LAUSR

The pancreatic islet is a complex tissue consisting of multiple endocrine cell types, capillaries, and a peri-islet basement membrane. The 3D organization of cells, blood vessels, and basement membrane (BM), enhances islet function by (1) supporting beta cell electrochemical coupling and synchronization through gap junctions between adjacent cells and (2) providing access to nutrients and integrin-mediated signals for beta cell survival and function through contact with capillaries and BM. Though a quantitative understanding of islet structure is lacking, there is strong evidence linking islet structural changes to diabetes progression. Studies of these changes in islet structure will enhance understanding of diabetes-related losses in islet function and lead to the development of new therapeutics for diabetic and prediabetic patients. Here, we present a novel method for quantitative analysis of islet structure in terms of local cell-cell and cell-BM interactions at endocrine cell plasma membrane surfaces. The number and surface area of individual cell-cell and cell-BM interfaces are measured from high-resolution 3D confocal images of human and mouse islets immunolabeled for endocrine cell markers, epithelial cell plasma membranes, and BM. These measurements quantify both cellular interconnectivity and access to signals supporting beta cell survival and function. We report a baseline quantification of structure for healthy adult human and mouse islets. These data both provide a definitive answer to the ongoing debate regarding the differences in structure between human and mouse islets and set the stage for future quantification of islet structure in diabetes. Disclosure O.A. Creasey: None. D. Elnatan: None. J.B. Sneddon: Advisory Panel; Spouse/Partner; Akouos. Advisory Panel; Self; Encellin. Advisory Panel; Spouse/Partner; Encellin. Consultant; Self; Semma Therapeutics, Inc. Z.J. Gartner: Stock/Shareholder; Self; Provenance, Scribe Biosciences. Funding National Institutes of Health; National Science Foundation Graduate Research Fellowship Program; National Science Foundation; University of California, San Francisco Center for Cellular Construction; University of California, San Francisco Diabetes Research Center