Abstract

Type 1 diabetes mellitus (T1DM) is due to the selective destruction of islet beta cells by immune cells. Current therapies focused on repressing the immune attack or stimulating beta cell regeneration still have limited clinical efficacy. Therefore, it is timely to identify innovative targets to dampen the immune process, while promoting beta cell survival and function. Liver receptor homologue-1 (LRH-1) is a nuclear receptor that represses inflammation in digestive organs, and protects pancreatic islets against apoptosis. Here, we show that BL001, a small LRH-1 agonist, impedes hyperglycemia progression and the immune-dependent inflammation of pancreas in murine models of T1DM, and beta cell apoptosis in islets of type 2 diabetic patients, while increasing beta cell mass and insulin secretion. Thus, we suggest that LRH-1 agonism favors a dialogue between immune and islet cells, which could be druggable to protect against diabetes mellitus.

Details

Title
LRH-1 agonism favours an immune-islet dialogue which protects against diabetes mellitus
Author
Cobo-Vuilleumier, Nadia 1 ; Lorenzo, Petra I 1 ; Noelia García Rodríguez 1 ; Irene de Gracia Herrera Gómez 1 ; Fuente-Martin, Esther 1 ; López-Noriega, Livia 1 ; Mellado-Gil, José Manuel 1 ; Romero-Zerbo, Silvana-Yanina 2 ; Baquié, Mathurin 3 ; Lachaud, Christian Claude 1 ; Stifter, Katja 4 ; Perdomo, German 5 ; Bugliani, Marco 6 ; De Tata, Vincenzo 7 ; Bosco, Domenico 8 ; Parnaud, Geraldine 8 ; Pozo, David 9   VIAFID ORCID Logo  ; Hmadcha, Abdelkrim 10   VIAFID ORCID Logo  ; Florido, Javier P 11 ; Toscano, Miguel G 12 ; de Haan, Peter 12 ; Schoonjans, Kristina 13 ; Luis Sánchez Palazón 14 ; Marchetti, Piero 6 ; Schirmbeck, Reinhold 4 ; Martín-Montalvo, Alejandro 1 ; Meda, Paolo 15 ; Soria, Bernat 10 ; Bermúdez-Silva, Francisco-Javier 2   VIAFID ORCID Logo  ; St-Onge, Luc 16 ; Gauthier, Benoit R 1   VIAFID ORCID Logo 

1  Department of Cell Regeneration and Advanced Therapies, Andalusian Center for Molecular Biology and Regenerative Medicine-CABIMER, Junta de Andalucia-University of Pablo de Olavide-University of Seville-CSIC, Seville, Spain 
2  Unidad de Gestión Clínica Intercentros de Endocrinología y Nutrición, Instituto de Investigación Biomédica de Málaga (IBIMA) Hospital Regional Universitario de Málaga, Universidad de Málaga, Málaga, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain 
3  Neurix SA, Geneva, Switzerland 
4  Ulm University Hospital, Ulm, Germany 
5  Facultad de Ciencias de la Salud, Universidad de Burgos, Burgos, Spain 
6  Department Clinical and Experimental Medicine, University of Pisa—AOUP University Hospital, Pisa, Italy 
7  Department of Translational Research and of New Surgical and Medical Technologies, University of Pisa, Pisa, Italy 
8  Cell Isolation and Transplantation Centre, University Hospital, Geneva, Switzerland 
9  Department of Cell Dynamics and Signalling, CABIMER-Andalusian Center for Molecular Biology and Regenerative Medicine, Seville, Spain 
10  Department of Cell Regeneration and Advanced Therapies, Andalusian Center for Molecular Biology and Regenerative Medicine-CABIMER, Junta de Andalucia-University of Pablo de Olavide-University of Seville-CSIC, Seville, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain 
11  Clinical Bioinformatics Area, Fundación Progreso y Salud, Consejería de Salud, Seville, Spain 
12  Amarna Therapeutics, Seville, Spain 
13  Laboratory of Metabolic Signaling, EPFL, Lausanne, Switzerland 
14  Biological Resources, CABIMER-Andalusian Center for Molecular Biology and Regenerative Medicine, Seville, Spain 
15  Department of Cell Physiology and Metabolism, University of Geneva, Geneva, Switzerland 
16  Munich, Germany 
Pages
1-15
Publication year
2018
Publication date
Apr 2018
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-018-03943-0
ProQuest document ID
2025799616
Copyright
© 2018. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.