{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T12:11:11Z","timestamp":1788869471953,"version":"build-2803163510"},"reference-count":34,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T00:00:00Z","timestamp":1788825600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J. Clin. Med.","JCM"],"abstract":"<jats:p>Background\/Objectives: Lower serum C-peptide, reflecting reduced beta-cell reserve, has been linked to diabetic complications, but whether these associations are independent of diabetes duration and glycaemic control is unclear. The objective of this study was to determine which microvascular and macrovascular complications of type 2 diabetes mellitus (T2DM) remain associated with fasting C-peptide after adjustment for these factors. Methods: In this single-centre, cross-sectional study with consecutive prospective enrolment, non-pregnant adults with an established diagnosis of T2DM attending routine outpatient follow-up were eligible; those with pancreatic malignancy or exocrine pancreatic insufficiency, monogenic or autoimmune diabetes, or acute hyperglycaemic crises were excluded. A total of 590 patients were stratified by fasting C-peptide into insufficient (&lt;1.0 ng\/mL; n = 35), borderline (1.0\u20131.8 ng\/mL; n = 212) and normal\/high (\u22651.8 ng\/mL; n = 343) groups. Logistic regression adjusted for age, sex, diabetes duration, HbA1c and body mass index assessed each complication. Receiver operating characteristic analysis using DeLong\u2019s test assessed incremental discrimination. Results: In the unadjusted analyses, every complication was more frequent at lower C-peptide. After adjustment, C-peptide was not associated with the presence of albuminuria (insufficient versus normal\/high, odds ratio 1.60, 95% CI 0.16\u201315.86) but was strongly associated with its severity: for severely increased or nephrotic-range albuminuria, the adjusted odds ratios were 13.47 (5.33\u201334.07) and 6.90 (3.83\u201312.44) in the insufficient and borderline groups (both p &lt; 0.001). Adding C-peptide to a model of diabetes duration, HbA1c and fasting glucose was associated with a statistically significant, but modest, improvement in discrimination for severe albuminuria (area under the curve of 0.748 to 0.783; \u0394AUC = 0.035, p = 0.027). Associations with macrovascular complications were present in the unadjusted analyses but were substantially attenuated after adjustment and no longer statistically significant, except for peripheral arterial disease and foot ulcer, which remained associated with insufficient C-peptide in models based on small numbers of events and should be regarded as exploratory. Conclusions: Low C-peptide was independently associated with the severity of albuminuria rather than its presence and was associated with a modest incremental improvement in discrimination. These exploratory findings suggest that C-peptide, an inexpensive and widely available measurement, may provide information associated with advanced diabetic kidney disease; prospective, externally validated studies are needed before clinical application.<\/jats:p>","DOI":"10.3390\/jcm15186950","type":"journal-article","created":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T11:23:51Z","timestamp":1788866631000},"page":"6950","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Low Serum C-Peptide and Albuminuria Severity in Type 2 Diabetes Mellitus: A Cross-Sectional Study"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9553-722X","authenticated-orcid":false,"given":"Bektas","family":"Isik","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, Adana Health Practice and Research Center, University of Health Sciences, 01230 Adana, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9185-7557","authenticated-orcid":false,"given":"Bekir Tamer","family":"Tetiker","sequence":"additional","affiliation":[{"name":"Division of Endocrinology and Metabolism, Department of Internal Medicine, \u00c7ukurova University Faculty of Medicine, 01790 Adana, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"American Diabetes Association Professional Practice Committee (2026). 2. Diagnosis and classification of diabetes: Standards of Care in Diabetes\u20142026. Diabetes Care, 49, S27\u2013S49.","DOI":"10.2337\/dc26-S002"},{"key":"ref_2","unstructured":"International Diabetes Federation (2025). IDF Diabetes Atlas, International Diabetes Federation. [11th ed.]."