Assessing the origin and velocity of Ca2+ waves in three-dimensional tissue: Insights from a mathematical model and confocal imaging in mouse pancreas tissue slices

Šterk, Marko; Dolenšek, Jurij; Bombek, Lidija Križančić; Markovič, Rene; Zakelšek, Darko; Perc, Matjaž; Pohorec, Viljem; Stožer, Andraž; Gosak, Marko

doi:10.1016/j.cnsns.2020.105495

Cited by 23 publications

(28 citation statements)

References 94 publications

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“…Higher stimulation led to a more synchronized behavior and hence to denser, more integral and efficient networks, functioning as a large single network. This importantly corroborates our previous findings, but on a larger dataset, on a wider range of glucose concentrations, and based on a different stimulation paradigm (66,101 (19,47,125,143). Such an analysis would enable us to also study the properties of the cells that initiate fast [Ca 2+ ]IC oscillations, i.e., pacemakers.…”

Section: Functional Networksupporting

confidence: 87%

“…However, some heterogeneity persists in beta cells in islets and recent research suggests that it plays a crucial role for normal beta cell function (21,106,118,131). One of the important tools to quantify heterogeneity are classical physiological and network analyses of complex spatiotemporal [Ca 2+ ]IC dynamics (78,140), which enable identification of cells that play important roles in an islet´s response to secretagogues, e.g., cells that respond first (i.e., first-responders), cells that start the [Ca 2+ ]IC waves that synchronize fast [Ca 2+ ]IC oscillations (i.e., pacemakers), cells that functionally interact with the most other cells (i.e., hubs), etc (19,66,78,139,140,143,146). These roles are probably crucial for generation of coordinated rhythmic activity (15,18,36,66,78,84,101,120,123,140,142) and there is growing evidence that both environmental and genetic factors may target connectivity and heterogeneity in the pathogenesis of diabetes mellitus (4,53,78,131,141,145).…”

Section: Functional Networkmentioning

confidence: 99%

“…Beta cells activate in small clusters dispersed over an islet with no predictable pattern (47, 67,142). During the plateau phase, [Ca 2+ ]IC oscillations are slightly phase-lagged due to intercellular depolarization, and [Ca 2+ ]IC waves repeatedly spread across islets with an average velocity of about 100 µm/s (10,19,30,47,80,129,139,143). Simultaneous measurements of membrane potential and [Ca 2+ ]IC oscillations demonstrated a tight coupling of the two processes (16,59,125), with membrane potential depolarization preceding the [Ca 2+ ]IC increase by about 150 ms (47).…”

Section: Introductionmentioning

confidence: 99%

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

Dolenšek

Klemen

Gosak

et al. 2020

Preprint

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Glucose progressively stimulates insulin release over a wide range of concentrations. However, the nutrient coding underlying activation, activity, and deactivation of beta cells affecting insulin release remains only partially described. Experimental data indicate that nutrient sensing in coupled beta cells in islets is predominantly a collective trait, overriding to a large extent functional differences between cells. However, some degree of heterogeneity between coupled beta cells may play important roles. To further elucidate glucose-dependent modalities in coupled beta cells, the degree of functional heterogeneity, and uncover the emergent collective operations, we combined acute mouse pancreas tissue slices with functional multicellular calcium imaging. We recorded beta cell calcium responses from threshold (7 mM) to supraphysiological (16 mM) glucose concentrations with high spatial and temporal resolution. This enabled the analysis of both classical physiological parameters and complex network parameters, as well as their comparison at the level of individual cells. The activation profile displayed two major glucose concentration-dependent features, shortening of delays to initial activation, and shortening of delays until half activation with increasing glucose concentration. Inversely, during deactivation both delays to initial deactivation and until half deactivation were progressively longer with increasing glucose concentration. The plateau activity with fast calcium oscillations expressed two types of glucose-dependence. Physiological concentrations mostly affected the frequency of oscillations, whereas supraphysiological concentrations progressively prolonged the duration of oscillations. Most of the measured functional network parameters also showed clear glucose-dependence. In conclusion, we propose novel understanding for glucose-dependent coding properties in beta cell networks, and its deciphering may have repercussions for our understanding of the normal physiology of glucose homeostasis as well as of disturbances of metabolic homeostasis, such as diabetes mellitus.

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Section: Functional Networksupporting

confidence: 87%

Section: Functional Networkmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Dolenšek

Klemen

Gosak

et al. 2020

Preprint

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“…This coupling enables neighboring beta cells to communicate and, in part, synchronize their dynamics. The diffusion of intermediate products of glycolysis, in particular glucose-6-phosphate, is probably responsible for the coupling of slow oscillations ( Tsaneva-Atanasova et al, 2006 ), while electrical depolarization with a space constant in the order of a few beta cell diameters accounts for the alignment of fast oscillations and explains the experimentally observed Ca 2+ waves ( Meissner, 1976 ; Meissner and Preissler, 1979 ; Eddlestone et al, 1984 ; Santos et al, 1991 ; Aslanidi et al, 2001 ; Benninger et al, 2008 ; Zhang et al, 2008 ; Skelin Klemen et al, 2017 ; Šterk et al, 2021 ). Furthermore, it was proposed that the electrical coupling increases with glucose concentrations ( Eddlestone et al, 1984 ).…”

Section: Introductionmentioning

confidence: 99%

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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“…Endocrine islet cells interact with each other, and this is another key player in hormonal rhythm control [ 69 , 78 , 79 , 80 , 81 , 82 , 83 ]. Beta cells are electrically coupled through gap-junctions, ensuring that the otherwise heterogeneous cell population works in synchrony [ 84 , 85 , 86 ]. In contrast, alpha cell populations’ activity is not synchronized, which collaborates the idea that these cells function individually within the islet to secrete glucagon rather than act as a syncytium [ 46 ].…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial Dysfunction in Pancreatic Alpha and Beta Cells Associated with Type 2 Diabetes Mellitus

Grubelnik

Zmazek

Markovič

et al. 2020

Life

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Type 2 diabetes mellitus is a complex multifactorial disease of epidemic proportions. It involves genetic and lifestyle factors that lead to dysregulations in hormone secretion and metabolic homeostasis. Accumulating evidence indicates that altered mitochondrial structure, function, and particularly bioenergetics of cells in different tissues have a central role in the pathogenesis of type 2 diabetes mellitus. In the present study, we explore how mitochondrial dysfunction impairs the coupling between metabolism and exocytosis in the pancreatic alpha and beta cells. We demonstrate that reduced mitochondrial ATP production is linked with the observed defects in insulin and glucagon secretion by utilizing computational modeling approach. Specifically, a 30–40% reduction in alpha cells’ mitochondrial function leads to a pathological shift of glucagon secretion, characterized by oversecretion at high glucose concentrations and insufficient secretion in hypoglycemia. In beta cells, the impaired mitochondrial energy metabolism is accompanied by reduced insulin secretion at all glucose levels, but the differences, compared to a normal beta cell, are the most pronounced in hyperglycemia. These findings improve our understanding of metabolic pathways and mitochondrial bioenergetics in the pathology of type 2 diabetes mellitus and might help drive the development of innovative therapies to treat various metabolic diseases.

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Assessing the origin and velocity of Ca2+ waves in three-dimensional tissue: Insights from a mathematical model and confocal imaging in mouse pancreas tissue slices

Cited by 23 publications

References 94 publications

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

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

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

Mitochondrial Dysfunction in Pancreatic Alpha and Beta Cells Associated with Type 2 Diabetes Mellitus

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