{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T16:51:58Z","timestamp":1791996718477,"version":"4.4.0"},"reference-count":36,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2026,2,28]],"date-time":"2026-02-28T00:00:00Z","timestamp":1772236800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Faculty of Medicine Osijek","award":["IP2025-14"],"award-info":[{"award-number":["IP2025-14"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Acute hyperglycaemia is a common COVID-19 complication linked to adverse outcomes. The combined prognostic value of cytokine activation and acute insulin resistance in non-diabetic patients remains unclear. In this prospective cohort study, we enrolled 144 hospitalised adults with RT-PCR-confirmed SARS-CoV-2 infection and no prior diabetes. We aimed to characterise metabolic\u2013inflammatory phenotypes and evaluate their association with disease severity and post-discharge glycaemic outcomes. Patients were classified as normoglycaemic or dysglycaemic based on repeated glucose profiles. Dysglycaemic patients were further phenotyped as stress hyperglycaemia (SHG) or newly diagnosed diabetes (NOD). This classification was based on post-discharge glycaemic assessment at 3 and 6 months, distinguishing transient from persistent hyperglycaemia. Admission hyperglycaemia was associated with a consistently elevated pro-inflammatory cytokine pattern. However, cytokine concentrations were comparable between stress hyperglycaemia and newly diagnosed diabetes, indicating that inflammatory burden alone does not explain metabolic persistence. In contrast, insulin resistance (HOMA-IR) was markedly higher in the newly diagnosed diabetes phenotype. Along with admission oxygenation and key cytokine signals, this contributed to risk stratification for severe disease. In conclusion, early admission assessment of glucose and insulin resistance identifies high-risk metabolic phenotypes. This enables targeted in-hospital risk stratification and post-discharge glycaemic surveillance.<\/jats:p>","DOI":"10.3390\/ijms27052292","type":"journal-article","created":{"date-parts":[[2026,3,2]],"date-time":"2026-03-02T12:39:56Z","timestamp":1772455196000},"page":"2292","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Acute Hyperglycaemia, Insulin Resistance, and Cytokine Dysregulation as Predictors of Disease Severity in Non-Diabetic Hospitalised COVID-19 Patients"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6668-7744","authenticated-orcid":false,"given":"Barbara","family":"Grubi\u0161i\u0107","sequence":"first","affiliation":[{"name":"Department of Infectious Diseases, University Hospital Centre Osijek, 4 Josip Huttler Street, HR-31000 Osijek, Croatia"},{"name":"Faculty of Medicine Osijek, Josip Juraj Strossmayer University of Osijek, 4 Josip Huttler Street, HR-31000 Osijek, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0208-5821","authenticated-orcid":false,"given":"Luka","family":"\u0160vitek","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, University Hospital Centre Osijek, 4 Josip Huttler Street, HR-31000 Osijek, Croatia"},{"name":"Faculty of Medicine Osijek, Josip Juraj Strossmayer University of Osijek, 4 Josip Huttler Street, HR-31000 Osijek, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-6131-3844","authenticated-orcid":false,"given":"Mihaela","family":"Zlosa","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, University Hospital Centre Osijek, 4 Josip Huttler Street, HR-31000 Osijek, Croatia"},{"name":"Faculty of Medicine Osijek, Josip Juraj Strossmayer University of Osijek, 4 Josip Huttler Street, HR-31000 Osijek, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7015-713X","authenticated-orcid":false,"given":"Petra","family":"Smaji\u0107","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, University Hospital Centre Osijek, 4 Josip Huttler Street, HR-31000 Osijek, Croatia"},{"name":"Faculty of Medicine Osijek, Josip Juraj Strossmayer University of Osijek, 4 Josip Huttler Street, HR-31000 Osijek, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-8029-3118","authenticated-orcid":false,"given":"David","family":"Mati\u0107","sequence":"additional","affiliation":[{"name":"Department of Orthopedics and Traumatology, University Hospital Centre Osijek, 4 Josip Huttler Street, HR-31000 