Beta-cell Metabolic Activity Rather than Gap Junction Structure Dictates Subpopulations in the Islet Functional Network

Briggs, Jennifer K.; Kravets, Vira; Dwulet, JaeAnn M.; Benninger, Richard K.P.

doi:10.1101/2022.02.06.479331

Cited by 5 publications

(3 citation statements)

References 90 publications

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“…We observed a high level of synchrony or correlation between voltage time-courses of islet electrodes, which are qualitatively similar to the synchrony in calcium measurements between beta-cells that has been previously reported and depends on gap junction coupling (23). Our network analysis demonstrated that islets have synchronized electrical activity (Figure 5B).…”

Section: Cmos-mea Recordings Reveal a Link Between Cellular Electrica...supporting

confidence: 87%

Resolving spatiotemporal electrical signaling within the islet via CMOS microelectrode arrays

Gresch,

Hüwel,

Briggs

et al. 2023

Preprint

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Glucose-stimulated beta-cells synchronize calcium waves across the islet to recruit more beta-cells for insulin secretion. Compared to calcium dynamics, the formation and cell-to-cell propagation of electrical signals within the islet are poorly characterized. To determine factors that influence the propagation of electrical activity across the islet underlying calcium oscillations and beta-cell synchronization, we used high-resolution CMOS multielectrode arrays (MEA) to measure voltage changes associated with the membrane potential of individual cells within intact mouse islets. We measured both fast (milliseconds, spikes) and slow (seconds, waves) voltage changes and analyzed the spatiotemporal voltage dynamics. Treatment of islets from C57BL6 mice with increasing glucose concentrations revealed that single spike activity and wave signal velocity were both glucose-dependent. A repeated glucose stimulus involved a highly active subset of cells in terms of spike activity. When islets were pretreated for 72 hours with glucolipotoxic medium, the wave velocity was significantly reduced. Network analysis confirmed that the synchrony of islet cells was affected due to slower propagating electrical waves and not due to altered spike activity. In summary, this approach provided novel insight regarding the propagation of electrical activity and opens a wide field for further studies on signal transduction in the islet cell network.Article HighlightsThis study presents a new method for characterizing islet spatiotemporal electrical dynamics and subpopulations of beta-cells. We asked whether a high-resolution CMOS-MEA is suited to detect electrical signals on a level close to single cells, and whether we can track the propagation of electrical activity through the islet on a cellular scale. A highly active subpopulation of islet cells was identified by action potential-like spike activity, whereas slower waves were a measure for synchronized electrical activity. Further, propagating waves were slowed by glucolipotoxicity. The technique is a useful tool for exploring the pancreatic islet network in health and disease.

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Section: Cmos-mea Recordings Reveal a Link Between Cellular Electrica...supporting

confidence: 87%

Resolving spatiotemporal electrical signaling within the islet via CMOS microelectrode arrays

Gresch,

Hüwel,

Briggs

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…Indeed, possible structural long-range connections typically prevent propagating waves ( 88 ) and the combination of experimentally observed intercellular waves and small-world functional network properties speaks against a structural small-world substrate. Notably, further research also suggested that the small-world characteristics can in part be attributed to the multimodal nature of the oscillatory β cell activity, whereby the slow oscillatory component contributes more directly to long-range connectivity ( 54 ) and that the slow-activity-derived networks are less dependent on the structural gap junctional network ( 62 , 91 ). Furthermore, both modeling and experimental studies suggest that the intercellular waves and functional networks in a single focal plane are largely representative of the behavior in the islet as a whole ( 59 , 61 , 64 ).…”

Section: Discussionmentioning

confidence: 99%

Functional characteristics of hub and wave-initiator cells in β cell networks

Šterk¹,

Dolenšek²,

Klemen³

et al. 2023

Biophysical Journal

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“…Gap junctional coupling of beta cells via Cx36 allows for the electrical linkage as well as the exchange of small molecules between neighboring cells and mediates principally the coherence of fast Ca 2+ dynamics ( 133 , 134 ). Correlations between slow Ca 2+ oscillations can be driven by metabolic coupling of neighboring cells, via feedback onto the slow dynamics by the fast dynamics due to same electrical coupling ( 77 , 135 – 139 ), as well as by intrinsic metabolic characteristics of beta cells ( 61 ). Since both fast and slow oscillations are synchronized among the cells in an islet, they both contribute to functional connectivity networks derived from Ca 2+ signals ( 56 , 133 , 140 , 141 ).…”

Section: Topological Analysis Of Functional Beta Cell Networkmentioning

confidence: 99%

From Isles of Königsberg to Islets of Langerhans: Examining the Function of the Endocrine Pancreas Through Network Science

Stožer

Šterk²,

Leitgeb³

et al. 2022

Front. Endocrinol.

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Islets of Langerhans are multicellular microorgans located in the pancreas that play a central role in whole-body energy homeostasis. Through secretion of insulin and other hormones they regulate postprandial storage and interprandial usage of energy-rich nutrients. In these clusters of hormone-secreting endocrine cells, intricate cell-cell communication is essential for proper function. Electrical coupling between the insulin-secreting beta cells through gap junctions composed of connexin36 is particularly important, as it provides the required, most important, basis for coordinated responses of the beta cell population. The increasing evidence that gap-junctional communication and its modulation are vital to well-regulated secretion of insulin has stimulated immense interest in how subpopulations of heterogeneous beta cells are functionally arranged throughout the islets and how they mediate intercellular signals. In the last decade, several novel techniques have been proposed to assess cooperation between cells in islets, including the prosperous combination of multicellular imaging and network science. In the present contribution, we review recent advances related to the application of complex network approaches to uncover the functional connectivity patterns among cells within the islets. We first provide an accessible introduction to the basic principles of network theory, enumerating the measures characterizing the intercellular interactions and quantifying the functional integration and segregation of a multicellular system. Then we describe methodological approaches to construct functional beta cell networks, point out possible pitfalls, and specify the functional implications of beta cell network examinations. We continue by highlighting the recent findings obtained through advanced multicellular imaging techniques supported by network-based analyses, giving special emphasis to the current developments in both mouse and human islets, as well as outlining challenges offered by the multilayer network formalism in exploring the collective activity of islet cell populations. Finally, we emphasize that the combination of these imaging techniques and network-based analyses does not only represent an innovative concept that can be used to describe and interpret the physiology of islets, but also provides fertile ground for delineating normal from pathological function and for quantifying the changes in islet communication networks associated with the development of diabetes mellitus.

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Beta-cell Metabolic Activity Rather than Gap Junction Structure Dictates Subpopulations in the Islet Functional Network

Cited by 5 publications

References 90 publications

Resolving spatiotemporal electrical signaling within the islet via CMOS microelectrode arrays

Resolving spatiotemporal electrical signaling within the islet via CMOS microelectrode arrays

Functional characteristics of hub and wave-initiator cells in β cell networks

From Isles of Königsberg to Islets of Langerhans: Examining the Function of the Endocrine Pancreas Through Network Science

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