Spatially Organized β-Cell Subpopulations Control Electrical Dynamics across Islets of Langerhans

Westacott, Matthew J.; Ludin, Nurin W.F.; Benninger, Richard K.P.

doi:10.1016/j.bpj.2017.07.021

Cited by 89 publications

(192 citation statements)

References 62 publications

(92 reference statements)

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“…62-65 Recent data have demonstrated that highly metabolic cells are more efficient at recruiting neighboring cells. 55 Upon glucose stimulation, GJ coupling between β-cells increases. 66 Furthermore, hub cells express less insulin, 33 and highly GJ coupled cells are known to express less insulin.…”

Section: Discussionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

“…55 As hub cells are highly metabolic, 33 this would imply that hub cells may be preferentially connected.…”

Section: Methodsmentioning

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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“…Saturated areas were also removed by limiting the area to intensities below the maximum. To determine if a cell was active, a peak detection algorithm was used to determine if areas of the islet had peak amplitudes greater than 1.5 times the average of quiescent reference cells [32]. A quiescent reference cell (or background region if no cells were quiescent) was chosen manually, and showed no significant fluctuations in intensity during the entire time course.…”

Section: Nad(p)h Imaging-nadh(p)mentioning

confidence: 99%

“…We and others have previously examined how heterogeneity in KATP channel activity and electrical coupling impact overall islet [Ca 2+ ] [9,22,24,26]. However, both single-cell based studies and in-situ analysis have demonstrated that β-cells exhibit substantial heterogeneity in glucose metabolism [27], which includes varying GK expression [21,25,28], metabolic fluxes [29][30][31][32], or mitochondrial function [19,21]. While extensive heterogeneity in glucose metabolism exists within the islet, it is not clear how cell sub-populations with differing GK expression or levels of glucose metabolism influence each other via electrical coupling.…”

Section: Introductionmentioning

confidence: 99%

How heterogeneity in glucokinase and gap junction coupling determines the islet electrical response

Dwulet

Ludin

Piscopio

et al. 2019

Preprint

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Understanding how cell sub-populations in a tissue impact the function of the overall system is often challenging. There is extensive heterogeneity among insulin-secreting β-cells within islets of Langerhans, including their insulin secretory response and gene expression profile; and this heterogeneity can be altered in diabetes. Several studies have identified variations in nutrient sensing between β-cells, including glucokinase (GK) levels, mitochondrial function or expression of genes important for glucose metabolism. Sub-populations of β-cells with defined electrical properties can disproportionately influence islet-wide free-calcium activity ([Ca2+]) and insulin secretion, via gap junction electrical coupling. However, it is poorly understood how sub-populations of β-cells with altered glucose metabolism may impact islet function. To address this, we utilized a multicellular computational model of the islet in which a population of cells deficient in GK activity and glucose metabolism was imposed on the islet, or where β-cells were heterogeneous in glucose metabolism and GK kinetics were altered. This included simulating Glucokinase gene (GCK) mutations that cause monogenic diabetes. We combined these approaches with experimental models in which gck was genetically deleted in a population of cells or GK was pharmacologically inhibited. In each case we modulated gap junction electrical coupling. Both the simulated islet and the experimental system required 30-50% of the cells to have near-normal glucose metabolism. Below this number, the islet lacked any glucose-stimulated [Ca2+] elevations. In the absence of electrical coupling the change in [Ca2+] was more gradual. As such, given heterogeneity in glucose metabolism, electrical coupling allows a large minority of cells with normal glucose metabolism to promote glucose-stimulated [Ca2+]. If insufficient numbers of cells are present, which we predict can be caused by a subset of GCK mutations that cause monogenic diabetes, electrical coupling exacerbates [Ca2+] suppression. This demonstrates precisely how heterogeneous β-cell populations interact to impact islet function.SIGNIFICANCEBiological tissues contain heterogeneous populations of cells. Insulin-secreting β-cells within the islets of Langerhans are critical for regulating blood glucose homeostasis. β-cells are heterogeneous but it is unclear how the islet response is impacted by different cell populations and their interactions. We use a multicellular computational model and experimental systems to predict and quantify how cellular populations defined by varied glucose metabolism interact via electrical communication to impact islet function. When glucose metabolism is heterogeneous, electrical coupling is critical to promote electrical activity. However, when cells deficient in glucose metabolism are in the majority, electrical activity is completely suppressed. Thus modulating electrical communication can promotes islet electrical activity, following dysfunction caused by gene mutations that impact glucose metabolism.