Osijek, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4481-6365","authenticated-orcid":false,"given":"Kristina","family":"Kralik","sequence":"additional","affiliation":[{"name":"Department of Medical Statistics and Medical Informatics, Faculty of Medicine, Josip Juraj Strossmayer University of Osijek, 4 Josip Huttler Street, HR-31000 Osijek, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3374-8512","authenticated-orcid":false,"given":"Anita","family":"Mati\u0107","sequence":"additional","affiliation":[{"name":"Department of Pathophysiology, Physiology and Immunology, Faculty of Dental Medicine and Health Osijek, Josip Juraj Strossmayer University of Osijek, 21 Crkvena Street, HR-31000 Osijek, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8492-1418","authenticated-orcid":false,"given":"Marija","family":"Santini","sequence":"additional","affiliation":[{"name":"Department for Infections in Immunocompromised, University Hospital for Infectious Diseases \u201cDr. Fran Mihaljevi\u0107\u201d, 16 Mirogojska Street, HR-10000 Zagreb, Croatia"},{"name":"Department of Infectious Diseases, School of Medicine, University of Zagreb, 3 \u0160alata, HR-10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8861-5987","authenticated-orcid":false,"given":"Ines","family":"Bili\u0107-\u0106ur\u010di\u0107","sequence":"additional","affiliation":[{"name":"Department for Pharmacology, Faculty of Medicine Osijek, Josip Juraj Strossmayer University of Osijek, 4 Josip Huttler Street, HR-31000 Osijek, Croatia"},{"name":"Department of Endocrinology and Metabolism Disorders, Internal Medicine Clinic, University Hospital Centre Osijek, 4 Josip Huttler Street, HR-31000 Osijek, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"108338","DOI":"10.1016\/j.diabres.2020.108338","article-title":"Hyperglycemia Is a Strong Predictor of Poor Prognosis in COVID-19","volume":"167","author":"Liu","year":"2020","journal-title":"Diabetes Res. Clin. Pract."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Chen, J., Wu, C., Wang, X., Yu, J., and Sun, Z. (2020). The Impact of COVID-19 on Blood Glucose: A Systematic Review and Meta-Analysis. Front. Endocrinol., 11.","DOI":"10.3389\/fendo.2020.574541"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2345","DOI":"10.2337\/dc20-1380","article-title":"Hyperglycemia at Hospital Admission Is Associated With Severity of the Prognosis in Patients Hospitalized for COVID-19: The Pisa COVID-19 Study","volume":"43","author":"Coppelli","year":"2020","journal-title":"Diabetes Care"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"774","DOI":"10.1038\/s42255-021-00407-6","article-title":"Acute and long-term disruption of glycometabolic control after SARS-CoV-2 infection","volume":"3","author":"Montefusco","year":"2021","journal-title":"Nat. Metab."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Parli\u0163eanu, O.A., Balteanu, M., Zaharia, D., Constantinescu, T., Cristea, A.M., Dumitrache-Rujinscki, \u015e., Nica, A.E., Voineag, C., Alexe, O., and Tabacu, E. (2025). The Impact of SARS-CoV-2 Infection on Glucose Homeostasis in Hospitalized Patients With Pulmonary Impairment. Diagnostics, 15.","DOI":"10.3390\/diagnostics15050554"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"275","DOI":"10.5501\/wjv.v10.i5.275","article-title":"New-Onset Diabetes in COVID-19 and Clinical Outcomes: A Systematic Review and Meta-Analysis","volume":"10","author":"Shrestha","year":"2021","journal-title":"World J. Virol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1408","DOI":"10.2337\/dc20-0723","article-title":"Outcomes in Patients with Hyperglycemia Affected by COVID-19: Can We Do More on Glycemic Control?","volume":"43","author":"Sardu","year":"2020","journal-title":"Diabetes Care"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2128","DOI":"10.1016\/j.cgh.2020.04.040","article-title":"ACE2 Expression in Pancreas May Cause Pancreatic Damage After SARS-CoV-2 Infection","volume":"18","author":"Liu","year":"2020","journal-title":"Clin. Gastroenterol. Hepatol."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Fignani, D., Licata, G., Brusco, N., Nigi, L., Grieco, G.E., Marselli, L., Overbergh, L., Gysemans, C., Colli, M.L., and Marchetti, P. (2020). SARS-CoV-2 Receptor Angiotensin I-Converting Enzyme Type 2 (ACE2) Is Expressed in Human Pancreatic \u03b2-Cells and in the Human Pancreas Microvasculature. Front. Endocrinol., 11.","DOI":"10.3389\/fendo.2020.596898"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"17","DOI":"10.30574\/gscarr.2021.6.1.0001","article-title":"Acute Uncontrolled Hyperglycemia, a Non-Specific Presentation and Predictor of Covid-19 Severity\u2014A Report of Three Cases","volume":"6","author":"Mensah","year":"2021","journal-title":"GSC Adv. Res. Rev."