Glucose-dependent activation, activity, and deactivation of beta cell networks in acute mouse pancreas tissue slices

Dolenšek, Jurij; Klemen, Maša Skelin; Gosak, Marko; Bombek, Lidija Križančić; Pohorec, Viljem; Rupnik, Marjan Slak; Stožer, Andraž

doi:10.1101/2020.03.11.986893

Cited by 5 publications

(23 citation statements)

References 160 publications

(331 reference statements)

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“…Both the frequency and the phase duration of the fast component increased with increasing glucose concentration (Figure 2), corroborating earlier studies on isolated islets (Santos et al, 1991;P. Gilon et al, 1993;Antunes et al, 2000;Nunemaker et al, 2006), in acute tissue slices (Markovič et al, 2015;Dolenšek et al, 2020), and of mathematical modeling (Nunemaker et al, 2006;Stamper and Wang, 2019). To study the interplay of the two, we correlated the two frequency domains from the same beta cells (Figure 2).…”

Section: Discussionsupporting

confidence: 86%

“…In 8 mM, values of TS and TP were approximately 5 and 8 min, whereas in 12 mM glucose, they shortened on average almost twofold (Figures 2N,O). These results are in good agreement with our previous reports (Dolenšek et al, 2020;Podobnik et al, 2020).…”

Section: Assessing the Multimodal Oscillatory Intracellular Ca 2+ Actsupporting

confidence: 94%

“…On the scale of slow oscillations, the difference in average synchronicity at different stimulation levels was not significant and the effect size was small (p = 0.529, d = 0.31) ( Figure 4A). On the contrary, higher glucose concentrations evoked more synchronized responses of the fast component ( Figure 4B), which corroborates our previous findings (Markovič et al, 2015;Gosak et al, 2018;Dolenšek et al, 2020). The difference was statistically significant and the effect size large (p = 0.048, d = 1.05).…”

Section: Synchronicity and Network Analysis Of Multiple Oscillatory Rsupporting

confidence: 92%

“…Superimposed on the slow oscillations are the so-called fast Ca 2+ oscillations with a frequency of about 5 min −1 and a duration of about 2-15 s. It is currently believed that these oscillations result from Ca 2+ feedback on ion channels, and therefore reflect the bursting pattern of electrical activity. The frequency and the duration of these oscillations are glucosedependent (Meissner, 1976;Santos et al, 1991;Nunemaker et al, 2006;Scarl et al, 2019;Dolenšek et al, 2020) and are considered essential for setting the amplitude of the slow plasma insulin oscillations (Bergsten, 2002;Hellman, 2009;Satin et al, 2015). Both slow and fast oscillations are well synchronized between different beta cells of the same islet (Satin et al, 2015;Skelin Klemen et al, 2017;Bertram et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

“…The methodology was not only found useful for demonstrating that beta cell networks share many similarities with several other biological networks, such as small-worldness, modularity, and a heterogeneous degree distribution (Stožer et al, 2013;Johnston et al, 2016;Gosak et al, 2018), but also that there are important relations between beta cell metabolic activity and the orchestration of collective islet behavior (Gosak et al, 2015;Johnston et al, 2016). Moreover, it turned out that beta cell networks are rather segregated, which is most probably linked to cellular variability and the existence of sub-populations (Markovič et al, 2015;Dwulet et al, 2019;Dolenšek et al, 2020;Nasteska et al, 2020). The beta cell connectivity architectures were also found to be very heterogeneous with a small fraction of very well connected cells, i.e., hub cells, which are believed to substantially affect the collective cellular activity (Johnston et al, 2016;Lei et al, 2018;Loppini and Chiodo, 2019;Salem et al, 2019;Nasteska et al, 2020), even though the precise mechanisms are still incompletely understood (Satin et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

