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Nat Commun. 2018 Apr 16;9(1):1488. doi: 10.1038/s41467-018-03943-0.

LRH-1 agonism favours an immune-islet dialogue which protects against diabetes mellitus.

Author information

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, 41092, 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, 29010, Spain.
3
Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, 28029, Spain.
4
Neurix SA, Geneva, 1228, Switzerland.
5
Ulm University Hospital, Ulm, 89081, Germany.
6
Facultad de Ciencias de la Salud, Universidad de Burgos, Burgos, 09001, Spain.
7
Department Clinical and Experimental Medicine, University of Pisa-AOUP University Hospital, Pisa, 56126, Italy.
8
Department of Translational Research and of New Surgical and Medical Technologies, University of Pisa, Pisa, 56126, Italy.
9
Cell Isolation and Transplantation Centre, University Hospital, Geneva, 1211, Switzerland.
10
Department of Cell Dynamics and Signalling, CABIMER-Andalusian Center for Molecular Biology and Regenerative Medicine, Seville, 41092, Spain.
11
Clinical Bioinformatics Area, Fundación Progreso y Salud, Consejería de Salud, Seville, 41013, Spain.
12
Amarna Therapeutics, Seville, 41092, Spain.
13
Laboratory of Metabolic Signaling, EPFL, Lausanne, 1015, Switzerland.
14
Biological Resources, CABIMER-Andalusian Center for Molecular Biology and Regenerative Medicine, Seville, 41092, Spain.
15
Department of Cell Physiology and Metabolism, University of Geneva, Geneva, 1211, Switzerland.
16
, Neuried, Munich, 82061, Germany.
17
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, 41092, Spain. benoit.gauthier@cabimer.es.

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.

PMID:
29662071
PMCID:
PMC5902555
DOI:
10.1038/s41467-018-03943-0
[Indexed for MEDLINE]
Free PMC Article

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