{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T14:01:00Z","timestamp":1785420060987,"version":"3.56.0"},"reference-count":35,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,7,4]],"date-time":"2026-07-04T00:00:00Z","timestamp":1783123200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Suzhou Gusu Health Talent Program","award":["2024-211"],"award-info":[{"award-number":["2024-211"]}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82273719"],"award-info":[{"award-number":["82273719"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"award":["82273719"],"award-info":[{"award-number":["82273719"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Metabolites"],"abstract":"<jats:p>Background: 4-Hydroxyproline, a product of collagen turnover generated through prolyl hydroxylation, has been implicated in metabolic regulation. While previous studies have associated circulating proline with diabetes, the relationship between 4-hydroxyproline and diabetes remains unclear. Methods: We conducted a cross-sectional analysis of 796 adults aged 35\u201374 years from Changshu, eastern China. Plasma 4-hydroxyproline levels were quantified using ultra-high-performance liquid chromatography\u2013tandem mass spectrometry. Unconditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). Results: Higher plasma 4-hydroxyproline levels were associated with increased odds of diabetes after multivariable adjustment (per SD increase: OR = 1.35, 95% CI: 1.10\u20131.66; p = 0.004). Participants in the highest quartile had higher odds of diabetes than those in the lowest quartile (Q4 vs. Q1: OR = 1.86, 95% CI: 1.01\u20133.47; p for trend = 0.006). The associations remained materially unchanged after excluding insulin users, individuals with diabetes-related complications, and those using antidiabetic medication. Further adjustment for dietary intake and proline did not materially alter the results. Conclusions: Higher plasma 4-hydroxyproline levels were associated with diabetes. Given the cross-sectional design, causality cannot be inferred, and reverse causation cannot be excluded. Prospective studies are needed to confirm these findings.<\/jats:p>","DOI":"10.3390\/metabo16070467","type":"journal-article","created":{"date-parts":[[2026,7,6]],"date-time":"2026-07-06T12:01:37Z","timestamp":1783339297000},"page":"467","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Plasma 4-Hydroxyproline Levels Are Associated with Diabetes in Chinese Adults: A Cross-Sectional Analysis"],"prefix":"10.3390","volume":"16","author":[{"given":"Qiaoliang","family":"Huang","sequence":"first","affiliation":[{"name":"School of Public Health, Fudan University, No. 130 Dong\u2019an Road, Shanghai 200032, China"},{"name":"Department of Health Education, Suzhou Center for Disease Control and Prevention, Suzhou 215131, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingjun","family":"Mu","sequence":"additional","affiliation":[{"name":"School of Public Health, Suzhou Medical College of Soochow University, 199 Ren\u2019ai Rd., Suzhou 215123, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruirui","family":"Ma","sequence":"additional","affiliation":[{"name":"School of Public Health, Suzhou Medical College of Soochow University, 199 Ren\u2019ai Rd., Suzhou 215123, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiayao","family":"Zhu","sequence":"additional","affiliation":[{"name":"School of Public Health, Suzhou Medical College of Soochow University, 199 Ren\u2019ai Rd., Suzhou 215123, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xudong","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Public Health, Suzhou Medical College of Soochow University, 199 Ren\u2019ai Rd., Suzhou 215123, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingyao","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Public Health, Suzhou Medical College of Soochow University, 199 Ren\u2019ai Rd., Suzhou 215123, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junyao","family":"Huang","sequence":"additional","affiliation":[{"name":"School of Public Health, Suzhou Medical College of Soochow University, 199 Ren\u2019ai Rd., Suzhou 215123, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3918-5754","authenticated-orcid":false,"given":"Hui","family":"Zuo","sequence":"additional","affiliation":[{"name":"School of Public Health, Suzhou Medical College of Soochow University, 199 Ren\u2019ai Rd., Suzhou 215123, China"},{"name":"Department of Clinical Nutrition, The Fourth Affiliated Hospital of Soochow University (Medical Center of Soochow University), Suzhou 215000, China"},{"name":"Jiangsu Key Laboratory of Preventive and Translational Medicine for Major Chronic Non-Communicable Diseases, Suzhou 215123, China"},{"name":"MOE Key Laboratory of Geriatric Diseases and Immunology, Suzhou Medical College of Soochow University, Suzhou 215123, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinming","family":"Yu","sequence":"additional","affiliation":[{"name":"School of Public Health, Fudan University, No. 130 Dong\u2019an Road, Shanghai 200032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,4]]},"reference":[{"key":"ref_1","unstructured":"GBD 2021 Diabetes Collaborators (2023). Global, Regional, and National Burden of Diabetes from 1990 to 2021, with Projections of Prevalence to 2050: A Systematic Analysis for the Global Burden of Disease Study 2021. Lancet, 402, 203\u2013234."