AimsG-protein coupled receptor 56 (GPR56) is the most abundant islet-expressed G-protein coupled receptor, suggesting a potential role in islet function. This study evaluated islet expression of GPR56 and its endogenous ligand collagen III, and their effects on β-cell function.MethodsGPR56 and collagen III expression in mouse and human pancreas sections was determined by fluorescence immunohistochemistry. Effects of collagen III on β-cell proliferation, apoptosis, intracellular calcium ([Ca2+]i) and insulin secretion were determined by cellular BrdU incorporation, caspase 3/7 activities, microfluorimetry and radioimmunoassay, respectively. The role of GPR56 in islet vascularisation and innervation was evaluated by immunohistochemical staining for CD31 and TUJ1, respectively, in pancreases from wildtype (WT) and Gpr56−/− mice, and the requirement of GPR56 for normal glucose homeostasis was determined by glucose tolerance tests in WT and Gpr56−/− mice.ResultsImmunostaining of mouse and human pancreases revealed that GPR56 was expressed by islet β-cells while collagen III was confined to the peri-islet basement membrane and islet capillaries. Collagen III protected β-cells from cytokine-induced apoptosis, triggered increases in [Ca2+]i and potentiated glucose-induced insulin secretion from WT islets but not from Gpr56−/− islets. Deletion of GPR56 did not affect glucose-induced insulin secretion in vitro and it did not impair glucose tolerance in adult mice. GPR56 was not required for normal islet vascularisation or innervation.ConclusionWe have demonstrated that collagen III improves islet function by increasing insulin secretion and protecting against apoptosis. Our data suggest that collagen III may be effective in optimising islet function to improve islet transplantation outcomes, and GPR56 may be a target for the treatment of type 2 diabetes.Electronic supplementary materialThe online version of this article (10.1007/s00018-018-2846-4) contains supplementary material, which is available to authorized users.

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The progress made in directed differentiation of stem cells has shown that understanding human pancreas development can provide cues for generating unlimited amounts of insulin-producing beta cells for transplantation therapy in diabetes. However, current differentiation protocols have not been successful in reproducibly generating functional human beta cells in vitro, partly due to incomplete understanding of human pancreas development. Here, we present detailed transcriptomic analysis of the various cell types of the developing human pancreas, including their spatial gene patterns. We integrated single cell RNA sequencing with spatial transcriptomics at multiple developmental timepoints and revealed distinct temporal-spatial gene cascades in the developing human pancreas. Cell trajectory inference identified endocrine progenitor populations and novel branch-specific genes as the progenitors differentiate towards alpha or beta cells, indicating that transcriptional maturation occurred over this developmental timeframe. Spatial differentiation trajectories indicated that immature Schwann cells are spatially co-located with endocrine progenitors and contribute to beta cell maturation via the L1CAM-EPHB2 pathway. Our integrated approach enabled us to identify heterogeneity and multiple lineage dynamics within the mesenchyme, showing that it contributed to the exocrine acinar cell state. Finally, we have generated an interactive web resource for interrogating human pancreas development for the research community.

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Aim This study investigated whether therapeutically relevant concentrations of fluoxetine, which have been shown to reduce plasma glucose and glycated haemoglobin independent of changes in food intake and body weight, regulate beta‐cell function and improve glucose homeostasis. Methods Cell viability, insulin secretion, beta‐cell proliferation and apoptosis were assessed after exposure of MIN6 beta cells or isolated mouse and human islets to 0.1, 1 or 10 μmol/L fluoxetine. The effect of fluoxetine (10 mg/kg body weight) administration on glucose homeostasis and islet function was also examined in ob/ob mice. Results Exposure of MIN6 cells and mouse islets to 0.1 and 1 μmol/L fluoxetine for 72 hours did not compromise cell viability but 10 μmol/L fluoxetine significantly increased Trypan blue uptake. The dose of 1 μmol/L fluoxetine significantly increased beta‐cell proliferation and protected islet cells from cytokine‐induced apoptosis. In addition, 1 μmol/L fluoxetine induced rapid and reversible potentiation of glucose‐stimulated insulin secretion from islets isolated from mice, and from lean and obese human donors. Finally, intraperitoneal administration of fluoxetine to ob/ob mice over 14 days improved glucose tolerance and resulted in significant increases in beta‐cell proliferation and enhanced insulin secretory capacity. Conclusions These data are consistent with a role for fluoxetine in regulating glucose homeostasis through direct effects on beta cells. Fluoxetine thus demonstrates promise as a preferential antidepressant for patients with concomitant occurrence of depression and diabetes.

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