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

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.

Time for a paradigm shift in treating type 1 diabetes mellitus: coupling inflammation to islet regeneration

“…While accumulating evidence confirms the anti-inflammatory role of LRH-1/NR5A2 on immune cells through GCs, the expression and function of this NR in such cells have remained scarce. We and others have recently shown that LRH-1/NR5A2 is expressed in macrophages where it plays a pivotal role in promoting the anti-inflammatory M2 phenotype [51,102]. LRH-1/NR5A2 expression was shown to be increased by the Th2 cytokine IL-13 with the subsequent stimulation of PPAR-gamma ligand synthesis and PPAR-gamma activation leading to M2 polarization.…”

“…In recent years, groundbreaking studies have revealed the plasticity of adult alpha-cells to spontaneously reprogram in vivo into insulin-producing cells under extreme beta-cell ablation in mouse pancreas. This alpha-to-beta-cell conversion, normally repressed by insulin and Smoothened-mediated signalling, involves a glucagon/insulin-positive bihormonal cell subpopulation that expresses beta-cell-enriched transcription factors such as MafA, Pdx1 and Nkx6.1 [49][50][51][52]. Consistent with this malleability, ectopic expression of Pax4 or conditional deletion of Arx in mouse alpha-cells led to their conversion into functional insulin-producing cells [53,54].…”

“…The cell protective benefits of BL001 were then assessed on human islets. BL001 treatment prevented both cytokine-and STZinduced cell death in human islets [51]. Furthermore, BL001 stimulated secretion of GCs from islets that were shown to improve islet survival [120,121].…”

“…Nonetheless, there anti-diabetic effect has had yet to be evaluated. Based on one of these published structures, we synthesized a compound denoted as BL001 and confirmed its LRH-1/NR5A2 agonistic activity using a fluorescent cell-based drug screening assay developed by our group [51,119]. ADME-TOX studies revealed no impact of BL001 on cell function or viability, cardiac toxicity, off-target binding as well as drug absorption and interactions.…”

Manipulation of Transmembrane Transport by Synthetic K+ Ionophore Depsipeptides and Its Implications in Glucose‐Stimulated Insulin Secretion in β‐Cells

“…These results may have direct relevance, as well as having direct applications in biomedicine, to the way processes related to K + equilibria can be controlled in metabolic disorders such as diabetes mellitus . Therefore, the use of the ionophores to modulate transport in live beta cells will open up a new avenue for the creation of useful new drugs.…”