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Grubi\u0161i\u0107, B., \u0160vitek, L., Ormanac, K., Sabo, D., Mihaljevi\u0107, I., Bili\u0107-\u0106ur\u010di\u0107, I., and Kolari\u0107, T.O. (2023). Molecular Mechanisms Responsible for Diabetogenic Effects of COVID-19 Infection\u2014Induction of Autoimmune Dysregulation and Metabolic Disturbances. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms241411576"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Porto, A.D., Tascini, C., Colussi, G., Peghin, M., Graziano, E., Carlo, C.D., Bulfone, L., Antonello, M., Sozio, E., and Fabris, M. (2022). Relationship between cytokine release and stress hyperglycemia in patients hospitalized with COVID-19 infection. Front. Med., 9.","DOI":"10.3389\/fmed.2022.988686"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2102","DOI":"10.1007\/s00125-020-05209-1","article-title":"Fasting blood glucose at admission is an independent predictor for 28-day mortality in patients with COVID-19 without previous diagnosis of diabetes: A multi-centre retrospective study","volume":"63","author":"Wang","year":"2020","journal-title":"Diabetologia"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"BSR20203584","DOI":"10.1042\/BSR20203584","article-title":"Hyperglycemia at admission is a strong predictor of mortality and severe\/critical complications in COVID-19 patients: A meta-analysis","volume":"41","author":"Yang","year":"2021","journal-title":"Biosci. Rep."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2067","DOI":"10.1161\/01.CIR.0000034509.14906.AE","article-title":"Inflammatory Cytokine Concentrations Are Acutely Increased by Hyperglycemia in Humans","volume":"106","author":"Esposito","year":"2002","journal-title":"Circulation"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"9526701","DOI":"10.1155\/2021\/9526701","article-title":"The Cytokine Profiles and Immune Response Are Increased in COVID-19 Patients with Type 2 Diabetes Mellitus","volume":"2021","author":"Zheng","year":"2021","journal-title":"J. Diabetes Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2645","DOI":"10.2337\/dc21-1318","article-title":"COVID-19, Hyperglycemia, and New-Onset Diabetes","volume":"44","author":"Khunti","year":"2021","journal-title":"Diabetes Care"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2909","DOI":"10.1007\/s10238-023-01064-7","article-title":"Modulation of IRAK enzymes as a therapeutic strategy against SARS-CoV-2 induced cytokine storm","volume":"23","author":"Mahmoud","year":"2023","journal-title":"Clin. Exp. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1636","DOI":"10.1038\/s41591-020-1051-9","article-title":"An inflammatory cytokine signature predicts COVID-19 severity and survival","volume":"26","author":"Valle","year":"2020","journal-title":"Nat. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1064","DOI":"10.1111\/jdi.13431","article-title":"Glycemic Control Before Admission Is an Important Determinant of Prognosis in Patients with Coronavirus Disease 2019","volume":"12","author":"Liu","year":"2021","journal-title":"J. Diabetes Investig."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1007\/BF00280883","article-title":"Homeostasis Model Assessment: Insulin Resistance and \u03b2-Cell Function from Fasting Plasma Glucose and Insulin Concentrations in Man","volume":"28","author":"Matthews","year":"1985","journal-title":"Diabetologia"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1487","DOI":"10.2337\/diacare.27.6.1487","article-title":"Use and Abuse of HOMA Modeling","volume":"27","author":"Wallace","year":"2004","journal-title":"Diabetes Care"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Mohamed, F., Gunter, S., Yirdaw, B.E., Raal, F.J., Millen, A.M.E., and Kalla, I.S. (2025). Predictive diagnostic models for newly diagnosed diabetes mellitus in moderate to severe COVID-19: The role of TyG Index, BMI, and inflammatory markers. BMC Endocr. Disord., 25.","DOI":"10.1186\/s12902-025-02056-2"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"789","DOI":"10.1056\/NEJMc2018688","article-title":"New-Onset Diabetes in COVID-19","volume":"383","author":"Rubino","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"762","DOI":"10.1093\/cid\/ciaa248","article-title":"Dysregulation of Immune Response in Patients with Coronavirus 2019 (COVID-19) in Wuhan, China","volume":"71","author":"Qin","year":"2020","journal-title":"Clin. Infect. Dis."