Targeted Proteomics Reveals Functional Targets for Early Diabetes Susceptibility in Young Adults-Reference-Cited by-同舟云学术

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

Published:2024-02 Issue:1 Volume:17 Page:
ISSN:2574-8300
Container-title:Circulation: Genomic and Precision Medicine
language:en
Short-container-title:Circ: Genomic and Precision Medicine

Author:

Shah Ravi V.¹,Zhong Jiawei²^ORCID,Massier Lucas²^ORCID,Tanriverdi Kahraman¹^ORCID,Hwang Shih-Jen³^ORCID,Haessler Jeffrey⁴,Nayor Matthew⁵⁶^ORCID,Zhao Shilin⁷^ORCID,Perry Andrew S.¹^ORCID,Wilkins John T.⁸^ORCID,Shadyab Aladdin H.⁹,Manson JoAnn E.¹⁰^ORCID,Martin Lisa¹¹^ORCID,Levy Daniel³^ORCID,Kooperberg Charles⁴^ORCID,Freedman Jane E.¹^ORCID,Rydén Mikael²^ORCID,Murthy Venkatesh L.¹²^ORCID

Affiliation:

1. Vanderbilt Translational and Clinical Cardiovascular Research Center, Vanderbilt University, Nashville, TN (R.V.S., K.T., A.S.P., J.E.F.).

2. Department of Medicine (H7), Karolinska Institutet, Stockholm, Sweden (J.Z., L.M., M.R.).

3. Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD (S.-J.H., D.L.).

4. Fred Hutchinson Cancer Research Center, Seattle, WA (J.H., C.K.).

5. 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.).

6. The Framingham Heart Study, MA (M.N.).

7. Department of Biostatistics, Vanderbilt University, Nashville, TN (S.Z.).

8. Northwestern University, Chicago, IL (J.T.W.).

9. Herbert Wertheim School of Public Health and Human Longevity Science, University of California, San Diego, La Jolla (A.H.S.).

10. Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA (J.E.M.).

11. George Washington University School of Medicine and Health Sciences (L.M.).

12. Department of Medicine and Radiology, University of Michigan, Ann Arbor (V.L.M.).

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 2 ), 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.

Publisher

Ovid Technologies (Wolters Kluwer Health)

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