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This polarity is consistently organised with respect to blood vessels with the basal region facing the capillaries and the apical region opposite. Rodent beta cells express proteins that maintain cell polarity, such as liver kinase B1 (LKB1) and polarity determinant proteins, including discs large (Dlg) and partitioning defective 3 homologue (Par3), in polar regions analogous to epithelial cells. In terms of subcellular organisation, older observations suggested beta cell polarity in rodents with the impact of polarisation increasingly being recognised. In contrast, in human islets, one study suggests a subpopulation of beta cells may not touch the capillaries, raising the possibility that some beta cells behave differently, consistent with current ideas that beta cell heterogeneity is important to islet function. In rodents, essentially every beta cell contacts a capillary and the capillary extracellular matrix exerts significant effects on beta cell function. Another important aspect of cell organisation is the endocrine cell contacts with the islet capillary bed. However, other reports suggest either a random arrangement of different endocrine cells or a laminar, folded structure. In terms of islet architecture, some studies indicate that human islets have an alpha cell mantle and beta cell core, similar to rodent islets, with a multi-lobular morphology in larger islets. There is controversy around the overall architecture of human islets and little is known about the subcellular organisation of endocrine cells. One knowledge gap is determining beta cell structure and function within native human islets. Understanding the functions of human pancreatic islets underpins future approaches to treating diabetes.
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Structural and functional polarisation is a defining feature of human pancreatic beta cells and plays an important role in the control of insulin secretion. Consistent with polarised function, isolated beta cells cultured onto laminin-coated coverslips target insulin granule fusion to the coverslip. We also observed the same polarisation of synaptic scaffold proteins in islets from type 2 diabetic patients. Interestingly, enrichment of presynaptic scaffold proteins also occurs where the beta cells contact peri-islet capillaries, suggesting functional interactions. The capillary interface/vascular face is enriched in presynaptic scaffold proteins, such as liprin, RIM2 and piccolo. Subcellularly, beta cells consistently position polar determinants, such as Par3, Dlg and scribble, with a basal domain towards the capillaries and apical domain at the opposite face. Measures of cell position demonstrate that most beta cells contact islet capillaries.
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ResultsĪssessment of the distribution of endocrine cells across human islets found that, despite distinct islet-to-islet complexity and variability, including multi-lobular islets, and intermixing of alpha and beta cells, there is still a striking enrichment of alpha cells at the islet mantle. Live 3D two-photon microscopy was used on cultured cells to image exocytic granule fusion events upon glucose stimulation. Isolated human islets were dispersed and cultured on laminin-511-coated coverslips. Slices were stained using immunofluorescence for polarity markers (scribble, discs large and partitioning defective 3 homologue ) and presynaptic markers (liprin, Rab3-interacting protein and piccolo) and imaged using 3D confocal microscopy. Human pancreas samples were rapidly fixed and processed using the pancreatic slice technique, which maintains islet structure and architecture. We set out to test this using confocal microscopy to map the 3D spatial arrangement of key proteins and live-cell imaging to determine the distribution of insulin granule fusion around the cells. We hypothesised that human beta cells are structurally and functional polarised with respect to the islet capillaries.