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Zanza, C., Romenskaya, T., Manetti, A.C., Franceschi, F., Russa, R.L., Bertozzi, G., Maiese, A., Savioli, G., Volonnino, G., and Longhitano, Y. (2022). Cytokine Storm in COVID-19: Immunopathogenesis and Therapy. Medicina, 58.","DOI":"10.3390\/medicina58020144"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1086","DOI":"10.1111\/jdi.13754","article-title":"Impact of Newly Diagnosed Diabetes on Coronavirus Disease 2019 Severity and Hyperglycemia","volume":"13","author":"Uchihara","year":"2022","journal-title":"J. Diabetes Investig."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1897","DOI":"10.1111\/dom.14099","article-title":"Newly Diagnosed Diabetes Is Associated with a Higher Risk of Mortality Than Known Diabetes in Hospitalized Patients with COVID-19","volume":"22","author":"Li","year":"2020","journal-title":"Diabetes Obes. Metab."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"108374","DOI":"10.1016\/j.diabres.2020.108374","article-title":"Newly-diagnosed diabetes and admission hyperglycemia predict COVID-19 severity by aggravating respiratory deterioration","volume":"168","author":"Fadini","year":"2020","journal-title":"Diabetes Res. Clin. Pract."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1751","DOI":"10.1007\/s00592-025-02507-1","article-title":"Hyperglycemia in the diabetic range, but not previous diagnosis of diabetes mellitus, is an independent indicator of poor outcome in patients hospitalized for severe COVID-19","volume":"62","author":"Cas","year":"2025","journal-title":"Acta Diabetol."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Annweiler, G., Corvaisier, M., Gautier, J., Dub\u00e9e, V., Legrand, \u00c9., Sacco, G., and Annweiler, C. (2020). Vitamin D Supplementation Associated to Better Survival in Hospitalized Frail Elderly COVID-19 Patients: The GERIA-COVID Quasi-Experimental Study. Nutrients, 12.","DOI":"10.3390\/nu12113377"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1111\/cen.14540","article-title":"Association of Vitamin D Deficiency with COVID-19 Infection Severity: Systematic Review and Meta-analysis","volume":"96","author":"Wang","year":"2021","journal-title":"Clin. Endocrinol."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Sobczak, M., and Pawliczak, R. (2024). Effect of Vitamin D3 Supplementation on Severe COVID-19: A Meta-Analysis of Randomized Clinical Trials. Nutrients, 16.","DOI":"10.3390\/nu16101402"},{"key":"ref_34","unstructured":"European Centre for Disease Prevention and Control (2026, January 15). Threat Assessment Brief: Implications for the EU\/EEA of the Spread of the SARS-CoV-2 Omicron XBB.1.5 Sub-Lineage. Available online: https:\/\/www.ecdc.europa.eu\/en\/publications-data\/covid-19-threat-assessment-brief-implications-spread-omicron-xbb."},{"key":"ref_35","unstructured":"European Centre for Disease Prevention and Control (2026, January 15). Communicable Disease Threats Report (CDTR), Week 2. Available online: https:\/\/www.ecdc.europa.eu\/en\/publications-data\/communicable-disease-threats-report-7-13-january-2024-week-2."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"American Diabetes Association Professional Practice Committee (2025). 2. Diagnosis and Classification of Diabetes: Standards of Care in Diabetes\u20142026. Diabetes Care, 49, S27\u2013S49.","DOI":"10.2337\/dc26-S002"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/5\/2292\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,2]],"date-time":"2026-03-02T12:40:59Z","timestamp":1772455259000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/5\/2292"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,28]]},"references-count":36,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2026,3]]}},"alternative-id":["ijms27052292"],"URL":"https:\/\/doi.org\/10.3390\/ijms27052292","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,28]]}}}