Reduced synchroneity of intra-islet Ca2+ oscillations in vivo in Robo-deficient β cells
Melissa T. Adams, JaeAnn M. Dwulet, Jennifer K. Briggs, Christopher A. Reissaus, Erli Jin, Joseph M. Szulczewski, Melissa R. Lyman, Sophia M. Sdao, Vira Kravets, Sutichot D. Nimkulrat, Suzanne M. Ponik, Matthew J. Merrins, Raghavendra G. Mirmira, Amelia K. Linnemann, Richard K.P. Benninger, Barak Blum
Abstract
The spatial architecture of the islets of Langerhans is hypothesized to facilitate synchronized insulin secretion among β cells, yet testing this in vivo in the intact pancreas is challenging. Robo βKO mice, in which the genes Robo1 and Robo2 are deleted selectively in β cells, provide a unique model of altered islet spatial architecture without loss of β cell differentiation or islet damage from diabetes. Combining Robo βKO mice with intravital microscopy, we show here that Robo βKO islets have reduced synchronized intra-islet Ca 2+ oscillations among β cells in vivo. We provide evidence that this loss is not due to a β cell-intrinsic 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 Ca 2+ oscillations. These results have implications for understanding structure-function relationships in the islets during progression to diabetes as well as engineering islets from stem cells.