@article{4e0105d281cd430293483d43384b02bd,
title = "Circulating metabolite profile in young adulthood identifies long-term diabetes susceptibility: the Coronary Artery Risk Development in Young Adults (CARDIA) study",
abstract = "Aims/hypothesis: The aim of this work was to define metabolic correlates and pathways of diabetes pathogenesis in young adults during a subclinical latent phase of diabetes development. Methods: We studied 2083 young adults of Black and White ethnicity in the prospective observational cohort Coronary Artery Risk Development in Young Adults (CARDIA) study (mean ± SD age 32.1 ± 3.6 years; 43.9% women; 42.7% Black; mean ± SD BMI 25.6 ± 4.9 kg/m2) and 1797 Framingham Heart Study (FHS) participants (mean ± SD age 54.7 ± 9.7 years; 52.1% women; mean ± SD BMI 27.4 ± 4.8 kg/m2), examining the association of comprehensive metabolite profiles with endophenotypes of diabetes susceptibility (adipose and muscle tissue phenotypes and systemic inflammation). Statistical learning techniques and Cox regression were used to identify metabolite signatures of incident diabetes over a median of nearly two decades of follow-up across both cohorts. Results: We identified known and novel metabolites associated with endophenotypes that delineate the complex pathophysiological architecture of diabetes, spanning mechanisms of muscle insulin resistance, inflammatory lipid signalling and beta cell metabolism (e.g. bioactive lipids, amino acids and microbe- and diet-derived metabolites). Integrating endophenotypes of diabetes susceptibility with the metabolome generated two multi-parametric metabolite scores, one of which (a proinflammatory adiposity score) was associated with incident diabetes across the life course in participants from both the CARDIA study (young adults; HR in a fully adjusted model 2.10 [95% CI 1.72, 2.55], p<0.0001) and FHS (middle-aged and older adults; HR 1.33 [95% CI 1.14, 1.56], p=0.0004). A metabolite score based on the outcome of diabetes was strongly related to diabetes in CARDIA study participants (fully adjusted HR 3.41 [95% CI 2.85, 4.07], p<0.0001) but not in the older FHS population (HR 1.15 [95% CI 0.99, 1.33], p=0.07). Conclusions/interpretation: Selected metabolic abnormalities in young adulthood identify individuals with heightened diabetes risk independent of race, sex and traditional diabetes risk factors. These signatures replicate across the life course. Graphical abstract: [Figure not available: see fulltext.].",
keywords = "Diabetes, Metabolomics, Prevention",
author = "Murthy, {Venkatesh L.} and Matthew Nayor and Mercedes Carnethon and Reis, {Jared P.} and Donald Lloyd-Jones and Allen, {Norrina B.} and Robert Kitchen and Paolo Piaggi and Steffen, {Lyn M.} and Vasan, {Ramachandran S.} and Freedman, {Jane E.} and Clish, {Clary B.} and Shah, {Ravi V.}",
note = "Funding Information: VLM owns stock in General Electric and Cardinal Health and stock options in Ionetix and has received research grants and speaking honoraria from Siemens Medical Imaging and expert testimony fees on behalf of Jubilant Draximage. VLM has served on medical advisory boards for Ionetix and Curium. RVS is supported in part by grants from the National Institutes of Health and the American Heart Association. In the past 36 months, RVS has served as a consultant for Myokardia (concluded 28 February 2021) and Best Doctors (completed June 2021), and has been on a scientific advisory board for Amgen (concluded February 2018). RVS is a co-inventor on a patent for ex-RNAs signatures of cardiac remodelling. All other authors declare that there are no relationships or activities that might bias, or be perceived to bias, their work. Funding Information: VLM and RVS are supported in part by grants from the National Institute on Aging (R01 AG059729) and National Heart, Lung and Blood Institute (R01 HL136685). MN is supported by grant K23 HL138260 from the National Heart, Lung, and Blood Institute. The CARDIA study is conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with the University of Alabama at Birmingham (HHSN268201800005I & HHSN268201800007I), Northwestern University (HHSN268201800003I), University of Minnesota (HHSN268201800006I) and Kaiser Foundation Research Institute (HHSN268201800004I). The FHS acknowledges the support of contracts NO1-HC-25195, HHSN268201500001I and 75N92019D00031 from the National Heart, Lung and Blood Institute and grant R01DK081572 for this research. RSV is supported in part by the Evans Medical Foundation and the Jay and Louis Coffman Endowment from the Department of Medicine, Boston University School of Medicine. This manuscript has been reviewed by CARDIA for scientific content. The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the NHLBI (the study funder); the National Institutes of Health; or the US Department of Health and Human Services. The study sponsors/funders were not involved in the design of the study; the collection, analysis, and interpretation of data; writing the report; and did not impose any restrictions regarding the publication of the report. Publisher Copyright: {\textcopyright} 2022, The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.",
year = "2022",
month = apr,
doi = "10.1007/s00125-021-05641-x",
language = "English (US)",
volume = "65",
pages = "657--674",
journal = "Diabetologia",
issn = "0012-186X",
publisher = "Springer Verlag",
number = "4",
}
