{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T14:15:13Z","timestamp":1789827313995,"version":"4.0.1"},"reference-count":44,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2023,4,14]],"date-time":"2023-04-14T00:00:00Z","timestamp":1681430400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004271","name":"Sapienza University of Rome","doi-asserted-by":"publisher","award":["RG11916B87F55459"],"award-info":[{"award-number":["RG11916B87F55459"]}],"id":[{"id":"10.13039\/501100004271","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004271","name":"Sapienza University of Rome","doi-asserted-by":"publisher","award":["RM11916B811AFD26"],"award-info":[{"award-number":["RM11916B811AFD26"]}],"id":[{"id":"10.13039\/501100004271","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Biliverdin reductase-A (BVRA) is involved in the regulation of insulin signaling and the maintenance of glucose homeostasis. Previous research showed that BVRA alterations are associated with the aberrant activation of insulin signaling in dysmetabolic conditions. However, whether BVRA protein levels change dynamically within the cells in response to insulin and\/or glucose remains an open question. To this aim, we evaluated changes of intracellular BVRA levels in peripheral blood mononuclear cells (PBMC) collected during the oral glucose tolerance test (OGTT) in a group of subjects with different levels of insulin sensitivity. Furthermore, we looked for significant correlations with clinical measures. Our data show that BVRA levels change dynamically during the OGTT in response to insulin, and greater BVRA variations occur in those subjects with lower insulin sensitivity. Changes of BVRA significantly correlate with indexes of increased insulin resistance and insulin secretion (HOMA-IR, HOMA-\u03b2, and insulinogenic index). At the multivariate regression analysis, the insulinogenic index independently predicted increased BVRA area under curve (AUC) during the OGTT. This pilot study showed, for the first time, that intracellular BVRA protein levels change in response to insulin during OGTT and are greater in subjects with lower insulin sensitivity, supporting the role of BVR-A in the dynamic regulation of the insulin signaling pathway.<\/jats:p>","DOI":"10.3390\/ijms24087282","type":"journal-article","created":{"date-parts":[[2023,4,14]],"date-time":"2023-04-14T09:23:43Z","timestamp":1681464223000},"page":"7282","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Dynamic Changes of BVRA Protein Levels Occur in Response to Insulin: A Pilot Study in Humans"],"prefix":"10.3390","volume":"24","author":[{"given":"Flavia Agata","family":"Cimini","sequence":"first","affiliation":[{"name":"Department of Experimental Medicine, Sapienza University of Rome, 00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9564-2086","authenticated-orcid":false,"given":"Antonella","family":"Tramutola","sequence":"additional","affiliation":[{"name":"Department of Biochemical Sciences \u201cA. Rossi-Fanelli\u201d, Sapienza University of Rome, 00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0530-8568","authenticated-orcid":false,"given":"Ilaria","family":"Barchetta","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine, Sapienza University of Rome, 00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentina","family":"Ceccarelli","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine, Sapienza University of Rome, 00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1044-2278","authenticated-orcid":false,"given":"Elena","family":"Gangitano","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine, Sapienza University of Rome, 00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8421-023X","authenticated-orcid":false,"given":"Simona","family":"Lanzillotta","sequence":"additional","affiliation":[{"name":"Department of Biochemical Sciences \u201cA. Rossi-Fanelli\u201d, Sapienza University of Rome, 00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6883-7806","authenticated-orcid":false,"given":"Chiara","family":"Lanzillotta","sequence":"additional","affiliation":[{"name":"Department of Biochemical Sciences \u201cA. Rossi-Fanelli\u201d, Sapienza University of Rome, 00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6630-8049","authenticated-orcid":false,"given":"Maria Gisella","family":"Cavallo","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine, Sapienza University of Rome, 00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7028-4251","authenticated-orcid":false,"given":"Eugenio","family":"Barone","sequence":"additional","affiliation":[{"name":"Department of Biochemical Sciences \u201cA. Rossi-Fanelli\u201d, Sapienza University of Rome, 00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,4,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Cimini, F.A., Perluigi, M., Barchetta, I., Cavallo, M.G., and Barone, E. (2022). Role of Biliverdin Reductase A in the Regulation of Insulin Signaling in Metabolic and Neurodegenerative Diseases: An Update. