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Repurposed Analog of GLP-1 Ameliorates Hyperglycemia in Type 1 Diabetic Mice Through Pancreatic Cell Reprogramming

dc.contributor.authorVillalba, Adrian
dc.contributor.authorRodríguez Fernández, Silvia
dc.contributor.authorPerna Barrull, David
dc.contributor.authorAmpudia, Rosa Maria
dc.contributor.authorGómez Muñoz, Laia
dc.contributor.authorPujol Autonell, Irma
dc.contributor.authorAguilera, Eva
dc.contributor.authorComa, Mireia
dc.contributor.authorCano Sarabia, Antonia María
dc.contributor.authorVázquez, Federico
dc.contributor.authorVerdaguer Autonell, Joan
dc.contributor.authorVives Pi, Marta
dc.date.accessioned2021-02-22T13:27:25Z
dc.date.available2021-02-22T13:27:25Z
dc.date.issued2020-05-13
dc.identifier.issn1664-2392
dc.identifier.urihttp://hdl.handle.net/10459.1/70586
dc.description.abstractType 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.sponsorshipThis 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.mimetypeapplication/pdf
dc.language.isoeng
dc.publisherFrontiers Media
dc.relation.isformatofReproducció del document publicat a https://doi.org/10.3389/fendo.2020.00258
dc.relation.ispartofFrontiers in Endocrinology, 2020, vol. 11, num. 258, p. 1-14
dc.rightscc-by (c) Villalba, Adrian et al., 2020
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectBeta cell regeneration
dc.subjectNeogenesis
dc.subjectTransdifferentiation
dc.subjectLiraglutide
dc.subjectDrug repositioning
dc.titleRepurposed Analog of GLP-1 Ameliorates Hyperglycemia in Type 1 Diabetic Mice Through Pancreatic Cell Reprogramming
dc.typeinfo:eu-repo/semantics/article
dc.date.updated2021-02-22T13:27:25Z
dc.identifier.idgrec031023
dc.type.versioninfo:eu-repo/semantics/publishedVersion
dc.rights.accessRightsinfo:eu-repo/semantics/openAccess
dc.identifier.doihttps://doi.org/10.3389/fendo.2020.00258


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cc-by (c) Villalba, Adrian et al., 2020
Except where otherwise noted, this item's license is described as cc-by (c) Villalba, Adrian et al., 2020