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

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.Consejeria de Salud PI-0727-2010 P10CTS6505Fundacion Publica Andaluza Progreso y Salud PI-0727-2010 P10CTS6505Junta de Andalucia PI-0727-2010 P10CTS6505Consejeria de Economia, Innovacion y Ciencia P10.CTS.6359Ministerio de Economía y Competitividad PI10/00871 PI13/00593 BFU2017-83588-P PI14/01015 RD12/0019/0028 RD16/0011/0034 PI16/00259Fondos Feder PI10/00871 PI13/00593 BFU2017-83588-P PI14/01015 RD12/0019/0028 RD16/0011/0034 PI16/00259Deutsche Forschungsgemeinschaft GRK-1789 SCHI-505/ 6-1Instituto de Salud Carlos III CP14/ 00105Fondos FEDER CP14/ 00105Juvenile Diabetes Research Foundation 17-2013-372 3-RSC-2016-162-I-