Membrane Potential and Calcium Dynamics in Beta Cells  from Mouse Pancreas Tissue Slices: Theory, Experimentation, and Analysis

Dolenšek, Jurij; Špelič, Denis; Klemen, Maša Skelin; Žalik, Borut; Gosak, Marko; Rupnik, Marjan Slak; Stožer, Andraž

doi:10.3390/s151127393

Cited by 25 publications

(22 citation statements)

References 173 publications

(249 reference statements)

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“…In β cells, Ca 2+ release occurs with insulin production and secretion [40–43]. As expected, Thaps-triggered ER stress in β cells significantly increased cytosolic Ca 2+ (Fig.…”

Section: Discussionmentioning

confidence: 60%

“…This efflux of Ca 2+ negatively affects protein folding in the ER since many chaperones require Ca 2+ [37–39] and also affects the function of Ca 2+ -dependent cytosolic enzymes. This Ca 2+ flux is observed in β cells during insulin production and secretion [40–43], confirming the occurrence of ER stress during glucose-stimulated insulin production.…”

Section: Introductionmentioning

confidence: 57%

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Inherent ER stress in pancreatic islet β cells causes self-recognition by autoreactive T cells in type 1 diabetes

Marre

Profozich

Coneybeer

et al. 2016

Journal of Autoimmunity

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Type 1 diabetes (T1D) is an autoimmune disease characterized by pancreatic β cell destruction induced by islet reactive T cells that have escaped central tolerance. Many physiological and environmental triggers associated with T1D result in β cell endoplasmic reticulum (ER) stress and dysfunction, increasing the potential for abnormal post-translational modification (PTM) of proteins. We hypothesized that β cell ER stress induced by environmental and physiological conditions generates abnormally-modified proteins for the T1D autoimmune response. To test this hypothesis we exposed the murine CD4+ diabetogenic BDC2.5 T cell clone to murine islets in which ER stress had been induced chemically (Thapsigargin). The BDC2.5 T cell IFNγ response to these cells was significantly increased compared to non-treated islets. This β cell ER stress increased activity of the calcium (Ca2+)-dependent PTM enzyme tissue transglutaminase 2 (Tgase2), which was necessary for full stress-dependent immunogenicity. Indeed, BDC2.5 T cells responded more strongly to their antigen after its modification by Tgase2. Finally, exposure of non-antigenic murine insulinomas to chemical ER stress in vitro or physiological ER stress in vivo caused increased ER stress and Tgase2 activity, culminating in higher BDC2.5 responses. Thus, β cell ER stress induced by chemical and physiological triggers leads to β cell immunogenicity through Ca2+-dependent PTM. These findings elucidate a mechanism of how β cell proteins are modified and become immunogenic, and reveal a novel opportunity for preventing β cell recognition by autoreactive T cells.

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“…In β cells, Ca 2+ release occurs with insulin production and secretion [40–43]. As expected, Thaps-triggered ER stress in β cells significantly increased cytosolic Ca 2+ (Fig.…”

Section: Discussionmentioning

confidence: 60%

Section: Introductionmentioning

confidence: 57%

Inherent ER stress in pancreatic islet β cells causes self-recognition by autoreactive T cells in type 1 diabetes

Marre

Profozich

Coneybeer

et al. 2016

Journal of Autoimmunity

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“…The introduction of modeling [64], [65] to islet biology revealed the dynamics of β-cell intercellular networks and the characteristics of particular cells governing it. Optogenetic silencing during live Ca 2+ imaging showed the existence of ‘hubs’–β-cells able to respond early to glucose stimuli and guide but not completely control the activity of the β-cell complement [50].…”

