Circulating metabolic biomarkers are consistently associated with incident type 2 diabetes in Asian and European populations – a metabolomics analysis in five prospective cohorts

Background While Asians have a higher risk of type 2 diabetes (T2D) than Europeans for a given BMI, it remains unclear whether the same markers of metabolic pathways are associated with diabetes. Objectives We evaluated associations between metabolic biomarkers and incident T2D in three major Asian ethnic groups (Chinese, Malay, and Indian) and a European population. Methods We analyzed data from adult males and females of two cohorts from Singapore (n = 6,393) consisting of Chinese, Malays and Indians, and three cohorts of European-origin participants from Finland (n = 14,558). We used nuclear magnetic resonance to quantify 154 circulating metabolic biomarkers at baseline and performed logistic regression to assess associations with T2D risk adjusted for age, sex, BMI and glycaemic markers. Results Of the 154 metabolic biomarkers, 59 were associated with higher risk of T2D in both Asians and Europeans ( P < 0.0003; Bonferroni-corrected). These included branched-chain and aromatic amino acids, the inflammatory marker glycoprotein acetyls, total fatty acids, monounsaturated fatty acids, apolipoprotein B, larger very low-density lipoprotein particle sizes, and triglycerides. In addition, 13 metabolites were associated with a lower T2D risk in both populations including omega-6 polyunsaturated fatty acids and larger high-density lipoprotein particle sizes. Associations were consistent within the Asian ethnic groups (all P het ≥ 0.05) and largely consistent for the Asian and European populations ( P het ≥ 0.05 for 128 of 154 metabolic biomarkers). Conclusion Metabolic biomarkers across several biological pathways were consistently associated with T2D risk in Asians and Europeans. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement The MEC is supported by grants from the Singapore Ministry of Health, including National Medical Research Council Large Collaborative Grant (MOH-000271-00), National University of Singapore and National University Health System, Singapore. Metabolic profiling for MEC was supported by NUHS Summit Research Program (Metabolic Diseases) and performed by Nightingale Health Ltd. The SEED cohorts are supported by the National Medical Research Council (NMRC), Singapore (grants 0796/2003, 1176/2008, 1149/2008, STaR/0003/2008, 1249/2010, CG/SERI/2010, CIRG/1371/2013, CIRG/1417/2015, CIRG/1488/2018 and OFLCG/004a/2018), and Biomedical Research Council (BMRC), Singapore (08/1/35/19/550 and 09/1/35/19/616). VS was supported by the Finnish Foundation for Cardiovascular Research. JYHS was supported by the Singapore Ministry of Health, National Medical Research Council Large Collaborative Grant (MOH-000271-00). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: MEC: We obtained ethics approval from SingHealth Centralised Institutional Review Board and the National University of Singapore Institutional Review Board. SEED: We obtained ethics approval from the Singapore Eye Research Institute (SERI) Institutional Review Board. FINRISK 2002, FINRISK 2012 and Health 2000: The Coordinating Ethical Committee of the Helsinki and Uusimaa Hospital District, Finland approved the cohort studies. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes Data described in the manuscript, code book and analytic code will be made available upon request pending application and approval. * ARIC : Atherosclerosis Risk in Communities BCAA : branched-chain amino acids BMI : body mass index GlycA : glycoprotein acetyls HbA1c : glycated hemoglobin HDL : high-density lipoprotein IDL : intermediate-density lipoprotein LDL : low-density lipoprotein MEC : Multiethnic Cohort MUFA : monounsaturated fat NMR : nuclear magnetic resonance PUFA : polyunsaturated fat SEED : Singapore Epidemiology of Eye Diseases SFA : saturated fat T2D : type 2 diabetes VLDL : very low-density lipoprotein