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

Author:

Adams Melissa T1ORCID,Dwulet JaeAnn M2ORCID,Briggs Jennifer K2,Reissaus Christopher A3,Jin Erli4,Szulczewski Joseph M1,Lyman Melissa R1ORCID,Sdao Sophia M4,Kravets Vira25ORCID,Nimkulrat Sutichot D1,Ponik Suzanne M1,Merrins Matthew J4,Mirmira Raghavendra G6,Linnemann Amelia K3,Benninger Richard KP25ORCID,Blum Barak1ORCID

Affiliation:

1. Department of Cell and Regenerative Biology, University of Wisconsin-Madison, Madison, United States

2. Department of Bioengineering, University of Colorado Denver, Anschutz Medical Campus, Aurora, United States

3. Herman B Wells Center for Pediatric Research and Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, Indianapolis, United States

4. Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, University of Wisconsin-Madison, Madison, United States

5. Barbara Davis Center for Diabetes, University of Colorado Anschutz Medical Campus, Aurora, United States

6. Kovler Diabetes Center and the Department of Medicine, University of Chicago, 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.

Funder

National Institute of Diabetes and Digestive and Kidney Diseases

Institute for Clinical and Translational Research, University of Wisconsin, Madison

National Cancer Institute

National Institute on Aging

American Diabetes Association

National Institute of General Medical Sciences

Publisher

eLife Sciences Publications, Ltd

Subject

General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience

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