Circulating metabolic biomarkers of renal function in diabetic and non-diabetic populations

Abstract

Using targeted NMR spectroscopy of 227 fasting serum metabolic traits, we searched for novel metabolic signatures of renal function in 926 type 2 diabetics (T2D) and 4838 non-diabetic individuals from four independent cohorts. We furthermore investigated longitudinal changes of metabolic measures and renal function and associations with other T2D microvascular complications. 142 traits correlated with glomerular filtration rate (eGFR) after adjusting for confounders and multiple testing: 59 in diabetics, 109 in non-diabetics with 26 overlapping. The amino acids glycine and phenylalanine and the energy metabolites citrate and glycerol were negatively associated with eGFR in all the cohorts, while alanine, valine and pyruvate depicted opposite association in diabetics (positive) and non-diabetics (negative). Moreover, in all cohorts, the triglyceride content of different lipoprotein subclasses showed a negative association with eGFR, while cholesterol, cholesterol esters (CE), and phospholipids in HDL were associated with better renal function. In contrast, phospholipids and CEs in LDL showed positive associations with eGFR only in T2D, while phospholipid content in HDL was positively associated with eGFR both cross-sectionally and longitudinally only in non-diabetics. In conclusion, we provide a wide list of kidney function-associated metabolic traits and identified novel metabolic differences between diabetic and non-diabetic kidney disease. ; TwinsUK was funded by the Wellcome Trust; European Community's Seventh Framework Programme (FP7/2007–2013). The study also receives support from the National Institute for Health Research (NIHR) Clinical Research Facility at Guy's & St Thomas' NHS Foundation Trust and NIHR Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust and King's College London. TS is holder of an ERC Advanced Principal Investigator award. CB and the Genodiab-Mar cohort is supported by a grant from the Institute Carlos III (FIS-FEDER PI16/00620) and RedinRen RD16/0013/0009. CM is funded by the MRC AimHy (MR/M016560/1) project grant. The KORA study was initiated and financed by the Helmholtz Zentrum München – German Research Center for Environmental Health, which is funded by the German Federal Ministry of Education and Research (BMBF) and by the State of Bavaria. Furthermore, KORA research has been supported within the Munich Center of Health Sciences (MC-Health), Ludwig-Maximilians-Universität, as part of LMUinnovativ. The research leading to these results has received funding from the European Union Seventh Framework Programme under grant agreement [n°313010] (Large-scale prospective cohort studies - BBMRI-LPC; www.bbmri-lpc.org), [n°305280] (Methods for Integrated analysis of multiple Omics datasets – MIMOmics; http://www.mimomics.eu/) and under grant agreements [n°603288] (Systems Biology to Identify Molecular Targets for Vascular Disease Treatment – SysVasc; http://www.sysvasc.eu/). The Young Finns Study has been financially supported by the Academy of Finland: grants 286284, 134309 (Eye), 126925, 121584, 124282, 129378 (Salve), 117787 (Gendi), and 41071 (Skidi); the Social Insurance Institution of Finland; Competitive State Research Financing of the Expert Responsibility area of Kuopio, Tampere and Turku University Hospitals (grant X51001); Juho Vainio Foundation; Paavo Nurmi Foundation; Finnish Foundation for Cardiovascular Research; Finnish Cultural Foundation; Tampere Tuberculosis Foundation; Emil Aaltonen Foundation; Yrjö Jahnsson Foundation; Signe and Ane Gyllenberg Foundation; and Diabetes Research Foundation of Finnish Diabetes Association. MAK was supported by the Sigrid Juselius Foundation, Finland. MAK works in a Unit that is supported by the University of Bristol and UK Medical Research Council (MC_UU_12013/1). PW is funded by the Academy of Finland (312476 & 312477), and the Novo Nordisk Foundation Competing Interests.