dc.contributor.author | Villalba, Adrian | |
dc.contributor.author | Rodríguez Fernández, Silvia | |
dc.contributor.author | Perna Barrull, David | |
dc.contributor.author | Ampudia, Rosa Maria | |
dc.contributor.author | Gómez Muñoz, Laia | |
dc.contributor.author | Pujol Autonell, Irma | |
dc.contributor.author | Aguilera, Eva | |
dc.contributor.author | Coma, Mireia | |
dc.contributor.author | Cano Sarabia, Antonia María | |
dc.contributor.author | Vázquez, Federico | |
dc.contributor.author | Verdaguer Autonell, Joan | |
dc.contributor.author | Vives Pi, Marta | |
dc.date.accessioned | 2021-02-22T13:27:25Z | |
dc.date.available | 2021-02-22T13:27:25Z | |
dc.date.issued | 2020-05-13 | |
dc.identifier.issn | 1664-2392 | |
dc.identifier.uri | http://hdl.handle.net/10459.1/70586 | |
dc.description.abstract | Type 1 diabetes is an autoimmune disease caused by the destruction of the insulin-producing β-cells. An ideal immunotherapy should combine the blockade of the autoimmune response with the recovery of functional target cell mass. With the aim to develop new therapies for type 1 diabetes that could contribute to β-cell mass restoration, a drug repositioning analysis based on systems biology was performed to identify the β-cell regenerative potential of commercially available compounds. Drug repositioning is a strategy used for identifying new uses for approved drugs that are outside the scope of the medical indication. A list of 28 non-synonymous repurposed drug candidates was obtained, and 16 were selected as diabetes mellitus type 1 treatment candidates regarding pancreatic β-cell regeneration. Drugs with poor safety profile were further filtered out. Lastly, we selected liraglutide for its predictive efficacy values for neogenesis, transdifferentiation of α-cells, and/or replication of pre-existing β-cells. Liraglutide is an analog of glucagon-like peptide-1, a drug used in patients with type 2 diabetes. Liraglutide was tested in immunodeficient NOD-Scid IL2rg−/− (NSG) mice with type 1 diabetes. Liraglutide significantly improved the blood glucose levels in diabetic NSG mice. During the treatment, a significant increase in β-cell mass was observed due to a boost in β-cell number. Both parameters were reduced after withdrawal. Interestingly, islet bihormonal glucagon+insulin+ cells and insulin+ ductal cells arose during treatment. In vitro experiments showed an increase of insulin and glucagon gene expression in islets cultured with liraglutide in normoglycemia conditions. These results point to β-cell replacement, including transdifferentiation and neogenesis, as aiding factors and support the role of liraglutide in β-cell mass restoration in type 1 diabetes. Understanding the mechanism of action of this drug could have potential clinical relevance in this autoimmune disease. | |
dc.description.sponsorship | This work has been funded by Fundació La Marató de TV3 (project 201632_10). CIBER of Diabetes and Associated Metabolic Diseases (CIBERDEM) is an initiative from Instituto de Salud Carlos III, Spanish Ministry of Science and Innovation. SR-F was supported by the Generalitat de Catalunya (AGAUR grant). | |
dc.format.mimetype | application/pdf | |
dc.language.iso | eng | |
dc.publisher | Frontiers Media | |
dc.relation.isformatof | Reproducció del document publicat a https://doi.org/10.3389/fendo.2020.00258 | |
dc.relation.ispartof | Frontiers in Endocrinology, 2020, vol. 11, num. 258, p. 1-14 | |
dc.rights | cc-by (c) Villalba, Adrian et al., 2020 | |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | |
dc.subject | Beta cell regeneration | |
dc.subject | Neogenesis | |
dc.subject | Transdifferentiation | |
dc.subject | Liraglutide | |
dc.subject | Drug repositioning | |
dc.title | Repurposed Analog of GLP-1 Ameliorates Hyperglycemia in Type 1 Diabetic Mice Through Pancreatic Cell Reprogramming | |
dc.type | info:eu-repo/semantics/article | |
dc.date.updated | 2021-02-22T13:27:25Z | |
dc.identifier.idgrec | 031023 | |
dc.type.version | info:eu-repo/semantics/publishedVersion | |
dc.rights.accessRights | info:eu-repo/semantics/openAccess | |
dc.identifier.doi | https://doi.org/10.3389/fendo.2020.00258 | |