Title:
|
Repurposed analog of GLP-1 ameliorates hyperglycemia in type 1 diabetic mice through pancreatic cell reprogramming
|
Author:
|
Villalba Felipe, Adrián; Rodríguez Fernández, Silvia; Perna-Barrull, David; Ampudia Carrasco, Rosa María; Gómez Muñoz, Laia; Pujol-Autonell, Irma; Aguilera, Eva; Coma, Mireia; Cano-Sarabia, Mary; Vázquez, Federico; Verdaguer, Joan; Vives Pi, Marta
|
Abstract:
|
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). |
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. |
Subject(s):
|
-Beta cell regeneration -Neogenesis -Transdifferentiation -Liraglutide -Drug repositioning |
Rights:
|
open access
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.
https://creativecommons.org/licenses/by/4.0/ |
Document type:
|
Article |
Published by:
|
|
Share:
|
|
Uri:
|
https://ddd.uab.cat/record/227795
|