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Human islet delta-cells exhibit long projections

These projections (arrowed) allow the cell to create an extensive communication network within the islet.

Granule and mitochondria distribution in a human delta-cell

Spatial location of granules (upper graphs) and mitochondria (lower graphs) within a human delta-cell. The upper graph shows a histogram of granule count, where the x axis is the distance along the long axis of the cell (from the ‘projection’ to the ‘cell body’). The lower graph shows the segmented granules and nucleus. Note the higher density of granules towards the cell body, where the alpha-cells are located. This distribution can also be seen. These plots were segmented from SBF EM data.

Linford Briant

PhD, MSci


Sir Henry Wellcome Postdoctoral Fellow & Junior Research Fellow at Trinity College

  • Mathematical modeller
  • Patch-clamp electrophysiologist
  • Dynamic imaging
  • Time-series analysis

Computational and experimental investigation of islet cells

The pancreatic islets contain beta-cells and alpha-cells, which are responsible for secreting two principle gluco-regulatory hormones; insulin and glucagon, respectively. However, they also contain delta-cells, a relatively sparse cell type that secretes somatostatin (SST). These cells have a complex morphology allowing them to establish an extensive communication network throughout the islet, despite their scarcity. Delta-cells are electrically excitable cells, and SST secretion is released in a glucose- and KATP-dependent manner. SST hyperpolarises the alpha-cell membrane and suppresses exocytosis. In this way, islet SST potently inhibits glucagon release.

Recent studies by myself and my colleagues has investigated the activity of delta-cells with optogenetics, electrophysiology and Ca2+ imaging, and revealed they are electrically coupled to beta-cells via gap junctions. This suggests that the delta-cell is more than just a paracrine inhibitor.

In my work, I aim to investigate delta-cell morphology, function, and the role of SST signalling for regulating islet hormonal output both in health and disease. I pay particular attention to the importance of this novel gap junction pathway, because it offers fresh insight into the contribution of delta-cells to the islet hormonal defects observed in both type 1 and type 2 diabetes. This reassessment of the role of the delta-cell is important as it may offer novel insights into how the physiology of this cell can be utilised to restore islet function in diabetes.

Computational tools to understand dynamic islet cell interactions in 3D

Islet cells from zebrafish were imaged in vivo. Cells (circles) were plotted in their 3D spatial location. The correlation between cell types was analysed. Line shading indicates correlation strength. Circle size indicates the number of connections that cell makes within the network. Blue = beta-cell, red = delta-cell. Data generated in collaboration with C. Yang (University of Exeter) and D. Stainier (Max-Planck).

ORCID

0000-0003-3619-3177

Human islet delta-cells exhibit long projections

3D reconstruction of a human islet cells reveals the long projections end at beta-cells and are flanked with more beta-cells (not shown). The cell body, where the bulk of the SST granules are located, is surrounded by alpha-cells.

Opto-genetic silencing of alpha-cells

Alpha-cells were patch-clamped in islets, where the light-sensitive channel ChR2 was expressed in beta-cells. Opto-activation of beta-cells triggered a suppression of activity in alpha-cells, demonstrating the importance of "paracrine" regulation of alpha-cell activity glucagon secretion.

Simulating the electrical activity of cells in human islet

Simulations demonstrate that glucagon secretion is suppressed by delta-cells in high glucose. The left hand image shows electrical activity in beta-cells; these become electrically active in high glucose, activating delta-cells (middle image). These, by releasing somatostatin, inhibit alpha-cells (right hand image). Hence glucagon secretion in human islets is regulated by this pathway. Each cell is represented by a sphere; colour of each cell represents electrical activity, changing in time (time step = 10ms).