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Review
. 2015 Feb;72(3):453-467.
doi: 10.1007/s00018-014-1755-4. Epub 2014 Oct 17.

Beta cell connectivity in pancreatic islets: a type 2 diabetes target?

Guy A Rutter  1 , David J Hodson  2
Affiliations
Review

Beta cell connectivity in pancreatic islets: a type 2 diabetes target?

Guy A Rutter et al. Cell Mol Life Sci. 2015 Feb.

Erratum in

Abstract

Beta cell connectivity describes the phenomenon whereby the islet context improves insulin secretion by providing a three-dimensional platform for intercellular signaling processes. Thus, the precise flow of information through homotypically interconnected beta cells leads to the large-scale organization of hormone release activities, influencing cell responses to glucose and other secretagogues. Although a phenomenon whose importance has arguably been underappreciated in islet biology until recently, a growing number of studies suggest that such cell-cell communication is a fundamental property of this micro-organ. Hence, connectivity may plausibly be targeted by both environmental and genetic factors in type 2 diabetes mellitus (T2DM) to perturb normal beta cell function and insulin release. Here, we review the mechanisms that contribute to beta cell connectivity, discuss how these may fail during T2DM, and examine approaches to restore insulin secretion by boosting cell communication.

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Conflict of interest statement

The authors have nothing to disclose.

Figures

Fig. 1
Fig. 1
Imaging and mapping beta cell network topology. (Above) Functional multicellular Ca2+ imaging is used to monitor the large-scale organization of glucose-induced population dynamics (above, left). By subjecting the resulting traces (from ~ 50–100 individual cells per islet) to correlation analyses, cells with coordinated activity can be identified and a functional connectivity map plotted based upon position within the imaged field (x–y) (above, right). Scale-free connection distributions are typified by a minority of cells that host the majority of connections (nodes), while maintaining streamlined information flow due to a short pathlength. Although robust in the face of random attack, they are prone to collapse following a targeted attack (below, left). By contrast, nonscale-free networks (e.g., random or lattice) may not efficiently propagate signals due to a long pathlength, and random attacks significantly reduce capacity (below, right)
Fig. 2
Fig. 2
Schematic showing single cell and population-level beta cell signaling. At the molecular level, glucose is transported into the beta cell before undergoing glycolysis to increase the ratio of free cytosolic ATP:ADP. This closes KATP channels, leading to opening of VDCC, Ca2+ influx, and Ca2+-dependent exocytosis. At the population-level, beta cell dynamics are further dictated by signaling circuits involving paracrine, juxtacrine, autocrine, electrotonic (GJ), neural and ciliary communications
Fig. 3
Fig. 3
Potential mechanisms by which T2D-associated genes may alter beta cell connectivity. ZnT8 gene variants disrupt cytosolic Ca2+ and Zn2+ handling, and both of these ions are required for normal GJ activity. ADCY5 gene variants decrease glucose-stimulated cAMP rises, a second messenger shown to increase GJ communications between beta cells. By contrast, TCF7L2 gene variants may disrupt normal GJ function through effects upon glucose-stimulated Ca2+ increases, as well as GLP-1-stimulated cAMP generation
See this image and copyright information in PMC

References

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