A Mathematical Model of Metformin Action on COVID-19 Risk Infection in Cardiovascular Diabetic Patients Studied by FTIR Spectroscopy

DOI record: { "DOI": "10.3390/ijms26136332", "ISSN": [ "1422-0067" ], "URL": "http://dx.doi.org/10.3390/ijms26136332", "abstract": "<jats:p>Several studies have revealed that patients with type 2 diabetes (T2D) infected with COVID-19 who were medicated with metformin showed higher recovery rates than those administered other antidiabetic drugs. To determine the mechanism of action of antidiabetic drugs against COVID-19, we developed a mathematical model that was based on the number of infected and recovered T2D patients. Moreover, the “diagnostic frequencies” of the infected T2D patients, determined using Fourier-Transform Infrared (FTIR) spectroscopy, were very helpful. In particular, the band at 1775 cm−1, attributed to IgG antibodies, could be used as a “diagnostic frequency” for COVID-19 infection. The increased intensity of the band of vC-O-C sugar moieties suggests an increased number of OH chemical groups that enhance the binding sites of SARS-CoV-2 spike protein for entering host cells. The changes were more pronounced in patients medicated with thiazolidinediones than those using insulin and metformin. Both FTIR spectra and the developed mathematical model confirmed that patients using thiazolidinediones showed a higher risk of COVID-19 infection and mortality. The data support the hypothesis that the NH chemical groups of metformin molecules interact directly through the SARS-CoV-2 spike protein, preventing the entry of COVID-19 into the host membrane cells. Indirectly, metformin inhibits the host binding sites for COVID-19 entry by lowering AGE production.</jats:p>", "alternative-id": [ "ijms26136332" ], "author": [ { "affiliation": [ { "name": "Department of Digital Systems, University of Piraeus, 80 M. Karaoli & A. Dimitriou, 18534 Piraeus, Greece" } ], "family": "Mylonas", "given": "Evangelos", "sequence": "first" }, { "affiliation": [ { "name": "Athens Institute for Education and Research, 9 Chalckokondili Str., 10677 Athens, Greece" } ], "family": "Mamareli", "given": "Christina", "sequence": "additional" }, { "affiliation": [ { "name": "Department of Digital Systems, University of Piraeus, 80 M. Karaoli & A. Dimitriou, 18534 Piraeus, Greece" } ], "family": "Filippakis", "given": "Michael", "sequence": "additional" }, { "affiliation": [ { "name": "Cardiology Department, 401 Military General Hospital, Mesogeion Av. 138 & Katechaki Georgiou Str., 11527 Athens, Greece" } ], "family": "Mamarelis", "given": "Ioannis", "sequence": "additional" }, { "affiliation": [ { "name": "Athens Institute for Education and Research, 9 Chalckokondili Str., 10677 Athens, Greece" } ], "family": "Anastassopoulou", "given": "Jane", "sequence": "additional" }, { "affiliation": [ { "name": "Athens Institute for Education and Research, 9 Chalckokondili Str., 10677 Athens, Greece" } ], "family": "Theophanides", "given": "Theophile", "sequence": "additional" } ], "container-title": "International Journal of Molecular Sciences", "container-title-short": "IJMS", "content-domain": { "crossmark-restriction": false, "domain": [] }, "created": { "date-parts": [ [ 2025, 7, 1 ] ], "date-time": "2025-07-01T10:56:54Z", "timestamp": 1751367414000 }, "deposited": { "date-parts": [ [ 2025, 7, 2 ] ], "date-time": "2025-07-02T08:13:19Z", "timestamp": 