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1257","DOI":"10.2337\/dci24-0032","article-title":"Hyperglycemic crises in adults with diabetes: A consensus report","volume":"47","author":"Umpierrez","year":"2024","journal-title":"Diabetes Care"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1870","DOI":"10.2337\/dc17-1583","article-title":"Trends in hospital admission for diabetic ketoacidosis in adults with type 1 and type 2 diabetes in England, 1998\u20132013: A retrospective cohort study","volume":"41","author":"Zhong","year":"2018","journal-title":"Diabetes Care"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Lamprou, S., Evangelidis, N., Koletsos, N., Zografou, I., Stoimeni, A., Mintziori, G., Gkolias, V., Trakatelli, C.-M., Savopoulos, C., and Doumas, M. (2026). Microvascular Dysfunction in Patients with Prediabetes: Novel Methods Identify Impaired Microcirculation. Life, 16.","DOI":"10.3390\/life16020326"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1761","DOI":"10.1007\/s00125-010-1736-6","article-title":"Cellular mechanisms by which proinsulin C-peptide prevents insulin-induced neointima formation in human saphenous vein","volume":"53","author":"Mughal","year":"2010","journal-title":"Diabetologia"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1159\/000289864","article-title":"C-peptide as a therapeutic tool in diabetic nephropathy","volume":"31","author":"Hills","year":"2010","journal-title":"Am. J. Nephrol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"41","DOI":"10.4093\/dmj.2011.35.1.41","article-title":"Basal C-peptide level as a surrogate marker of subclinical atherosclerosis in type 2 diabetic patients","volume":"35","author":"Kim","year":"2011","journal-title":"Diabetes Metab. J."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Liu, M., Ao, L., Hu, X., Ma, J., Bao, K., Gu, Y., Zhao, J., and Huang, X. (2019). Influence of blood glucose fluctuation, C-peptide level and conventional risk factors on carotid artery intima-media thickness in Chinese Han patients with type 2 diabetes mellitus. Eur. J. Med. Res., 24.","DOI":"10.1186\/s40001-019-0370-0"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1055\/a-1017-3048","article-title":"Association between serum C-peptide level and cardiovascular autonomic neuropathy according to estimated glomerular filtration rate in individuals with type 2 diabetes","volume":"128","author":"Chung","year":"2020","journal-title":"Exp. Clin. Endocrinol. Diabetes"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Singh, J., Owusu Konadu, A.S., Li, Y., Shabaltiy, B., and Li, Y.-L. (2026). Impact of PKC-MAPK Signaling on Cardiac Sympathetic Overactivation in Type-2 Diabetes Mellitus. Int. J. Mol. Sci., 27.","DOI":"10.3390\/ijms27020723"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"World Medical Association (2013). World Medical Association Declaration of Helsinki: Ethical principles for medical research involving human subjects. JAMA, 310, 2191\u20132194.","DOI":"10.1001\/jama.2013.281053"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1097\/MED.0000000000000947","article-title":"The evolution of C-peptide\u2019s role in diabetes care","volume":"33","author":"Briggs","year":"2026","journal-title":"Curr. Opin. Endocrinol. Diabetes Obes."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"American Diabetes Association Professional Practice Committee (2026). 11. Chronic kidney disease and risk management: Standards of Care in Diabetes\u20142026. Diabetes Care, 49, S246\u2013S260.","DOI":"10.2337\/dc26-S011"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"American Diabetes Association Professional Practice Committee (2026). 12. Retinopathy, neuropathy, and foot care: Standards of Care in Diabetes\u20142026. Diabetes Care, 49, S261\u2013S276.","DOI":"10.2337\/dc26-S012"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1677","DOI":"10.1016\/S0161-6420(03)00475-5","article-title":"Proposed international clinical diabetic retinopathy and diabetic macular edema disease severity scales","volume":"110","author":"Wilkinson","year":"2003","journal-title":"Ophthalmology"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2231","DOI":"10.1016\/j.jacc.2018.08.1038","article-title":"Fourth universal definition of myocardial infarction (2018)","volume":"72","author":"Thygesen","year":"2018","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2064","DOI":"10.1161\/STR.0b013e318296aeca","article-title":"An updated definition of stroke for the 21st century: A statement for healthcare professionals from the American Heart Association\/American Stroke Association","volume":"44","author":"Sacco","year":"2013","journal-title":"Stroke"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"e1313","DOI":"10.1161\/CIR.0000000000001251","article-title":"2024 ACC\/AHA\/AACVPR\/APMA\/ABC\/SCAI\/SVM\/SVN\/SVS\/SIR\/VESS guideline for the management of lower extremity peripheral artery disease","volume":"149","author":"Gornik","year":"2024","journal-title":"Circulation"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Schaper, N.C., van Netten, J.J., Apelqvist, J., Bus, S.A., Fitridge, R., Game, F., Monteiro-Soares, M., Senneville, E., and IWGDF Editorial Board (2024). Practical guidelines on the prevention and management of diabetes-related foot disease (IWGDF 2023 update). Diabetes Metab. Res. Rev., 40.","DOI":"10.1002\/dmrr.3804"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"American Diabetes Association Professional Practice Committee (2026). 