Targeted Proteomics Reveals Functional Targets for Early Diabetes Susceptibility in Young Adults

Ravi V. Shah, Vanderbilt Translational and Clinical Cardiovascular Research Center, Vanderbilt University, Nashville, TN (R.V.S., K.T., A.S.P., J.E.F.).
Jiawei Zhong, Department of Medicine (H7), Karolinska Institutet, Stockholm, Sweden (J.Z., L.M., M.R.).
Lucas Massier, Department of Medicine (H7), Karolinska Institutet, Stockholm, Sweden (J.Z., L.M., M.R.).
Kahraman Tanriverdi, Vanderbilt Translational and Clinical Cardiovascular Research Center, Vanderbilt University, Nashville, TN (R.V.S., K.T., A.S.P., J.E.F.).
Shih-Jen Hwang, Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD (S.-J.H., D.L.).
Jeffrey Haessler, Fred Hutchinson Cancer Research Center, Seattle, WA (J.H., C.K.).
Matthew Nayor, Sections of Preventive Medicine and Epidemiology and Cardiovascular Medicine, Department of Medicine, and Department of Epidemiology, Boston University Schools of Medicine and Public Health, MA (M.N.).
Shilin Zhao, Department of Biostatistics, Vanderbilt University, Nashville, TN (S.Z.).
Andrew S. Perry, Vanderbilt Translational and Clinical Cardiovascular Research Center, Vanderbilt University, Nashville, TN (R.V.S., K.T., A.S.P., J.E.F.).
John T. Wilkins, Northwestern University, Chicago, IL (J.T.W.).
Aladdin H. Shadyab, Herbert Wertheim School of Public Health and Human Longevity Science, University of California, San Diego, La Jolla (A.H.S.).
JoAnn E. Manson, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (J.E.M.).
Lisa Martin, George Washington University School of Medicine and Health Sciences (L.M.).
Daniel Levy, Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD (S.-J.H., D.L.).
Charles Kooperberg, Fred Hutchinson Cancer Research Center, Seattle, WA (J.H., C.K.).
Jane E. Freedman, Vanderbilt Translational and Clinical Cardiovascular Research Center, Vanderbilt University, Nashville, TN (R.V.S., K.T., A.S.P., J.E.F.).
Mikael Rydén, Department of Medicine (H7), Karolinska Institutet, Stockholm, Sweden (J.Z., L.M., M.R.).
Venkatesh L. Murthy, Department of Medicine and Radiology, University of Michigan, Ann Arbor (V.L.M.).

Document Type

Journal Article

Publication Date

2-1-2024

Journal

Circulation. Genomic and precision medicine

Volume

17

Issue

1

DOI

10.1161/CIRCGEN.123.004192

Keywords

insulin resistance; metabolism; proteomics; transcriptomics

Abstract

BACKGROUND: The circulating proteome may encode early pathways of diabetes susceptibility in young adults for surveillance and intervention. Here, we define proteomic correlates of tissue phenotypes and diabetes in young adults. METHODS: We used penalized models and principal components analysis to generate parsimonious proteomic signatures of diabetes susceptibility based on phenotypes and on diabetes diagnosis across 184 proteins in >2000 young adults in the CARDIA (Coronary Artery Risk Development in Young Adults study; mean age, 32 years; 44% women; 43% Black; mean body mass index, 25.6±4.9 kg/m), with validation against diabetes in >1800 individuals in the FHS (Framingham Heart Study) and WHI (Women's Health Initiative). RESULTS: In 184 proteins in >2000 young adults in CARDIA, we identified 2 proteotypes of diabetes susceptibility-a proinflammatory fat proteotype (visceral fat, liver fat, inflammatory biomarkers) and a muscularity proteotype (muscle mass), linked to diabetes in CARDIA and WHI/FHS. These proteotypes specified broad mechanisms of early diabetes pathogenesis, including transorgan communication, hepatic and skeletal muscle stress responses, vascular inflammation and hemostasis, fibrosis, and renal injury. Using human adipose tissue single cell/nuclear RNA-seq, we demonstrate expression at transcriptional level for implicated proteins across adipocytes and nonadipocyte cell types (eg, fibroadipogenic precursors, immune and vascular cells). Using functional assays in human adipose tissue, we demonstrate the association of expression of genes encoding these implicated proteins with adipose tissue metabolism, inflammation, and insulin resistance. CONCLUSIONS: A multifaceted discovery effort uniting proteomics, underlying clinical susceptibility phenotypes, and tissue expression patterns may uncover potentially novel functional biomarkers of early diabetes susceptibility in young adults for future mechanistic evaluation.

Department

Medicine

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