1751443999000 }, "indexed": { "date-parts": [ [ 2025, 7, 3 ] ], "date-time": "2025-07-03T04:04:10Z", "timestamp": 1751515450046, "version": "3.41.0" }, "is-referenced-by-count": 0, "issue": "13", "issued": { "date-parts": [ [ 2025, 6, 30 ] ] }, "journal-issue": { "issue": "13", "published-online": { "date-parts": [ [ 2025, 7 ] ] } }, "language": "en", "license": [ { "URL": "https://creativecommons.org/licenses/by/4.0/", "content-version": "vor", "delay-in-days": 0, "start": { "date-parts": [ [ 2025, 6, 30 ] ], "date-time": "2025-06-30T00:00:00Z", "timestamp": 1751241600000 } } ], "link": [ { "URL": "https://www.mdpi.com/1422-0067/26/13/6332/pdf", "content-type": "unspecified", "content-version": "vor", "intended-application": "similarity-checking" } ], "member": "1968", "original-title": [], "page": "6332", "prefix": "10.3390", "published": { "date-parts": [ [ 2025, 6, 30 ] ] }, "published-online": { "date-parts": [ [ 2025, 6, 30 ] ] }, "publisher": "MDPI AG", "reference": [ { "article-title": "Evidence from the influence of diabetes on atherosclerosis and amyloid fibril formation of coronary arteries. An FT-IR spectroscopic study", "author": "Kotoulas", "first-page": "15", "journal-title": "Hell. J. Atheroscler.", "key": "ref_1", "volume": "8", "year": "2017" }, { "DOI": "10.1007/s11239-022-02667-9", "article-title": "Metformin therapy in COVID-19: Inhibition of NETosis", "author": "Know", "doi-asserted-by": "crossref", "first-page": "217", "journal-title": "J. Thromb. Thrombolysis", "key": "ref_2", "volume": "54", "year": "2022" }, { "DOI": "10.1038/s41574-020-00435-4", "article-title": "COVID-19 and diabetes mellitus: From pathophysiology to clinical management", "author": "Lim", "doi-asserted-by": "crossref", "first-page": "11", "journal-title": "Nat. Rev. Endocrinol.", "key": "ref_3", "volume": "17", "year": "2021" }, { "DOI": "10.3390/medicina59101810", "doi-asserted-by": "crossref", "key": "ref_4", "unstructured": "Gonikman, D., and Kustovs, D. (2023). Antidiabetic Drug Efficacy in Reduction of Mortality during the COVID-19 Pandemic. Medicina, 59." }, { "DOI": "10.1080/07853890.2024.2425829", "article-title": "Metformin use and its association with various outcomes in COVID-19 patients with diabetes mellitus: A retrospective cohort study in a tertiary care facility", "author": "Somasundarem", "doi-asserted-by": "crossref", "first-page": "2425829", "journal-title": "Ann. Med.", "key": "ref_5", "volume": "56", "year": "2024" }, { "DOI": "10.3390/vaccines11111648", "doi-asserted-by": "crossref", "key": "ref_6", "unstructured": "Marín-Machuca, O., Chacón, R.D., Alvarez-Lovera, N., Pesantes-Grados, P., Pérez-Timaná, L., and Marín-Sánchez, O. (2023). Mathematical Modeling of COVID-19 Cases and Deaths and the Impact of Vaccinations during Three Years of the Pandemic in Peru. Vaccines, 11." }, { "DOI": "10.1186/s12879-024-09354-5", "doi-asserted-by": "crossref", "key": "ref_7", "unstructured": "Manabe, H., Manabe, T., Honda, Y., Kawade, Y., Kambayashi, D., Manabe, Y., and Kudo, K. (2024). Simple mathematical model for predicting COVID-19 outbreaks in Japan based on epidemic waves with a cyclical trend. BMC Infect. Dis., 24." }, { "DOI": "10.1016/j.matpr.2021.11.480", "article-title": "A mathematical model of COVID-19 transmission", "author": "Jayatilaka", "doi-asserted-by": "crossref", "first-page": "101", "journal-title": "Mater. Today