Reduced synchroneity of intra-islet Ca2+ oscillations in vivo in Robo-deficient β cells

The spatial architecture of the islets of Langerhans is hypothesized to facilitate synchronized insulin secretion among beta cells, yet testing this in vivo in the intact pancreas is challenging. Robo beta KO mice, in which the genes Robo1 and Robo2 are deleted selectively in beta cells, provide a unique model of altered islet spatial architecture without loss of beta cell differentiation or islet damage from diabetes. Combining Robo beta KO mice with intravital microscopy, we show here that Robo beta KO islets have reduced synchronized intra-islet Ca2+ oscillations among beta cells in vivo. We provide evidence that this loss is not due to a beta cellintrinsic function of Robo, mis-expression or mis-localization of Cx36 gap junctions, or changes in islet vascularization or innervation, suggesting that the islet architecture itself is required for synchronized Ca2+ oscillations. These results have implications for understanding structurefunction relationships in the islets during progression to diabetes as well as engineering islets from stem cells.