Ravi V Shah, Jiawei Zhong, Lucas Massier, Kahraman Tanriverdi, Shih-Jen Hwang, Jeffrey Haessler, Matthew Nayor, Shilin Zhao, Andrew S Perry, John T Wilkins, Aladdin H Shadyab, JoAnn E Manson, Lisa Martin, Daniel Levy, Charles Kooperberg, Jane E Freedman, Mikael Rydén, Venkatesh L Murthy
{"title":"靶向蛋白质组学揭示年轻人早期糖尿病易感性的功能靶点","authors":"Ravi V Shah, Jiawei Zhong, Lucas Massier, Kahraman Tanriverdi, Shih-Jen Hwang, Jeffrey Haessler, Matthew Nayor, Shilin Zhao, Andrew S Perry, John T Wilkins, Aladdin H Shadyab, JoAnn E Manson, Lisa Martin, Daniel Levy, Charles Kooperberg, Jane E Freedman, Mikael Rydén, Venkatesh L Murthy","doi":"10.1161/CIRCGEN.123.004192","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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<sup>2</sup>), with validation against diabetes in >1800 individuals in the FHS (Framingham Heart Study) and WHI (Women's Health Initiative).</p><p><strong>Results: </strong>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.</p><p><strong>Conclusions: </strong>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.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":null,"pages":null},"PeriodicalIF":6.0000,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10940209/pdf/","citationCount":"0","resultStr":"{\"title\":\"Targeted Proteomics Reveals Functional Targets for Early Diabetes Susceptibility in Young Adults.\",\"authors\":\"Ravi V Shah, Jiawei Zhong, Lucas Massier, Kahraman Tanriverdi, Shih-Jen Hwang, Jeffrey Haessler, Matthew Nayor, Shilin Zhao, Andrew S Perry, John T Wilkins, Aladdin H Shadyab, JoAnn E Manson, Lisa Martin, Daniel Levy, Charles Kooperberg, Jane E Freedman, Mikael Rydén, Venkatesh L Murthy\",\"doi\":\"10.1161/CIRCGEN.123.004192\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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<sup>2</sup>), with validation against diabetes in >1800 individuals in the FHS (Framingham Heart Study) and WHI (Women's Health Initiative).</p><p><strong>Results: </strong>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.</p><p><strong>Conclusions: </strong>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.</p>\",\"PeriodicalId\":10326,\"journal\":{\"name\":\"Circulation: Genomic and Precision Medicine\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":6.0000,\"publicationDate\":\"2024-02-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10940209/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Circulation: Genomic and Precision Medicine\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1161/CIRCGEN.123.004192\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/2/7 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q1\",\"JCRName\":\"CARDIAC & CARDIOVASCULAR SYSTEMS\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Circulation: Genomic and Precision Medicine","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1161/CIRCGEN.123.004192","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/2/7 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"CARDIAC & CARDIOVASCULAR SYSTEMS","Score":null,"Total":0}
Targeted Proteomics Reveals Functional Targets for Early Diabetes Susceptibility in Young Adults.
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/m2), 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.
期刊介绍：
Circulation: Genomic and Precision Medicine is a distinguished journal dedicated to advancing the frontiers of cardiovascular genomics and precision medicine. It publishes a diverse array of original research articles that delve into the genetic and molecular underpinnings of cardiovascular diseases. The journal's scope is broad, encompassing studies from human subjects to laboratory models, and from in vitro experiments to computational simulations.
Circulation: Genomic and Precision Medicine is committed to publishing studies that have direct relevance to human cardiovascular biology and disease, with the ultimate goal of improving patient care and outcomes. The journal serves as a platform for researchers to share their groundbreaking work, fostering collaboration and innovation in the field of cardiovascular genomics and precision medicine.
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