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23105574"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1016\/j.tips.2008.12.003","article-title":"Pleiotropic functions of biliverdin reductase: Cellular signaling and generation of cytoprotective and cytotoxic bilirubin","volume":"30","author":"Kapitulnik","year":"2009","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"3181","DOI":"10.1016\/j.bbadis.2018.07.005","article-title":"Biliverdin reductase-A impairment links brain insulin resistance with increased Abeta production in an animal model of aging: Implications for Alzheimer disease","volume":"1864","author":"Triani","year":"2018","journal-title":"Biochim. Biophys. Acta Mol. Basis Dis."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1066","DOI":"10.1074\/jbc.M111.279612","article-title":"Formation of ternary complex of human biliverdin reductase-protein kinase Cdelta-ERK2 protein is essential for ERK2-mediated activation of Elk1 protein, nuclear factor-kappaB, and inducible nitric-oxidase synthase (iNOS)","volume":"287","author":"Gibbs","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"3949","DOI":"10.1096\/fj.07-8544com","article-title":"Regulation of TNF-alpha-activated PKC-zeta signaling by the human biliverdin reductase: Identification of activating and inhibitory domains of the reductase","volume":"21","author":"Miralem","year":"2007","journal-title":"FASEB J."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2926","DOI":"10.1096\/fj.201600330RR","article-title":"Interaction of human biliverdin reductase with Akt\/protein kinase B and phosphatidylinositol-dependent kinase 1 regulates glycogen synthase kinase 3 activity: A novel mechanism of Akt activation","volume":"30","author":"Miralem","year":"2016","journal-title":"FASEB J."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"eabh3066","DOI":"10.1126\/scisignal.abh3066","article-title":"Biliverdin reductase bridges focal adhesion kinase to Src to modulate synaptic signaling","volume":"15","author":"Vasavda","year":"2022","journal-title":"Sci. Signal."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Lanzillotta, C., Zuliani, I., Vasavda, C., Snyder, S.H., Paul, B.D., Perluigi, M., Di Domenico, F., and Barone, E. (2020). BVR-A Deficiency Leads to Autophagy Impairment through the Dysregulation of AMPK\/mTOR Axis in the Brain-Implications for Neurodegeneration. Antioxidants, 9.","DOI":"10.3390\/antiox9080671"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1016\/j.nbd.2019.02.003","article-title":"Loss of biliverdin reductase-A favors Tau hyper-phosphorylation in Alzheimer\u2019s disease","volume":"125","author":"Sharma","year":"2019","journal-title":"Neurobiol. Dis."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1042\/BJ20080018","article-title":"Biliverdin reductase is a transporter of haem into the nucleus and is essential for regulation of HO-1 gene expression by haematin","volume":"413","author":"Tudor","year":"2008","journal-title":"Biochem. J."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"7109","DOI":"10.1073\/pnas.0502173102","article-title":"Human biliverdin reductase: A member of the insulin receptor substrate family with serine\/threonine\/tyrosine kinase activity","volume":"102","author":"Shen","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2478","DOI":"10.1096\/fj.13-247015","article-title":"Human biliverdin reductase-based peptides activate and inhibit glucose uptake through direct interaction with the kinase domain of insulin receptor","volume":"28","author":"Gibbs","year":"2014","journal-title":"FASEB J."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2187","DOI":"10.1089\/ars.2007.1805","article-title":"Biliverdin reductase: PKC interaction at the cross-talk of MAPK and PI3K signaling pathways","volume":"9","author":"Maines","year":"2007","journal-title":"Antioxid. Redox Signal."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"6870","DOI":"10.1073\/pnas.0800750105","article-title":"Human biliverdin reductase is an ERK activator; hBVR is an ERK nuclear transporter and is required for MAPK signaling","volume":"105","author":"Miralem","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1450","DOI":"10.1016\/j.chembiol.2019.07.006","article-title":"Bilirubin Links Heme Metabolism to Neuroprotection by Scavenging Superoxide","volume":"26","author":"Vasavda","year":"2019","journal-title":"Cell Chem. Biol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1490","DOI":"10.1089\/ars.2011.4312","article-title":"Redox proteomics analyses of the influence of co-expression of wild-type or mutated LRRK2 and Tau on C. elegans protein expression and oxidative modification: Relevance to Parkinson disease","volume":"17","author":"Sultana","year":"2012","journal-title":"Antioxid. Redox Signal."