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Assessing Different Temporal Scales of Calcium Dynamics in Networks of Beta Cell Populations

et al. 2021

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Beta cells within the pancreatic islets of Langerhans respond to stimulation with coherent oscillations of membrane potential and intracellular calcium concentration that presumably drive the pulsatile exocytosis of insulin. Their rhythmic activity is multimodal, resulting from networked feedback interactions of various oscillatory subsystems, such as the glycolytic, mitochondrial, and electrical/calcium components. How these oscillatory modules interact and affect the collective cellular activity, which is a prerequisite for proper hormone release, is incompletely understood. In the present work, we combined advanced confocal Ca2+ imaging in fresh mouse pancreas tissue slices with time series analysis and network science approaches to unveil the glucose-dependent characteristics of different oscillatory components on both the intra- and inter-cellular level. Our results reveal an interrelationship between the metabolically driven low-frequency component and the electrically driven high-frequency component, with the latter exhibiting the highest bursting rates around the peaks of the slow component and the lowest around the nadirs. Moreover, the activity, as well as the average synchronicity of the fast component, considerably increased with increasing stimulatory glucose concentration, whereas the stimulation level did not affect any of these parameters in the slow component domain. Remarkably, in both dynamical components, the average correlation decreased similarly with intercellular distance, which implies that intercellular communication affects the synchronicity of both types of oscillations. To explore the intra-islet synchronization patterns in more detail, we constructed functional connectivity maps. The subsequent comparison of network characteristics of different oscillatory components showed more locally clustered and segregated networks of fast oscillatory activity, while the slow oscillations were more global, resulting in several long-range connections and a more cohesive structure. Besides the structural differences, we found a relatively weak relationship between the fast and slow network layer, which suggests that different synchronization mechanisms shape the collective cellular activity in islets, a finding which has to be kept in mind in future studies employing different oscillations for constructing networks.

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Section: Discussionsupporting

confidence: 86%

Section: Assessing the Multimodal Oscillatory Intracellular Ca 2+ Actsupporting

confidence: 94%

Section: Synchronicity and Network Analysis Of Multiple Oscillatory Rsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Assessing Different Temporal Scales of Calcium Dynamics in Networks of Beta Cell Populations

et al. 2021

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Do oscillations in pancreatic islets require pacemaker cells?

Peercy

Sherman

2022

J Biosci

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The pancreatic islets of Langerhans are biomedically important because they are home to the beta cells that secrete insulin and are hence important for understanding diabetes. They are also an important case study for the mechanisms of bursting oscillations and how these oscillations emerge from the electrical coupling of highly heterogeneous cells. Early work has pointed to a voting/democratic paradigm, where the islet properties are a nonlinear average of the cell properties, with no 'conductor leading the orchestra'. Recent experimental work has uncovered new facets of this heterogeneity, and has identified small world networks dominated by a small subset of cells with a high degree of functional connectivity, assessed via correlations of calcium oscillations. It has also been suggested that these connectivity hubs act as pacemakers necessary for islet oscillations. We reviewed modeling studies that have confirmed the existence of small worldness, and we did not find evidence for obligatory pacemakers. We conclude that democracy rather than oligarchy remains the most likely organizing principle of the islets.

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The Effect of cAMP and the Role of Epac2A During Activation, Activity, and Deactivation of Beta Cell Networks

M¹,

Dolenšek²,

Bombek³

et al. 2021

Preprint

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Beta cells couple stimulation by glucose with insulin secretion and impairments in this coupling play a central role in diabetes mellitus. To clarify the effect of cAMP and the role of Epac2A in intracellular calcium signals and intercellular coupling, we performed functional multicellular calcium imaging in beta cells in mouse pancreas tissue slices after stimulation with glucose and forskolin in wild-type and Epac2A knock-out mice. Increased cAMP evoked calcium signals in otherwise sub-stimulatory glucose and beta cells from Epac2A knock-out mice displayed a faster activation. During the plateau phase, beta cells from Epac2A knock-out mice displayed a slightly higher active time in response to glucose compared with wild-type littermates, and increased cAMP increased the active time via a large increase in oscillation frequency and small decrease in oscillation duration in both Epac2A knock-out and wild-type mice. Functional network properties during stimulation with glucose did not differ in Epac2A knock-out mice, but the presence of Epac2A was crucial for the protective effect of increased cAMP in preventing a decline in beta cell functional connectivity with time. Finally, increased cAMP prolonged beta cell activity during deactivation in an Epac2A-independent manner.

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Glucose-dependent activation, activity, and deactivation of beta cell networks in acute mouse pancreas tissue slices

Cited by 5 publications

References 160 publications

Assessing Different Temporal Scales of Calcium Dynamics in Networks of Beta Cell Populations

Assessing Different Temporal Scales of Calcium Dynamics in Networks of Beta Cell Populations

Do oscillations in pancreatic islets require pacemaker cells?

The Effect of cAMP and the Role of Epac2A During Activation, Activity, and Deactivation of Beta Cell Networks

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