1. LRH-1 agonism favours an immune-islet dialogue which protects against diabetes mellitus
- Author
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Francisco-Javier Bermúdez-Silva, Reinhold Schirmbeck, Piero Marchetti, Livia López-Noriega, Paolo Meda, Nadia Cobo-Vuilleumier, Christian Claude Lachaud, Petra I. Lorenzo, Noelia García Rodríguez, Abdelkrim Hmadcha, Bernat Soria, Marco Bugliani, Esther Fuente-Martin, Katja Stifter, Peter de Haan, Alejandro Martin-Montalvo, Miguel G. Toscano, Luc St-Onge, Géraldine Parnaud, Vincenzo De Tata, Germán Perdomo, Silvana-Yanina Romero-Zerbo, Luis Sánchez Palazón, David Pozo, Benoit R. Gauthier, Kristina Schoonjans, Javier Florido, Irene de Gracia Herrera Gómez, José Manuel Mellado-Gil, Domenico Bosco, Mathurin Baquié, Centro Andaluz de Biología Molecular y Medicina Regenerativa (CABIMER), Juvenile Diabetes Research Foundation, Junta de Andalucía, Ministerio de Economía y Competitividad (España), European Commission, German Research Foundation, Instituto de Salud Carlos III, Amarna Therapeutics, Centro Andaluz de Investigaciones en Biología Molecular y Medina Regenerativa (CABIMER), [Cobo-Vuilleumier,N, Lorenzo,PI, García Rodríguez,N, Herrera Gómez,IG, Fuente-Martin,E, López-Noriega,L, Mellado-Gil,JM, Claude Lachaud,C, Hmadcha,A, Martín-Montalvo,A, Soria,B, Gauthier, BR] 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. [Romero-Zerbo,SY, Bermúdez-Silva,FJ] 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. [Romero-Zerbo,SY, Bermúdez-Silva,FJ] Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, 28029, Spain. [Baquié,M] Neurix SA, Geneva, 1228, Switzerland. [Stifter,K, Schirmbeck,R] Ulm University Hospital, Ulm, 89081, Germany. [Perdomo,G] Facultad de Ciencias de la Salud, Universidad de Burgos, Burgos, 09001, Spain. [Bugliani,M, Marchetti,P] Department Clinical and Experimental Medicine, University of Pisa—AOUP University Hospital, Pisa, 56126, Italy. [De Tata,V] Department of Translational Research and of New Surgical and Medical Technologies, University of Pisa, Pisa, 56126, Italy. [Bosco,D, Parnaud,G] Cell Isolation and Transplantation Centre, University Hospital, Geneva, 1211, Switzerland. [Pozo,D] Department of Cell Dynamics and Signalling, CABIMER-Andalusian Center for Molecular Biology and Regenerative Medicine, Seville, 41092, Spain. [Florido,JP] Clinical Bioinformatics Area, Fundación Progreso y Salud, Consejería de Salud, Seville, 41013, Spain. [Toscano,MG, and de Haan,P] Amarna Therapeutics, Seville, 41092, Spain. [Schoonjans,K] Laboratory of Metabolic Signaling, EPFL, Lausanne, 1015, Switzerland. [Sánchez Palazón,L] Biological Resources, CABIMER-Andalusian Center for Molecular Biology and Regenerative Medicine, Seville, 41092, Spain. [Meda,P] Department of Cell Physiology and Metabolism, University of Geneva, Geneva, 1211, Switzerland. [St-Onge,L] Neuried Munich, 82061, Germany.