10. Cardiovascular disease and risk management: Standards of Care in Diabetes\u20142026. Diabetes Care, 49, S216\u2013S245.","DOI":"10.2337\/dc26-S010"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1097\/HJH.0000000000002289","article-title":"STRIDE BP: An international initiative for accurate blood pressure measurement","volume":"38","author":"Stergiou","year":"2020","journal-title":"J. Hypertens."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"3099","DOI":"10.1016\/j.dsx.2019.11.010","article-title":"C-peptide concentrations in patients with type 2 diabetes treated with insulin","volume":"13","author":"Uzunlulu","year":"2019","journal-title":"Diabetes Metab. Syndr."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"486","DOI":"10.5812\/ijem.3505","article-title":"Normality Tests for Statistical Analysis: A Guide for Non-Statisticians","volume":"10","author":"Ghasemi","year":"2012","journal-title":"Int. J. Endocrinol. Metab."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"928","DOI":"10.1161\/CIRCULATIONAHA.106.672402","article-title":"Use and misuse of the receiver operating characteristic curve in risk prediction","volume":"115","author":"Cook","year":"2007","journal-title":"Circulation"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Chen, J., Huang, Y., Liu, C., Chi, J., Wang, Y., and Xu, L. (2023). The role of C-peptide in diabetes and its complications: An updated review. Front. Endocrinol., 14.","DOI":"10.3389\/fendo.2023.1256093"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1111\/joim.12548","article-title":"C-peptide and diabetic kidney disease","volume":"281","author":"Brunskill","year":"2017","journal-title":"J. Intern. Med."},{"key":"ref_28","first-page":"16","article-title":"The correlation between C-peptide level and diabetic nephropathy in patients with type 2 diabetes","volume":"10","author":"Jiang","year":"2013","journal-title":"Med. Innov. China"},{"key":"ref_29","first-page":"295","article-title":"Analysis of the relationship between serum C-peptide and complications of patients with type 2 diabetes","volume":"43","author":"Huang","year":"2015","journal-title":"Youjiang Med. J."},{"key":"ref_30","unstructured":"Kumar, N., Khan, A.A., Yadav, A., Yadav, S., Gautam, B.K., Rai, R.K., and Mishra, K. (2025). Correlation of C-peptide levels with complications of type 2 diabetes mellitus. Cureus, 17."},{"key":"ref_31","first-page":"1113","article-title":"Relationship between C-peptide and chronic complications in type 2 diabetes mellitus","volume":"97","author":"Sari","year":"2005","journal-title":"J. Natl. Med. Assoc."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"385108","DOI":"10.1155\/2008\/385108","article-title":"C-peptide and atherogenesis: C-peptide as a mediator of lesion development in patients with type 2 diabetes mellitus?","volume":"2008","author":"Marx","year":"2008","journal-title":"J. Diabetes Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1007\/s00592-010-0249-6","article-title":"Association between serum C-peptide levels and chronic microvascular complications in Korean type 2 diabetic patients","volume":"49","author":"Kim","year":"2012","journal-title":"Acta Diabetol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1453","DOI":"10.1016\/S0140-6736(07)61602-X","article-title":"The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: Guidelines for reporting observational studies","volume":"370","author":"Altman","year":"2007","journal-title":"Lancet"}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/15\/18\/6950\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T11:35:10Z","timestamp":1788867310000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/15\/18\/6950"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,8]]},"references-count":34,"journal-issue":{"issue":"18","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["jcm15186950"],"URL":"https:\/\/doi.org\/10.3390\/jcm15186950","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,8]]}}}