BMP5 signalling in beta cells and the impact on insulin secretion in the context of type 2 diabetes.

AIMS/HYPOTHESIS: Identifying signalling pathways that are important in pancreatic beta cell stress and failure can give insight into possible treatment options to prevent the loss of functional beta cell mass in diabetes. The bone morphogenetic protein (BMP)/SMAD family member BMP5 has been reported to be specifically expressed in human beta cells, but its function is unknown. Here we hypothesised that BMP5 plays a role in the maintenance of beta cell function. METHODS: We assessed the expression of BMP5 in publicly available single-cell RNA sequencing (scRNA-seq) datasets of primary human pancreatic islet cells from donors with or without type 2 diabetes, or islets exposed to stress conditions. Human islets and EndoC-βH1 cells were exposed to recombinant BMP5 and used for gene analysis, mitochondrial respiration and glucose-stimulated insulin secretion tests. In addition, we performed lentivirus-mediated knockdown using short hairpin RNAs targeting BMP5 in human islets and EndoC-βH1 cells for gene expression and glucose-stimulated insulin secretion analyses. RESULTS: scRNA-seq data revealed that BMP5 is the most predominantly expressed BMP ligand in beta cells. BMP5 and its target genes are upregulated in beta cells from donors with type 2 diabetes. Enhanced BMP5 signalling triggered an upregulation of stress-related genes, and a reduction in glucose-stimulated mitochondrial oxygen consumption and insulin secretion. In contrast, downregulation of BMP5 in primary human islets enhanced beta cell function, which was associated with increased expression of key beta cell genes. CONCLUSIONS/INTERPRETATION: Altogether, these findings point toward a role for BMP5 in the regulation of beta cell function.