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Genetics and Molecular Biology (all) ,Male ,endocrine system diseases ,Trans-Differentiation ,Cell Communication/drug effects ,Islets of Langerhans Transplantation ,Receptors, Cytoplasmic and Nuclear ,Apoptosis ,Cell Communication ,T-Lymphocytes, Regulatory ,Biochemistry ,Mice ,Endocrinology ,Islet Regeneration ,Organisms::Eukaryota::Animals [Medical Subject Headings] ,Insulin ,Macrophages/drug effects/immunology/pathology ,lcsh:Science ,geography.geographical_feature_category ,Islets of Langerhans/drug effects/immunology/pathology ,ddc:617 ,Type 1 diabetes ,Phenalenes/pharmacology ,Pancreas ,Regulatory/drug effects/immunology/pathology ,Islotes Pancreáticos ,Science ,General Biochemistry, Genetics and Molecular Biology ,Streptozocin ,03 medical and health sciences ,Physics and Astronomy (all) ,Islets of Langerhans ,Cytoplasmic and Nuclear/agonists/genetics/immunology ,Diabetes Mellitus ,Humans ,Diseases::Endocrine System Diseases::Diabetes Mellitus::Diabetes Mellitus, Type 1 [Medical Subject Headings] ,Macrophages ,Apoptosis/drug effects ,Immunity ,Diseases::Endocrine System Diseases::Diabetes Mellitus::Diabetes Mellitus, Type 2 [Medical Subject Headings] ,nutritional and metabolic diseases ,Insulin-Secreting Cells/drug effects/immunology/pathology ,medicine.disease ,Immunity, Innate ,Lrh-1 ,Mice, Inbred C57BL ,030104 developmental biology ,Diabetes Mellitus, Type 2 ,Nr5a2 ,lcsh:Q ,Chemistry (all) ,Biochemistry, Genetics and Molecular Biology (all) ,0301 basic medicine ,T-Lymphocytes ,General Physics and Astronomy ,Diabetes Mellitus Tipo 2 ,Type 2 diabetes ,Diabetes Mellitus Tipo 1 ,Inbred C57BL ,Insulin-Secreting Cells ,Receptors ,Endocrinología ,Innate ,Heterologous ,Multidisciplinary ,Diabetes ,Type 2/genetics/immunology/pathology ,Phenalenes ,Islet ,medicine.anatomical_structure ,Female ,medicine.symptom ,Beta cell ,Cell Survival/drug effects ,Insulin/metabolism ,Cell Survival ,Transplantation, Heterologous ,Inflammation ,Diabetes Mellitus, Experimental ,Hypoglycemic Agents/pharmacology ,Immune system ,Anatomy::Endocrine System::Endocrine Glands::Islets of Langerhans [Medical Subject Headings] ,Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae [Medical Subject Headings] ,Immune Tolerance ,medicine ,Hypoglycemic Agents ,Animals ,ddc:612 ,geography ,Transplantation ,Diseases::Endocrine System Diseases::Diabetes Mellitus [Medical Subject Headings] ,business.industry ,Pancreatic islets ,General Chemistry ,Microreview ,Experimental/chemically induced/genetics/immunology/therapy ,Gene Expression Regulation ,Cancer research ,Therapy ,business - Abstract
Cobo-Vuilleumier, Nadia et al., 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., This work was funded by grants from the Juvenile Diabetes Research Foundation (17-2013-372 to B.R.G.), the Consejeria de Salud, Fundacion Publica Andaluza Progreso y Salud, Junta de Andalucia (PI-0727-2010 to B.R.G. and P10CTS6505 to B.S.), Consejeria de Economia, Innovacion y Ciencia (P10.CTS.6359 to B.R.G.), the Ministerio de Economia y Competidividad co-funded by Fondos FEDER (PI10/00871, PI13/00593, and BFU2017-83588-P to B.R.G.; PI14/01015, RD12/0019/0028, and RD16/0011/0034 to B.S.; PI16/00259 to A.H.) and Deutsche Forschungsgemeinschaft (GRK-1789 ´CEMMA´ and DFG SCHI-505/6-1 to R.S.). Special thanks to the families of the DiabetesCero Foundation that graciously supported this work (to B.R.G.). A.M.M. is a recipient of a Miguel Servet grant (CP14/00105) from the Instituto de Salud Carlos III co-funded by Fondos FEDER whereas E.F.M. is a recipient of a Juan de la Cierva Fellowship. I.G.H.G. is supported by a fellowship from Amarna Therapeutics. In some instances, human islets were procured through the European Consortium for Islet Transplantation funded by Juvenile Diabetes Research Foundation (3-RSC-2016-162-I-X).
- Published
- 2018