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e1098","DOI":"10.1016\/S2468-2667(24)00251-2","article-title":"Diabetes in China Part 2: Prevention, Challenges, and Progress","volume":"9","author":"Xu","year":"2024","journal-title":"Lancet Public Health"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e1143","DOI":"10.1111\/hsc.13522","article-title":"Diabetes-Related Avoidable Hospitalisations and Its Relationship with Primary Healthcare Resourcing in China: A Cross-Sectional Study from Sichuan Province","volume":"30","author":"Zhao","year":"2022","journal-title":"Health Soc. Care Community"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"e1089","DOI":"10.1016\/S2468-2667(24)00250-0","article-title":"Diabetes in China Part 1: Epidemiology and Risk Factors","volume":"9","author":"Xu","year":"2024","journal-title":"Lancet Public Health"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"596","DOI":"10.2174\/1389203717666151201192247","article-title":"Hydroxyproline: A Potential Biochemical Marker and Its Role in the Pathogenesis of Different Diseases","volume":"17","author":"Srivastava","year":"2016","journal-title":"Curr. Protein Pept. Sci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"10857","DOI":"10.1021\/ja103082y","article-title":"The Aberrance of the 4S Diastereomer of 4-Hydroxyproline","volume":"132","author":"Shoulders","year":"2010","journal-title":"J. Am. Chem. Soc."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"674","DOI":"10.1089\/ars.2017.7338","article-title":"Metabolism, Nutrition, and Redox Signaling of Hydroxyproline","volume":"30","author":"Wu","year":"2019","journal-title":"Antioxid. Redox Signal."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"10485","DOI":"10.1074\/jbc.M702181200","article-title":"A Novel Function for Hydroxyproline Oxidase in Apoptosis through Generation of Reactive Oxygen Species","volume":"283","author":"Cooper","year":"2008","journal-title":"J. Biol. Chem."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1007\/s00726-020-02823-6","article-title":"Important Roles of Dietary Taurine, Creatine, Carnosine, Anserine and 4-Hydroxyproline in Human Nutrition and Health","volume":"52","author":"Wu","year":"2020","journal-title":"Amino Acids"},{"key":"ref_10","first-page":"361","article-title":"Assessment of Hydroxyproline Levels in Non-Ischemic Diabetic Foot Ulcers During Recovery. A Prospective Case-Control Study","volume":"22","author":"Alamshah","year":"2015","journal-title":"Rom. J. Diabetes Nutr. Metab. Dis."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"107797","DOI":"10.1016\/j.jdiacomp.2020.107797","article-title":"Non-Targeted Metabolomic Analysis Predicts the Therapeutic Effects of Exenatide on Endothelial Injury in Patients with Type 2 Diabetes","volume":"35","author":"Yang","year":"2021","journal-title":"J. Diabetes Its Complicat."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/j.exer.2018.05.004","article-title":"Free Amino Acids Hydroxyproline, Lysine, and Glycine Promote Differentiation of Retinal Pericytes to Adipocytes: A Protective Role against Proliferative Diabetic Retinopathy","volume":"173","author":"Vidhya","year":"2018","journal-title":"Exp. Eye Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"783","DOI":"10.1021\/acs.jafc.0c06445","article-title":"The Effect of Exogenous Free N\u03b5-(Carboxymethyl)Lysine on Diabetic-Model Goto-Kakizaki Rats: Metabolomics Analysis in Serum and Urine","volume":"69","author":"Quan","year":"2021","journal-title":"J. Agric. Food Chem."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1162","DOI":"10.1016\/j.tjnut.2023.02.029","article-title":"Plasma \u03b2-Alanine Is Positively Associated with Risk of Ischemic Stroke: A Nested Case-Control Study","volume":"153","author":"Zhang","year":"2023","journal-title":"J. Nutr."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1111\/joim.13572","article-title":"Associations of Plasma TMAO and Its Precursors with Stroke Risk in the General Population: A Nested Case-control Study","volume":"293","author":"Liu","year":"2023","journal-title":"J. Intern. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1016\/j.clnu.2025.07.003","article-title":"Plasma Kynurenine Pathway Metabolites in Association with Diabetes: A Cross-Sectional Study","volume":"51","author":"Mu","year":"2025","journal-title":"Clin. Nutr."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"183","DOI":"10.7326\/M20-4366","article-title":"Development and Validation of a Modified Full Age Spectrum Creatinine-Based Equation to Estimate Glomerular Filtration Rate: A Cross-Sectional Analysis of Pooled Data","volume":"174","author":"Pottel","year":"2021","journal-title":"Ann. Intern. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1093\/ajcn\/nqx012","article-title":"The PAr Index, an Indicator Reflecting Altered Vitamin B-6 Homeostasis, Is Associated with Long-Term Risk of Stroke in the General Population: The Hordaland Health Study (HUSK)","volume":"107","author":"Zuo","year":"2018","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Tsai, M.-K., Gao, W., and Wen, C.