Repurposed analog of GLP-1 ameliorates hyperglycemia in type 1 diabetic mice through pancreatic cell reprogramming
Villalba Felipe, Adrián (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol)
Rodríguez Fernández, Silvia (Institut Germans Trias i Pujol)
Perna-Barrull, David (Institut Germans Trias i Pujol)
Ampudia Carrasco, Rosa María (Institut Germans Trias i Pujol)
Gómez Muñoz, Laia (Institut Germans Trias i Pujol)
Pujol-Autonell, Irma (Institut Germans Trias i Pujol)
Aguilera, Eva (Institut Germans Trias i Pujol)
Coma, Mireia (Anaxomics Biotech SL)
Cano-Sarabia, Mary (Institut Català de Nanociència i Nanotecnologia)
Vázquez, Federico (Institut Germans Trias i Pujol)
Verdaguer, Joan (Universitat de Lleida. Departament de Medicina Experimental)
Vives Pi, Marta (Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas)

Date:	2020
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.
Note:	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).
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	Beta cell regeneration ; Neogenesis ; Transdifferentiation ; Liraglutide ; Drug repositioning
Published in:	Frontiers in endocrinology, Vol. 11 (May 2020) , art. 258, ISSN 1664-2392

DOI: 10.3389/fendo.2020.00258
PMID: 32477262

14 p, 2.6 MB

The record appears in these collections:
Research literature > UAB research groups literature > Research Centres and Groups (research output) > Health sciences and biosciences > Institut d'Investigació en Ciencies de la Salut Germans Trias i Pujol (IGTP)
Research literature > UAB research groups literature > Research Centres and Groups (research output) > Experimental sciences > Catalan Institute of Nanoscience and Nanotechnology (ICN2)
Articles > Research articles
Articles > Published articles