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Longitudinal Plasma Lipidome and Risk of Type 2 Diabetes in a Large Sample of American Indians With Normal Fasting Glucose: The Strong Heart Family Study

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posted on 26.10.2021, 15:43 by Guanhong Miao, Ying Zhang, Zhiguang Huo, Wenjie Zeng, Jianhui Zhu, Jason G. Umans, Gert Wohlgemuth, Diego Pedrosa, Brian DeFelice, Shelley A. Cole, Amanda M. Fretts, Elisa T. Lee, Barbara V. Howard, Oliver Fiehn, Jinying Zhao
OBJECTIVE: Comprehensive assessment of alterations in lipid species preceding T2D is largely unknown. We aimed to identify plasma molecular lipids associated with risk of T2D in American Indians.

RESEARCH DESIGN AND METHODS: Using an untargeted LC-MS, we repeatedly measured 3,907 fasting plasma samples from 1,958 participants who attended two exams (~5.5 year apart) and were followed up to 16 years in the Strong Heart Study. Mixed-effect logistic regression was used to identify lipids associated with risk of T2D adjusting for traditional risk factors. Repeated measurement analysis was performed to examine the association between change in lipidome and change in continuous measures of T2D adjusting for baseline lipids. Multiple testing was controlled by false discovery rate at 0.05.

RESULTS: Higher baseline level of 33 lipid species, including TAGs, DAGs, PEs, and PCs, was significantly associated with increased risk of T2D (odds ratio [OR] per SD increase in log2-transformed baseline lipids: 1.50-2.85) at 5-year follow-up. Of these, 21 lipids were also associated with risk of T2D at 16-year follow-up. Aberrant lipid profiles were also observed in prediabetes (OR per SD increase in log2-transformed baseline lipids: 1.30-2.19 for risk lipids; 0.70-0.78 for protective lipids). Longitudinal changes in 568 lipids were significantly associated with changes in continuous measures of T2D. Multivariate analysis identified distinct lipidomic signatures differentiating high from low risk groups.

CONCLUSIONS: Lipid dysregulation occurs many years preceding T2D, and novel molecular lipids (both baseline level and longitudinal change over time) are significantly associated with risk of T2D beyond traditional risk factors. Our findings shed light on the mechanisms linking dyslipidemia to T2D and may yield novel therapeutic targets for early intervention tailored to American Indians.

Funding

This study was supported by the National Institutes of Health grants R01DK107532. The Strong Heart Study has been funded in whole or in part with federal funds from the National Heart, Lung, and Blood Institute, National Institute of Health, Department of Health and Human Services, under contract numbers 75N92019D00027, 75N92019D00028, 75N92019D00029, and 75N92019D00030. The study was previously supported by research grants: R01HL109315, R01HL109301, R01HL109284, R01HL109282, and R01HL109319 and by cooperative agreements: U01HL41642, U01HL41652, U01HL41654, U01HL65520, and U01HL65521.

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