Section: Why Might Regenerated β-Cells Function Relatively Poorly?mentioning

confidence: 99%

Informing β-cell regeneration strategies using studies of heterogeneity

Nasteska

Viloria

Everett

et al. 2019

Molecular Metabolism

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BackgroundCurrent therapeutic strategies for type 1 (T1DM) and type 2 diabetes mellitus (T2DM) rely on increasing or substituting endogenous insulin secretion in combination with lifestyle changes. β-cell regeneration, a process whereby new β-cells arise from progenitors, self-renewal or transdifferentiation, has the potential to become a viable route to insulin self-sufficiency. Current regeneration strategies capture many of the transcriptomic and protein features of native β-cells, generating cells capable of glucose-dependent insulin secretion in vitro and alleviation of hyperglycemia in vivo. However, whether novel β-cells display appreciable heterogeneity remains poorly understood, with potential consequences for long-term functional robustness.Scope of reviewThe review brings together crucial discoveries in the β-cell regeneration field with state-of-the-art knowledge regarding β-cell heterogeneity. Aspects that might aid production of longer-lasting and more plastic regenerated β-cells are highlighted and discussed.Major conclusionsDifferent β-cell regeneration approaches result in a similar outcome: glucose-sensitive, insulin-positive cells that mimic the native β-cell phenotype but which lack normal plasticity. The β-cell subpopulations identified to date expand our understanding of β-cell survival, proliferation and function, signposting the direction for future regeneration strategies. Therefore, regenerated β-cells should exhibit stimulus-dependent differences in gene and protein expression, as well as establish a functional network with different β-cells, all while coexisting with other cell types on a three-dimensional platform.

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“…Contributing to electrical coupling between adjacent β cells, Connexin36 (Cx36) serves as a prominent gap junction protein inherently involved in glucose-induced calcium oscillations [63]. Islets that lack Cx36 present with increased basal insulin secretion, alongside compromised glucose-induced insulin secretion [64].…”

Section: Effect Of β Cells On Ecmentioning

confidence: 99%

Differences between studying an islet β cell and studying whole pancreatic islets: immunological implications

2017

JCEI

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The main role of the pancreatic islet β cell is to release the appropriate amount of insulin upon glucose stimulation. For this reason, islet transplantation has been advancing in the past few years as a therapeutic alternative for patients with diabetes, alongside the exciting field of manipulating β cell differentiation for the sake of β cell transplantation. However, do isolated β cells function the same as β cells within an intact islet? Within islets, β cells are surrounded by other cell types, including endocrine cells, endothelial cells and immune cells, a proximity which appears to be relevant for proper glucose homeostasis. Although insulin and glucose are the main regulators in this scenario, other factors, such as angiogenesis, local anti-inflammatory components and the activity profile of resident macrophages, have a profound effect on the function and fate of β cells. A paracrine interaction between β cells and α cell holds a dramatic effect on β cell function, which is additionally dependent on blood flow through the islet. Another important intercellular communication exists between β cells and endothelial cells, in this case a bidirectional interface. Moreover, β cell survival and proliferation is dependent on the potency of ECM proteins. Further parameters distinguish functionally between the isolated β cell and the intact islet, including the deposition of Zinc by β cells, synchronicity by electrical and calcium routes, the physical innervation of islets and more. In this review, we explore major parameters that relate to differences between the function of the isolated β cell and that of the β cell within an intact islet. These and some yet to be investigated aspects of β cell function should be included in the list of considerations when examining therapeutic targets for β cell–related pathologies and for the prospect of effective β cell replacement therapy

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Membrane Potential and Calcium Dynamics in Beta Cells from Mouse Pancreas Tissue Slices: Theory, Experimentation, and Analysis

Cited by 25 publications

References 173 publications

Inherent ER stress in pancreatic islet β cells causes self-recognition by autoreactive T cells in type 1 diabetes

Inherent ER stress in pancreatic islet β cells causes self-recognition by autoreactive T cells in type 1 diabetes

Informing β-cell regeneration strategies using studies of heterogeneity

Differences between studying an islet β cell and studying whole pancreatic islets: immunological implications

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