Targeted serum proteomics of longitudinal samples from newly diagnosed youth with type 1 diabetes affirms markers of disease

IF 8.4 1区医学 Q1 ENDOCRINOLOGY & METABOLISM

Diabetologia Pub Date : 2025-02-28 DOI:10.1007/s00125-025-06394-7

Robert Moulder, M. Karoliina Hirvonen, Tommi Välikangas, Tomi Suomi, Lut Overbergh, Mark Peakman, Søren Brunak, Chantal Mathieu, Mikael Knip, Laura L. Elo, Riitta Lahesmaa

{"title":"Targeted serum proteomics of longitudinal samples from newly diagnosed youth with type 1 diabetes affirms markers of disease","authors":"Robert Moulder, M. Karoliina Hirvonen, Tommi Välikangas, Tomi Suomi, Lut Overbergh, Mark Peakman, Søren Brunak, Chantal Mathieu, Mikael Knip, Laura L. Elo, Riitta Lahesmaa","doi":"10.1007/s00125-025-06394-7","DOIUrl":null,"url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Aims/hypothesis</h3><p>While investigating markers for declining beta cell function in type 1 diabetes, we previously demonstrated 11 statistically significant protein associations with fasting C-peptide/glucose ratios in longitudinal serum samples from newly diagnosed (ND) individuals (<i>n</i>=86; 228 samples in total) participating in the INNODIA (Innovative approaches to understanding and arresting type 1 diabetes) study. Furthermore, comparison with protein measurements from age- and sex-matched autoantibody-negative unaffected family members (UFMs, <i>n</i>=194) revealed differences in the serum levels of 13 target proteins. To further evaluate these findings, we analysed longitudinal serum drawn during the first year after diagnosis from a new group of ND individuals subsequently enrolled in the study, together with samples from additional UFMs.</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>To validate the previously reported statistically significant protein associations with type 1 diabetes progression, selected reaction monitoring (SRM) MS analyses were carried out. Sera from individuals diagnosed with type 1 diabetes under the age of 18 years (<i>n</i>=146) were collected within 6 weeks of diagnosis and at 3, 6 and 12 months after diagnosis (560 samples in total). The resulting SRM data were compared with fasting C-peptide/glucose measurements, which were used as a proxy for beta cell function. The protein data were further compared with cross-sectional SRM measurements from age- and sex-matched UFMs (<i>n</i>=272).</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>Our results confirmed the presence of significant (<i>p</i><0.05) inverse associations between fasting C-peptide/glucose ratios and peptides from apolipoprotein B-100, apolipoprotein M and glutathione peroxidase 3 (GPX3) in ND individuals. Additionally, we observed consistent differences in the levels of ten of the 13 targeted proteins between individuals with type 1 diabetes and UFMs. These proteins included GPX3, transthyretin, prothrombin, apolipoprotein C1 and afamin.</p><h3 data-test=\"abstract-sub-heading\">Conclusions/interpretation</h3><p>The validated results reflect the landscape of biological changes accompanying type 1 diabetes. For example, the association of the targeted apolipoproteins with fasting C-peptide/glucose ratios in the first year after diagnosis is likely to relate to lipid abnormalities observed in individuals with type 1 diabetes, and reiterates the connection of apolipoproteins with the underlying changes accompanying the disease. Further research is needed to explore the clinical value and relevance of these targets.</p><h3 data-test=\"abstract-sub-heading\">Graphical Abstract</h3>\n","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"32 1","pages":""},"PeriodicalIF":8.4000,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Diabetologia","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1007/s00125-025-06394-7","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ENDOCRINOLOGY & METABOLISM","Score":null,"Total":0}

引用次数: 0

Abstract

Aims/hypothesis

While investigating markers for declining beta cell function in type 1 diabetes, we previously demonstrated 11 statistically significant protein associations with fasting C-peptide/glucose ratios in longitudinal serum samples from newly diagnosed (ND) individuals (n=86; 228 samples in total) participating in the INNODIA (Innovative approaches to understanding and arresting type 1 diabetes) study. Furthermore, comparison with protein measurements from age- and sex-matched autoantibody-negative unaffected family members (UFMs, n=194) revealed differences in the serum levels of 13 target proteins. To further evaluate these findings, we analysed longitudinal serum drawn during the first year after diagnosis from a new group of ND individuals subsequently enrolled in the study, together with samples from additional UFMs.

