Reduced synchroneity of intra-islet Ca2+ oscillations in vivo in Robo-deficient β cells
- University of Wisconsin-Madison, United States
- University of Colorado Denver, Anschutz Medical Campus, United States
- Indiana University School of Medicine, United States
- University of Colorado-Denver, United States
- University of Chicago, United States
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 Ca2+ 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 Ca2+ 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.
Data availability
All data generated or analyzed during this study are included in the manuscript and supporting files.
Article and author information
Author details
Richard KP Benninger
Funding
National Institute of Diabetes and Digestive and Kidney Diseases (R01DK121706)
- Barak Blum
American Diabetes Association (ADA 1-16-IBS-212)
- Matthew J Merrins
National Institute of General Medical Sciences (5T32GM007133-44)
- Melissa T Adams
National Institute of Diabetes and Digestive and Kidney Diseases (P30DK020579)
- Barak Blum
UW-Madison Institute for Clinical and Translational Research (UL1TR000427)
- Matthew J Merrins
- Barak Blum
National Institute of Diabetes and Digestive and Kidney Diseases (R01DK060581)
- Raghavendra G Mirmira
National Institute of Diabetes and Digestive and Kidney Diseases (R01DK102950)
- Richard KP Benninger
National Institute of Diabetes and Digestive and Kidney Diseases (R01DK106412)
- Richard KP Benninger
National Cancer Institute (R01CA216248)
- Suzanne M Ponik
National Institute of Diabetes and Digestive and Kidney Diseases (R01DK113103)
- Matthew J Merrins
National Institute on Aging (R01AG062328)
- Matthew J Merrins
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Guy A Rutter, Imperial College London, United Kingdom
Ethics
Animal experimentation: The experimental protocol for animal usage was reviewed and approved by the University of Wisconsin-Madison Institutional Animal Care and Use Committee (IACUC) under Protocol #M005221 and Protocol #M005333, and all animal experiments were conducted in accordance with the University of Wisconsin-Madison IACUC guidelines under the approved protocol.
Version history
- Received: July 22, 2020
- Accepted: July 6, 2021
- Accepted Manuscript published: July 7, 2021 (version 1)
- Version of Record published: July 19, 2021 (version 2)
Copyright
© 2021, Adams et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Reduced synchroneity of intra-islet Ca2+ oscillations in vivo in Robo-deficient β cells
eLife 10:e61308.
https://doi.org/10.7554/eLife.61308
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