Proc.", "key": "ref_8", "volume": "54", "year": "2021" }, { "DOI": "10.7717/peerj.10019", "article-title": "Θ-SEIHRD mathematical model of COVID-19 stability analysis using fast-slow decomposition", "author": "Nave", "doi-asserted-by": "crossref", "first-page": "e10019", "journal-title": "PeerJ", "key": "ref_9", "volume": "8", "year": "2020" }, { "article-title": "FT-IR spectroscopic study of coronary artery in cardiovascular patients and Mathematical simulation model of COVID-19 binding", "author": "Anastassopoulou", "first-page": "1006", "journal-title": "Ann. Forensic Sci. Res.", "key": "ref_10", "volume": "1", "year": "2022" }, { "DOI": "10.1016/j.atherosclerosis.2024.118237", "article-title": "Mathematical Simulation of COVID-19 infection risk factor in cardiovascular diabetic patients. The effect of metformin and the act of viral volume", "author": "Mylonas", "doi-asserted-by": "crossref", "first-page": "117627", "journal-title": "Atherosclerosis", "key": "ref_11", "volume": "395", "year": "2024" }, { "DOI": "10.3390/jcm14072331", "doi-asserted-by": "crossref", "key": "ref_12", "unstructured": "Mylonas, E., Mamareli, C., Filippakis, M., Mamarelis, I., Anastassopoulou, J., and Theophanides, T. (2025). A Mathematical Model of Statin Anti-Hyperlipidemic Drug Reactivity and Diverse Concentrations of Risk Toxicity. J. Clin. Med., 14." }, { "DOI": "10.1016/j.saa.2023.123066", "doi-asserted-by": "crossref", "key": "ref_13", "unstructured": "Glöckler, J., Mizaikoff, B., and Díaz de León-Martínez, L. (2023). SARS CoV-2 infection screening via the exhaled breath fingerprint obtained by FTIR spectroscopic gas-phase analysis. A proof of concept. Spectrochim. Acta Part A Mol. Biomol. Spectrosc., 302." }, { "DOI": "10.21873/cdp.10170", "article-title": "Fourier Transform Infrared spectroscopy in the study of discrimination of lobular breast cancers", "author": "Markouizou", "doi-asserted-by": "crossref", "first-page": "750", "journal-title": "Cancer Diagn. Progn.", "key": "ref_14", "volume": "2", "year": "2022" }, { "key": "ref_15", "unstructured": "Theophanides, T., Anastassopoulou, J., and Mavrogenis, A. (2023). Infrared and Raman spectroscopy of human diseases. Mol. Biophys. IJMS." }, { "DOI": "10.1017/S0033583502003815", "article-title": "What vibrations tell us about proteins", "author": "Barth", "doi-asserted-by": "crossref", "first-page": "343", "journal-title": "Q. Rev. Biophys.", "key": "ref_16", "volume": "35", "year": "2002" }, { "DOI": "10.3233/BSI-200203", "article-title": "ATR-FTIR Spectroscopy for Virus Identification: A Powerful Alternative", "author": "Santos", "doi-asserted-by": "crossref", "first-page": "103", "journal-title": "Biomed. Spectrosc. Imaging", "key": "ref_17", "volume": "9", "year": "2020" }, { "DOI": "10.1021/acsomega.2c01374", "article-title": "Potential of ATR-FTIR-Chemometrics in COVID-19: Disease Recognition", "author": "Calvo", "doi-asserted-by": "crossref", "first-page": "30756", "journal-title": "ACS Omega", "key": "ref_18", "volume": "7", "year": "2022" }, { "DOI": "10.1038/s41598-022-08156-6", "doi-asserted-by": "crossref", "key": "ref_19", "unstructured": "Bandeira, C.C.S., Madureira, K.C.R., Rossi, M.B., Gallo, J.F., Aguirra da Silva, A.P.R., Torres, V.L., Alves de Lima, V., Júnior, N.K., Almeida, J.D., and Zerbinati, R.M. (2022). Micro-Fourier-transform infrared reflectance spectroscopy as tool for