Methods

To validate the previously reported statistically significant protein associations with type 1 diabetes progression, selected reaction monitoring (SRM) MS analyses were carried out. Sera from individuals diagnosed with type 1 diabetes under the age of 18 years (n=146) were collected within 6 weeks of diagnosis and at 3, 6 and 12 months after diagnosis (560 samples in total). The resulting SRM data were compared with fasting C-peptide/glucose measurements, which were used as a proxy for beta cell function. The protein data were further compared with cross-sectional SRM measurements from age- and sex-matched UFMs (n=272).

Results

Our results confirmed the presence of significant (p<0.05) inverse associations between fasting C-peptide/glucose ratios and peptides from apolipoprotein B-100, apolipoprotein M and glutathione peroxidase 3 (GPX3) in ND individuals. Additionally, we observed consistent differences in the levels of ten of the 13 targeted proteins between individuals with type 1 diabetes and UFMs. These proteins included GPX3, transthyretin, prothrombin, apolipoprotein C1 and afamin.

Conclusions/interpretation

The validated results reflect the landscape of biological changes accompanying type 1 diabetes. For example, the association of the targeted apolipoproteins with fasting C-peptide/glucose ratios in the first year after diagnosis is likely to relate to lipid abnormalities observed in individuals with type 1 diabetes, and reiterates the connection of apolipoproteins with the underlying changes accompanying the disease. Further research is needed to explore the clinical value and relevance of these targets.

Graphical Abstract

查看原文本刊更多论文

新诊断的青年1型糖尿病纵向样本的靶向血清蛋白质组学证实了疾病的标志物

目的/假设：在研究1型糖尿病患者β细胞功能下降的标志物时，我们先前在新诊断（ND）患者的纵向血清样本中发现了11种具有统计学意义的蛋白质与空腹c肽/葡萄糖比率的关联(n=86；共有228个样本)参加INNODIA（了解和阻止1型糖尿病的创新方法）研究。此外，与年龄和性别匹配的自身抗体阴性未受影响的家庭成员（UFMs, n=194）的蛋白质测量结果进行比较，发现13种靶蛋白的血清水平存在差异。为了进一步评估这些发现，我们分析了随后加入研究的一组新ND个体在诊断后第一年提取的纵向血清，以及来自其他UFMs的样本。方法为了验证先前报道的具有统计学意义的蛋白与1型糖尿病进展的相关性，进行了选择性反应监测（SRM）质谱分析。在诊断后6周和诊断后3个月、6个月和12个月（共560份样本）收集被诊断为1型糖尿病的18岁以下个体（n=146）的血清。所得的SRM数据与空腹c肽/葡萄糖测量值进行比较，后者被用作β细胞功能的代理。蛋白质数据进一步与年龄和性别匹配的UFMs （n=272）的横截面SRM测量值进行比较。结果证实ND患者空腹c肽/葡萄糖比值与载脂蛋白B-100、载脂蛋白M和谷胱甘肽过氧化物酶3 （GPX3）呈显著（p<0.05）负相关。此外，我们观察到在1型糖尿病患者和ufm患者之间，13种靶向蛋白中有10种的水平存在一致的差异。这些蛋白包括GPX3、转甲状腺素、凝血酶原、载脂蛋白C1和afamin。结论/解释验证的结果反映了1型糖尿病的生物学变化景观。例如，在诊断后的第一年，靶载脂蛋白与空腹c肽/葡萄糖比率的关联可能与在1型糖尿病患者中观察到的脂质异常有关，并重申载脂蛋白与疾病伴随的潜在变化之间的联系。这些靶点的临床价值和相关性有待进一步研究。图形抽象

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Diabetologia 医学-内分泌学与代谢

CiteScore

18.10

自引率

2.40%

发文量

193

审稿时长

1 months

期刊介绍： Diabetologia, the authoritative journal dedicated to diabetes research, holds high visibility through society membership, libraries, and social media. As the official journal of the European Association for the Study of Diabetes, it is ranked in the top quartile of the 2019 JCR Impact Factors in the Endocrinology & Metabolism category. The journal boasts dedicated and expert editorial teams committed to supporting authors throughout the peer review process.