Repurposed Analog of GLP-1 Ameliorates Hyperglycemia in Type 1 Diabetic Mice Through Pancreatic Cell Reprogramming
Rodríguez Fernández, Silvia
Perna Barrull, David
Ampudia, Rosa Maria
Gómez Muñoz, Laia
Pujol Autonell, Irma
Cano Sarabia, Antonia María
Vives Pi, Marta
MetadataShow full item record
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.
Is part ofFrontiers in Endocrinology, 2020, vol. 11, num. 258, p. 1-14
European research projects
Except where otherwise noted, this item's license is described as cc-by (c) Villalba, Adrian et al., 2020
Showing items related by title, author, creator and subject.
Phosphatidylserine-liposomes Promote Tolerogenic Features on Dendritic cells in human Type 1 Diabetes by apoptotic Mimicry Rodríguez Fernández, Silvia; Pujol Autonell, Irma; Briansó Castilla, Ferran; Perna Barrull, David; Cano Sarabia, Antonia María; García Jimeno, Sonia; Villalba, Adrian; Sánchez (Sànchez Pla), Álex; Aguilera, Eva; Vázquez San Miguel, Federico; Verdaguer Autonell, Joan; Maspoch, Daniel; Vives Pi, Marta (Frontiers Media, 2018)Type 1 diabetes (T1D) is a metabolic disease caused by the autoimmune destruction of insulin-producing β-cells. With its incidence increasing worldwide, to find a safe approach to permanently cease autoimmunity and allow ...
Pujol Autonell, Irma; Serracant Prat, Arnau; Cano Sarabia, Antonia María; Ampudia, Rosa Maria; Rodríguez Fernández, Silvia; Sánchez (Sànchez Pla), Álex; Izquierdo, Cristina; Stratmann, Thomas; Puig-Domingo, Manuel; Maspoch, Daniel; Verdaguer Autonell, Joan; Vives Pi, Marta (Public Library Science, 2015-06-03)
Efferocytosis promotes suppressive effects on dendritic cells through prostaglandin E2 production in the context of autoimmunity Pujol-Autonell, Irma; Ampudia, Rosa Maria; Planas, Raquel; Marin-Gallen, Silvia; Carrascal, Jorge; Sanchez, Alex; Marin, Ana; Puig-Domingo, Manuel; Pujol-Borrell, Ricardo; Verdaguer Autonell, Joan; Vives Pi, Marta (Public Library of Science, 2013)Introduction: Efferocytosis is a crucial process by which apoptotic cells are cleared by phagocytes, maintaining immune tolerance to self in the absence of inflammation. Peripheral tolerance, lost in autoimmune processes, ...