probing IgG glycosylation in COVID-19 patients. Sci. Rep., 12." }, { "DOI": "10.1177/1179547620980381", "article-title": "SARS-CoV-2 and Anti-Cardiolipin Antibodies", "author": "Jizzini", "doi-asserted-by": "crossref", "first-page": "1179547620980381", "journal-title": "Clin. Med. Insights Case Rep.", "key": "ref_20", "volume": "13", "year": "2020" }, { "DOI": "10.1098/rspa.1927.0118", "article-title": "A contribution to the mathematical theory of epidemics", "author": "Kermack", "doi-asserted-by": "crossref", "first-page": "700", "journal-title": "Proc. R. Soc. Lond. Ser. A", "key": "ref_21", "volume": "115", "year": "1927" }, { "DOI": "10.1016/j.cnsns.2016.09.006", "article-title": "A Caputo fractional derivative of a function with respect to another function", "author": "Almeida", "doi-asserted-by": "crossref", "first-page": "460", "journal-title": "Commun. Nonlinear Sci. Numer. Simul.", "key": "ref_22", "volume": "44", "year": "2017" }, { "DOI": "10.4134/BKMS.b150901", "article-title": "A predictor-corrector method for fractional evolution equations", "author": "Choi", "doi-asserted-by": "crossref", "first-page": "1725", "journal-title": "Bull. Korean Math. Soc.", "key": "ref_23", "volume": "53", "year": "2016" }, { "key": "ref_24", "unstructured": "Garrappa, R. (2024, December 21). Predictor-Corrector PECE Method for Fractional Differential Equations. MATLAB Central File Exchange. Available online: https://www.mathworks.com/matlabcentral/fileexchange/32918-predictor-corrector-pece-method-for-fractional-dif-ferential-equations." }, { "key": "ref_25", "unstructured": "Greek National Public Health Organization (2024, December 21). Responsible for the Surveillance and Control of Diseases in Greece, Available online: https://eody.gov.gr/." }, { "DOI": "10.3390/microorganisms11061416", "doi-asserted-by": "crossref", "key": "ref_26", "unstructured": "Akinosoglou, K., Schinas, K., Bletsa, E., Bristianou, M., Lanaras, L., Michailides, C., Katsikas, T., Barkas, F., Liberopoulos, E., and Kotsis, V. (2023). COVID-19 Outcomes and Diabetes Mellitus: A Comprehensive Multicenter Prospective Cohort Study. Microorganisms, 11." }, { "DOI": "10.1002/dmrr.3388", "article-title": "Characteristics and outcomes of COVID-19 in hospitalized patients with and without diabetes", "author": "Lanoix", "doi-asserted-by": "crossref", "first-page": "e3388", "journal-title": "Diabetes Metab. Res. Rev.", "key": "ref_27", "volume": "37", "year": "2021" }, { "DOI": "10.1016/j.diabet.2022.101359", "article-title": "Protection by metformin against severe COVID-19: An in-depth mechanistic analysis", "author": "Wiernsperger", "doi-asserted-by": "crossref", "first-page": "101359", "journal-title": "Diabetes Metab.", "key": "ref_28", "volume": "48", "year": "2022" }, { "DOI": "10.1016/j.cmet.2020.11.014", "article-title": "Insulin treatment is associated with increased mortality in patients with COVID-19 and Type 2 diabetes", "author": "Yu", "doi-asserted-by": "crossref", "first-page": "65", "journal-title": "Cell Metab.", "key": "ref_29", "volume": "33", "year": "2021" }, { "DOI": "10.1016/j.intimp.2021.107806", "article-title": "Advanced glycation end products (AGEs) and its receptor, RAGE, modulate age-dependent COVID-19 morbidity and mortality. A review and