Cellular communication and heterogeneity in pancreatic islet insulin secretion dynamics

Benninger, Richard K.P.; Piston, David W.

doi:10.1016/j.tem.2014.02.005

Cited by 136 publications

(131 citation statements)

References 75 publications

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“…Since these micro-organs are conserved throughout the mammalian kingdom and beyond [25], albeit with important differences in the numbers of each cell type and their arrangement within the islet (see below), the intraislet mechanisms governing insulin secretion may represent an underappreciated target through which T2DM insults provoke hyperglycemia. Building upon recent findings from our own [26][27][28] and others' [20][21][22][29][30][31] laboratories, the aim of the present review is to describe our current understanding as to how beta cell-beta cell communication (hereafter referred to as ''connectivity'') contributes to the normal regulation of insulin secretion in healthy subjects. We also discuss how changes in this property may contribute to T2DM risk in genetically susceptible individuals.…”

Section: Introductionmentioning

confidence: 99%

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

Rutter

Hodson

2014

Cell. Mol. Life Sci.

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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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Section: Introductionmentioning

confidence: 99%

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

Rutter

Hodson

2014

Cell. Mol. Life Sci.

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“…29 A similar system has long been postulated to exist in the islet, whereby specialized β-cells generate and pace the Ca 2+ oscillations necessary for insulin secretion. 30-32 Recently, Johnston et al . 33 demonstrated, by using functional cell mapping and optogenetics, that certain β-cells (termed ‘hubs’) are indispensable for the maintenance of Ca 2+ activity in the islet.…”

Section: Introductionmentioning

confidence: 99%

Beta-cell hubs maintain Ca²⁺ oscillations in human and mouse islet simulations

Lei

Kellard

Hara

et al. 2018

Islets

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Islet β-cells are responsible for secreting all circulating insulin in response to rising plasma glucose concentrations. These cells are a phenotypically diverse population that express great functional heterogeneity. In mice, certain β-cells (termed ‘hubs’) have been shown to be crucial for dictating the islet response to high glucose, with inhibition of these hub cells abolishing the coordinated Ca2+ oscillations necessary for driving insulin secretion. These β-cell hubs were found to be highly metabolic and susceptible to pro-inflammatory and glucolipotoxic insults. In this study, we explored the importance of hub cells in human by constructing mathematical models of Ca2+ activity in human islets. Our simulations revealed that hubs dictate the coordinated Ca2+ response in both mouse and human islets; silencing a small proportion of hubs abolished whole-islet Ca2+ activity. We also observed that if hubs are assumed to be preferentially gap junction coupled, then the simulations better adhere to the available experimental data. Our simulations of 16 size-matched mouse and human islet architectures revealed that there are species differences in the role of hubs; Ca2+ activity in human islets was more vulnerable to hub inhibition than mouse islets. These simulation results not only substantiate the existence of β-cell hubs, but also suggest that hubs may be favorably coupled in the electrical and metabolic network of the islet, and that targeted destruction of these cells would greatly impair human islet function.

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“…We used FACS analysis to confirm human ␤-cell expression of CADM1 protein and, since human ␤-cells are heterogeneous, to ask whether there is a population of ␤-cells lacking CADM1 expression (4). Human ␤-cells were uniformly positive for CADM1 expression (Fig.…”

Section: Cadm Expression In Human and Rat Isletsmentioning

confidence: 99%

Extracellular CADM1 interactions influence insulin secretion by rat and human islet β-cells and promote clustering of syntaxin-1

Zhang

Caldwell

Mirbolooki

et al. 2016

American Journal of Physiology-Endocrinology and Metabolism

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N, Chessler SD. Extracellular CADM1 interactions influence insulin secretion by rat and human islet ␤-cells and promote clustering of syntaxin-1. Am J Physiol Endocrinol Metab 310: E874 -E885, 2016. First published April 12, 2016 doi:10.1152/ajpendo.00318.2015-Contact between ␤-cells is necessary for their normal function. Identification of the proteins mediating the effects of ␤-cell-to-␤-cell contact is a necessary step toward gaining a full understanding of the determinants of ␤-cell function and insulin secretion. The secretory machinery of the ␤-cells is nearly identical to that of central nervous system (CNS) synapses, and we hypothesize that the transcellular protein interactions that drive maturation of the two secretory machineries upon contact of one cell (or neural process) with another are also highly similar. Two such transcellular interactions, important for both synaptic and ␤-cell function, have been identified: EphA/ephrin-A and neuroligin/neurexin. Here, we tested the role of another synaptic cleft protein, CADM1, in insulinoma cells and in rat and human islet ␤-cells. We found that CADM1 is a predominant CADM isoform in ␤-cells. In INS-1 cells and primary ␤-cells, CADM1 constrains insulin secretion, and its expression decreases after prolonged glucose stimulation. Using a coculture model, we found that CADM1 also influences insulin secretion in a transcellular manner. We asked whether extracellular CADM1 interactions exert their influence via the same mechanisms by which they influence neurotransmitter exocytosis. Our results suggest that, as in the CNS, CADM1 interactions drive exocytic site assembly and promote actin network formation. These results support the broader hypothesis that the effects of cell-cell contact on ␤-cell maturation and function are mediated by the same extracellular protein interactions that drive the formation of the presynaptic exocytic machinery. These interactions may be therapeutic targets for reversing ␤-cell dysfunction in diabetes.cell adhesion molecule 1; SynCam; pancreatic islet; insulin secretion

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Cellular communication and heterogeneity in pancreatic islet insulin secretion dynamics

Cited by 136 publications

References 75 publications

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

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

Beta-cell hubs maintain Ca²⁺ oscillations in human and mouse islet simulations

Extracellular CADM1 interactions influence insulin secretion by rat and human islet β-cells and promote clustering of syntaxin-1

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Cellular communication and heterogeneity in pancreatic islet insulin secretion dynamics

Cited by 136 publications

References 75 publications

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

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

Beta-cell hubs maintain Ca2+ oscillations in human and mouse islet simulations

Extracellular CADM1 interactions influence insulin secretion by rat and human islet β-cells and promote clustering of syntaxin-1

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Beta-cell hubs maintain Ca²⁺ oscillations in human and mouse islet simulations