-P. (2023). The Relationship between Alcohol Consumption and Health: J-Shaped or Less Is More?. BMC Med., 21.","DOI":"10.1186\/s12916-023-02911-w"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"e133","DOI":"10.1038\/nutd.2014.32","article-title":"Plasma Amino Acid Profiles Are Associated with Insulin, C-Peptide and Adiponectin Levels in Type 2 Diabetic Patients","volume":"4","author":"Nakamura","year":"2014","journal-title":"Nutr. Diabetes"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"8207","DOI":"10.1038\/s41598-018-26320-9","article-title":"Serum Metabolite Profile Associated with Incident Type 2 Diabetes in Koreans: Findings from the Korean Genome and Epidemiology Study","volume":"8","author":"Yang","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2416","DOI":"10.1016\/j.numecd.2021.05.004","article-title":"Associations between Serum Amino Acids and Incident Type 2 Diabetes in Chinese Rural Adults","volume":"31","author":"Chen","year":"2021","journal-title":"Nutr. Metab. Cardiovasc. Dis."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Ken\u00e9z, \u00c1., Warnken, T., Feige, K., and Huber, K. (2018). Lower Plasma Trans-4-Hydroxyproline and Methionine Sulfoxide Levels Are Associated with Insulin Dysregulation in Horses. BMC Vet. Res., 14.","DOI":"10.1186\/s12917-018-1479-z"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1740","DOI":"10.1007\/s00125-017-4325-0","article-title":"Early Metabolic Markers Identify Potential Targets for the Prevention of Type 2 Diabetes","volume":"60","author":"Peddinti","year":"2017","journal-title":"Diabetologia"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"e2219419120","DOI":"10.1073\/pnas.2219419120","article-title":"Proline Hydroxylation of CREB-Regulated Transcriptional Coactivator 2 Controls Hepatic Glucose Metabolism","volume":"120","author":"Xue","year":"2023","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"254","DOI":"10.1002\/nau.20489","article-title":"Expression of Transforming Growth Factor \u03b21 Gene, Basic Fibroblast Growth Factor Gene and Hydroxyproline in Diabetes-induced Bladder Dysfunction in a Rat Model","volume":"27","author":"Li","year":"2008","journal-title":"Neurourol. Urodyn."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1038\/s42255-024-01206-5","article-title":"Proline Exacerbates Hepatic Gluconeogenesis via Paraspeckle-Dependent mRNA Retention","volume":"7","author":"Zhao","year":"2025","journal-title":"Nat. Metab."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1080\/07853890801986594","article-title":"Prolyl 4-Hydroxylases, Key Enzymes in the Synthesis of Collagens and Regulation of the Response to Hypoxia, and Their Roles as Treatment Targets","volume":"40","author":"Myllyharju","year":"2008","journal-title":"Ann. Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"3324","DOI":"10.2337\/db14-0472","article-title":"HIF Prolyl 4-Hydroxylase-2 Inhibition Improves Glucose and Lipid Metabolism and Protects against Obesity and Metabolic Dysfunction","volume":"63","author":"Karsikas","year":"2014","journal-title":"Diabetes"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1","DOI":"10.2174\/0113862073370028250326071104","article-title":"Shenhuang Liuwei Powder Alleviates Streptozotocin-Induced Diabetic Ulcers in Rats through the Inhibition of the AGE\/RAGE Signaling Pathway and Promotion of Antibacterial Activity and Angiogenesis via Activation of the PI3K\/Akt\/eNOS\/HIF-1\u03b1 Pathway","volume":"28","author":"Li","year":"2025","journal-title":"Comb. Chem. High Throughput Screen."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"709","DOI":"10.1007\/s00125-021-05380-z","article-title":"Hypoxia and Hypoxia-Inducible Factors in Diabetes and Its Complications","volume":"64","author":"Catrina","year":"2021","journal-title":"Diabetologia"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"106","DOI":"10.3109\/10409231003627991","article-title":"Prolyl 4-Hydroxylase","volume":"45","author":"Gorres","year":"2010","journal-title":"Crit. Rev. Biochem. Mol. Biol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1016\/j.cmet.2025.10.016","article-title":"A Metabolic Atlas of Mouse Aging","volume":"38","author":"Pilley","year":"2026","journal-title":"Cell Metab."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"154887","DOI":"10.1016\/j.phymed.2023.154887","article-title":"Quercetin: A Promising Therapy for Diabetic Encephalopathy through Inhibition of Hippocampal Ferroptosis","volume":"126","author":"Cheng","year":"2024","journal-title":"Phytomedicine"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1541","DOI":"10.2174\/0113816128302667240422110226","article-title":"The Regulation of Selenoproteins in Diabetes: A New Way to Treat Diabetes","volume":"30","author":"Liang","year":"2024","journal-title":"Curr. Pharm. Des."}],"container-title":["Metabolites"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-1989\/16\/7\/467\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,6]],"date-time":"2026-07-06T13:22:14Z","timestamp":1783344134000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-1989\/16\/7\/467"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,4]]},"references-count":35,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2026,7]]}},"alternative-id":["metabo16070467"],"URL":"https:\/\/doi.org\/10.3390\/metabo16070467","relation":{},"ISSN":["2218-1989"],"issn-type":[{"value":"2218-1989","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,4]]}}}