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“…In response to elevated blood glucose concentrations, pancreatic β cells secrete insulin by Ca 2+ -triggered exocytosis. [4][5][6] Although these findings provide important insights into β-cell function, the results are exclusively based either on ex vivo or in vitro data and disregard important factors provided by blood supply, innervation, as well as the metabolic state of islet/β cells under in vivo conditions. 3 A β-cell dysfunction in combination with peripheral insulin resistance is central to the development of type 2 diabetes, a still growing pandemic disease leading to hyperglycemia.…”

Section: Introductionmentioning

confidence: 99%

In vivo Ca ²⁺ dynamics in single pancreatic β cells

et al. 2019

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contributed equally to the presented work.Abbreviations: 2-NBDG, 2-(N-(7-Nitrobenz-2-oxa-1,3-diazol-4-yl)Amino)-2-Deoxyglucose; ACE, anterior chamber of the eye; EMCCD, electron multiplying charge-coupled device; HBSS, Hank's Balanced Salt Solution; Hyp/Mid, hypnorm/midazolam; IpGTT, intraperitoneal glucose tolerance test; IpITT, intraperitoneal insulin tolerance test; [Ca 2+ ] i , intracellular free calcium ion concentration; RIP, rat insulin promoter. AbstractThe dynamics of cytoplasmic free Ca 2+ concentration ([Ca 2+ ] i ) in pancreatic β cells is central to our understanding of β-cell physiology and pathology. In this context, there are numerous in vitro studies available but existing in vivo data are scarce. We now critically evaluate the anterior chamber of the eye as an in vivo, non-invasive, imaging site for measuring [Ca 2+ ] i dynamics longitudinally in three dimensions and at single-cell resolution. By applying a fluorescently labeled glucose analogue 2-(N-(7-Nitrobenz-2-oxa-1,3-diazol-4-yl)Amino)-2-Deoxyglucose in vivo, we followed how glucose almost simultaneously distributes to all cells within the islet volume, resulting in [Ca 2+ ] i changes. We found that almost all β cells in healthy mice responded to a glucose challenge, while in hyperinsulinemic, hyperglycemic mice about 80% of the β cells could not be further stimulated from fasting basal conditions. This finding indicates that our imaging modality can resolve functional heterogeneity within the β-cell population in terms of glucose responsiveness. Importantly, we demonstrate that glucose homeostasis is markedly affected using isoflurane compared to hypnorm/ midazolam anesthetics, which has major implications for [Ca 2+ ] i measurements. In summary, this setup offers a powerful tool to further investigate in vivo pancreatic β-cell [Ca 2+ ] i response patterns at single-cell resolution in health and disease. K E Y W O R D Scalcium dynamics, diabetes mellitus, fluorescence microscopy, in vivo imaging, pancreatic islets 946 | JACOB et Al.

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Spatially Organized β-Cell Subpopulations Control Electrical Dynamics across Islets of Langerhans

Cited by 89 publications

References 62 publications

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

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

How heterogeneity in glucokinase and gap junction coupling determines the islet electrical response

In vivo Ca ²⁺ dynamics in single pancreatic β cells

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Spatially Organized β-Cell Subpopulations Control Electrical Dynamics across Islets of Langerhans

Cited by 89 publications

References 62 publications

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

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

How heterogeneity in glucokinase and gap junction coupling determines the islet electrical response

In vivo Ca 2+ dynamics in single pancreatic β cells

Contact Info

Product

Resources

About

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

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

In vivo Ca ²⁺ dynamics in single pancreatic β cells