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1038\/nrm.2017.89","article-title":"Biochemical and cellular properties of insulin receptor signalling","volume":"19","author":"Haeusler","year":"2018","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"101162","DOI":"10.1016\/j.redox.2019.101162","article-title":"Restoration of aberrant mTOR signaling by intranasal rapamycin reduces oxidative damage: Focus on HNE-modified proteins in a mouse model of down syndrome","volume":"23","author":"Tramutola","year":"2019","journal-title":"Redox Biol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/j.ceb.2017.01.005","article-title":"AMPK signalling in health and disease","volume":"45","author":"Carling","year":"2017","journal-title":"Curr. Opin. Cell Biol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/j.freeradbiomed.2021.09.006","article-title":"The interplay among oxidative stress, brain insulin resistance and AMPK dysfunction contribute to neurodegeneration in type 2 diabetes and Alzheimer disease","volume":"176","author":"Barone","year":"2021","journal-title":"Free Radic Biol. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"25179","DOI":"10.1074\/jbc.M116.731703","article-title":"Biliverdin Reductase A Attenuates Hepatic Steatosis by Inhibition of Glycogen Synthase Kinase (GSK) 3beta Phosphorylation of Serine 73 of Peroxisome Proliferator-activated Receptor (PPAR) alpha","volume":"291","author":"Hinds","year":"2016","journal-title":"J. Biol. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"4712053","DOI":"10.1155\/2016\/4712053","article-title":"Nanoparticle Delivered Human Biliverdin Reductase-Based Peptide Increases Glucose Uptake by Activating IRK\/Akt\/GSK3 Axis: The Peptide Is Effective in the Cell and Wild-Type and Diabetic Ob\/Ob Mice","volume":"2016","author":"Gibbs","year":"2016","journal-title":"J. Diabetes Res."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Stec, D.E., Gordon, D.M., Nestor-Kalinoski, A.L., Donald, M.C., Mitchell, Z.L., Creeden, J.F., and Hinds, T.D. (2020). Biliverdin Reductase A (BVRA) Knockout in Adipocytes Induces Hypertrophy and Reduces Mitochondria in White Fat of Obese Mice. Biomolecules, 10.","DOI":"10.3390\/biom10030387"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"104772","DOI":"10.1016\/j.nbd.2020.104772","article-title":"Brain insulin resistance triggers early onset Alzheimer disease in Down syndrome","volume":"137","author":"Tramutola","year":"2020","journal-title":"Neurobiol. Dis."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1016\/j.freeradbiomed.2015.12.012","article-title":"Impairment of biliverdin reductase-A promotes brain insulin resistance in Alzheimer disease: A new paradigm","volume":"91","author":"Barone","year":"2016","journal-title":"Free Radic Biol. Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1016\/j.freeradbiomed.2021.01.042","article-title":"Insulin resistance, oxidative stress and mitochondrial defects in Ts65dn mice brain: A harmful synergistic path in down syndrome","volume":"165","author":"Lanzillotta","year":"2021","journal-title":"Free Radic Biol. Med."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Tramutola, A., Lanzillotta, S., Aceto, G., Pagnotta, S., Ruffolo, G., Cifelli, P., Marini, F., Ripoli, C., Palma, E., and Grassi, C. (2023). Intranasal Administration of KYCCSRK Peptide Rescues Brain Insulin Signaling Activation and Reduces Alzheimer\u2019s Disease-like Neuropathology in a Mouse Model for Down Syndrome. Antioxidants, 12.","DOI":"10.3390\/antiox12010111"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2922","DOI":"10.1007\/s12035-018-1231-5","article-title":"Biliverdin Reductase-A Mediates the Beneficial Effects of Intranasal Insulin in Alzheimer Disease","volume":"56","author":"Barone","year":"2019","journal-title":"Mol. Neurobiol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1490","DOI":"10.1016\/j.bbadis.2019.02.021","article-title":"Reduced biliverdin reductase-A levels are associated with early alterations of insulin signaling in obesity","volume":"1865","author":"Cimini","year":"2019","journal-title":"Biochim. Biophys. Acta Mol. Basis Dis."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Ceccarelli, V., Barchetta, I., Cimini, F.A., Bertoccini, L., Chiappetta, C., Capoccia, D., Carletti, R., Di Cristofano, C., Silecchia, G., and Fontana, M. (2020). Reduced Biliverdin Reductase-A Expression in Visceral Adipose Tissue is Associated with Adipocyte Dysfunction and NAFLD in Human Obesity. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21239091"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"119913","DOI":"10.1016\/j.lfs.2021.119913","article-title":"Biliverdin reductase-A protein levels are reduced in type 2 diabetes and are associated with poor glycometabolic control","volume":"284","author":"Cimini","year":"2021","journal-title":"Life Sci."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1007\/s11010-007-9643-y","article-title":"The protective role of carotenoids against 7-keto-cholesterol formation in solution","volume":"309","author":"Palozza","year":"2008","journal-title":"Mol. Cell Biochem."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1111\/j.1365-2362.2007.01786.x","article-title":"Glucose transporter expression on the plasma membrane of resting and activated white blood cells","volume":"37","author":"Maratou","year":"2007","journal-title":"Eur. J. Clin. Investig."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1002\/cyto.a.20108","article-title":"Evaluation of glucose transport and its regulation by insulin in human monocytes using flow cytometry","volume":"64","author":"Dimitriadis","year":"2005","journal-title":"Cytometry A"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1530\/EJE-08-0797","article-title":"Studies of insulin resistance in patients with clinical and subclinical hypothyroidism","volume":"160","author":"Maratou","year":"2009","journal-title":"Eur. J. Endocrinol."},{"key":"ref_36","first-page":"182","article-title":"Investigations of cellular glucose transport and its regulation under the influence of insulin in human peripheral blood lymphocytes","volume":"61","author":"Piatkiewicz","year":"2010","journal-title":"Endokrynol. Pol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1007\/s00005-009-0052-7","article-title":"Cellular glucose transport and glucotransporter 4 expression as a therapeutic target: Clinical and experimental studies","volume":"57","author":"Czech","year":"2009","journal-title":"Arch. Immunol. Ther. Exp."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2060","DOI":"10.1007\/s00125-008-1132-7","article-title":"Downregulation of genes involved in NFkappaB activation in peripheral blood mononuclear cells after weight loss is associated with the improvement of insulin sensitivity in individuals with the metabolic syndrome: The GENOBIN study","volume":"51","author":"Kolehmainen","year":"2008","journal-title":"Diabetologia"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1016\/j.metabol.2007.08.024","article-title":"Effect of weight loss on cytokine messenger RNA expression in peripheral blood mononuclear cells of obese subjects with the metabolic syndrome","volume":"57","author":"Kolehmainen","year":"2008","journal-title":"Metabolism"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1564","DOI":"10.1161\/01.CIR.0000142055.53122.FA","article-title":"Circulating mononuclear cells in the obese are in a proinflammatory state","volume":"110","author":"Ghanim","year":"2004","journal-title":"Circulation"},{"key":"ref_41","first-page":"ra25","article-title":"A dynamic network model of mTOR signaling reveals TSC-independent mTORC2 regulation","volume":"5","author":"Sonntag","year":"2012","journal-title":"Sci. Signal."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1148","DOI":"10.1007\/BF00422363","article-title":"Alterations in insulin signalling pathway induced by prolonged insulin treatment of 3T3-L1 adipocytes","volume":"38","author":"Ricort","year":"1995","journal-title":"Diabetologia"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1089\/ars.2016.6686","article-title":"Polyubiquitinylation Profile in Down Syndrome Brain Before and After the Development of Alzheimer Neuropathology","volume":"26","author":"Tramutola","year":"2017","journal-title":"Antioxid. Redox Signal."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"S212","DOI":"10.2337\/diabetes.51.2007.S212","article-title":"Accurate assessment of beta-cell function: The hyperbolic correction","volume":"51","author":"Bergman","year":"2002","journal-title":"Diabetes"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/8\/7282\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:15:59Z","timestamp":1760123759000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/8\/7282"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,4,14]]},"references-count":44,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2023,4]]}},"alternative-id":["ijms24087282"],"URL":"https:\/\/doi.org\/10.3390\/ijms24087282","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,4,14]]}}}