included. Up to 7 years follow-up was available in 1100 individuals from 2 of the cohorts.Main outcome measures: Plasma metabolites (n = 149) were measured by nuclear magnetic resonance spectroscopy. Associations between metabolites and estimated glomerular filtration rate (eGFR), urinary albumin-to-creatinine ratio (UACR), and eGFR slopes were investigated in each study followed by random effect meta-analysis. Adjustments included traditional cardiovascular risk factors and correction for multiple testing.Results: In total, 125 metabolites were significantly associated (P-FDR = 1.5x10(-32) - 0.046; beta = -11.98-2.17) with eGFR. Inverse associations with eGFR were demonstrated for branched-chain and aromatic amino acids (AAAs), glycoprotein acetyls, triglycerides (TGs), lipids in very low-density lipoproteins (VLDL) subclasses, and fatty acids (P-FDR <0.03). We observed positive associations with cholesterol and phospholipids in high-density lipoproteins (HDL) and apolipoprotein A1 (P-FDR <0.05). Albeit some metabolites were associated with UACR levels (P <0.05), significance was lost after correction for multiple testing. Tyrosine and HDL-related metabolites were positively associated with eGFR slopes before adjustment for multiple testing (P-Tyr = 0.003; P-HDLrelated <0.05), but not after.Conclusions: This study identified metabolites associated with impaired kidney function in T2D, implying involvement of lipid and amino acid metabolism in the pathogenesis. Whether these processes precede or are consequences of renal impairment needs further investigation.
KW - metabolomics
KW - NMR
KW - renal function
KW - albuminuria
KW - meta-analysis
KW - CHAIN AMINO-ACIDS
KW - KIDNEY-DISEASE
KW - TYROSINE METABOLISM
KW - INSULIN-RESISTANCE
KW - WIDE ASSOCIATION
KW - RISK
KW - TRIGLYCERIDES
KW - PHENYLALANINE
KW - EPIDEMIOLOGY
KW - CHOLESTEROL
U2 - 10.1210/clinem/dgaa173
DO - 10.1210/clinem/dgaa173
M3 - Article
C2 - 32271379
SN - 0021-972X
VL - 105
SP - 2275
EP - 2287
JO - Journal of Clinical Endocrinology & Metabolism
JF - Journal of Clinical Endocrinology & Metabolism
IS - 7
ER -