hypothesis", "author": "Sellegounder", "doi-asserted-by": "crossref", "first-page": "107806", "journal-title": "Int. Immunopharmacol.", "key": "ref_30", "volume": "98", "year": "2021" }, { "DOI": "10.3390/ijerph18147236", "doi-asserted-by": "crossref", "key": "ref_31", "unstructured": "Salazar, J., Navarro, C., Ortega, A., Nava, M., Morillo, D., Torres, W., Hernández, M., Cabrera, M., Angarita, M., and Ortiz, R. (2021). Advanced glycation end products: New clinical and molecular perspectives. Int. J. Environ. Res. Public Health, 18." }, { "DOI": "10.1002/anie.202011015", "article-title": "Structural Characterization of N-Linked Glycans in the Receptor Binding Domain of the SARS-CoV-2 Spike Protein and their Interactions with Human Lectins", "author": "Lenza", "doi-asserted-by": "crossref", "first-page": "23763", "journal-title": "Angew. Chem. Int. Ed.", "key": "ref_32", "volume": "59", "year": "2020" }, { "DOI": "10.1002/slct.202201793", "article-title": "Designing of Thiazolidinones for COVID-19 and its Allied Diseases: An In silic Evaluation", "author": "Raza", "doi-asserted-by": "crossref", "first-page": "e202201793", "journal-title": "ChemistrySelect", "key": "ref_33", "volume": "7", "year": "2022" }, { "DOI": "10.1002/open.202400147", "article-title": "Medical perspective of 2,4-thiazolidinediones derivatives: An insight into recent advancements", "author": "Gupta", "doi-asserted-by": "crossref", "first-page": "e202400147", "journal-title": "ChemistryOpen", "key": "ref_34", "volume": "13", "year": "2024" }, { "DOI": "10.1016/j.plipres.2021.101099", "article-title": "Lipid homeostasis and mevalonate pathway in COVID-19: Basic concepts and potential therapeutic targets", "author": "Proto", "doi-asserted-by": "crossref", "first-page": "101099", "journal-title": "Prog. Lipid Res.", "key": "ref_35", "volume": "82", "year": "2021" }, { "DOI": "10.1038/s41598-021-86380-2", "doi-asserted-by": "crossref", "key": "ref_36", "unstructured": "Jafary, F., Jafari, S., and Ganjalikhany, M.R. (2021). In silico investigation of critical binding pattern in SARS-CoV-2 spike protein with angiotensin-converting enzyme 2. Sci. Rep., 11." }, { "article-title": "Effects of metformin, insulin on COVID-19 patients with pre-existed type 2 diabetes: A multicentral retrospective study", "author": "Cheng", "first-page": "275", "journal-title": "Life Sci.", "key": "ref_37", "volume": "15", "year": "2021" }, { "DOI": "10.1016/j.phrs.2020.105390", "article-title": "Mechanisms of action of metformin and its regulatory effect on microRNAs related to angiogenesis", "author": "Wang", "doi-asserted-by": "crossref", "first-page": "105390", "journal-title": "Pharm. Res.", "key": "ref_38", "volume": "164", "year": "2021" }, { "DOI": "10.21926/obm.geriatr.2104180", "article-title": "Study of the development of carotid artery atherosclerosis upon oxidative stress using infrared spectroscopy and scanning electron microscopy", "author": "Anastassopoulou", "doi-asserted-by": "crossref", "first-page": "180", "journal-title": "OBM Geriatr.", "key": "ref_39", "volume": "5", "year": "2021" } ], "reference-count": 39, "references-count": 39, "relation": {}, "resource": { "primary": { "URL": "https://www.mdpi.com/1422-0067/26/13/6332" } }, "score": 1, "short-title": [], "source": "Crossref", "subject": [], "subtitle": [], "title": "A Mathematical Model of Metformin Action on COVID-19 Risk Infection in Cardiovascular Diabetic Patients Studied by FTIR Spectroscopy", "type": "journal-article", "volume": "26" }