Mathematical modelling of local calcium and regulated exocytosis during inhibition and stimulation of glucagon secretion from pancreatic alpha‐cells

Montefusco, Francesco; Pedersen, Morten Gram

doi:10.1113/jp270777

Cited by 30 publications

(46 citation statements)

References 54 publications

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“…We conducted a computational α-cell model to simulate and explore several interconnected steps in the glucose-dependent signalling cascade from the initial metabolic processes to exocytosis. We combined a mathematical model for glycolysis and glucose-driven mitochondrial activity [30] with a model for simulating α-cell electrical and Ca 2+ activity and finally with glucagon secretion [31]. This unique coupling of the α-cell metabolism with the electrical activity enabled us to study the interplay royalsocietypublishing.org/journal/rsos R. Soc.…”

Section: Mathematical α-Cell Modelmentioning

confidence: 99%

“…The model for simulating α-cell electrical activity and exocytosis is a modified version of previous endeavours [31,46]. The aim of this part of the model is to link metabolic processes and glucagon secretion.…”

Section: Glucagon Secretionmentioning

confidence: 99%

“…In α-cells, Ca 2+ predominately enters through L-type channels, but exocytosis is mediated by P/Q-type channels [51]. Finally, glucagon secretion in the P/Q-type and L-type microdomains is defined as follows: As described in more detail in [31]. The overall secreted glucagon is finally computed as…”

Section: Glucagon Secretionmentioning

confidence: 99%

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Modelling of dysregulated glucagon secretion in type 2 diabetes by considering mitochondrial alterations in pancreatic α-cells

et al. 2020

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Type 2 diabetes mellitus (T2DM) has been associated with insulin resistance and the failure of β-cells to produce and secrete enough insulin as the disease progresses. However, clinical treatments based solely on insulin secretion and action have had limited success. The focus is therefore shifting towards α-cells, in particular to the dysregulated secretion of glucagon. Our qualitative electron-microscopy-based observations gave an indication that mitochondria in α-cells are altered in Western-diet-induced T2DM. In particular, α-cells extracted from mouse pancreatic tissue showed a lower density of mitochondria, a less expressed matrix and a lower number of cristae. These deformities in mitochondrial ultrastructure imply a decreased efficiency in mitochondrial ATP production, which prompted us to theoretically explore and clarify one of the most challenging problems associated with T2DM, namely the lack of glucagon secretion in hypoglycaemia and its oversecretion at high blood glucose concentrations. To this purpose, we constructed a novel computational model that links α-cell metabolism with their electrical activity and glucagon secretion. Our results show that defective mitochondrial metabolism in α-cells can account for dysregulated glucagon secretion in T2DM, thus improving our understanding of T2DM pathophysiology and indicating possibilities for new clinical treatments.

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Section: Mathematical α-Cell Modelmentioning

confidence: 99%

Section: Glucagon Secretionmentioning

confidence: 99%

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Modelling of dysregulated glucagon secretion in type 2 diabetes by considering mitochondrial alterations in pancreatic α-cells

et al. 2020

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“…In particular, fusion of glucagon-containing granules have been found to depend on P/Q-type Ca 2+ channels [84]. GLP-1 raises cAMP modestly, which inhibits Figure 5: Overview of the main mechanisms underlying glucagon secretion from α-cells in response to glucose and hormones considered in the model [85]. Box A: Ion channels determining α-cell electrical activity.…”

Section: Control Of Exocytosis By Different Types Of Ca 2+ Channelsmentioning

confidence: 99%

Recent advances in mathematical modeling and statistical analysis of exocytosis in endocrine cells

Pedersen

Tagliavini

Cortese

et al. 2017

Mathematical Biosciences

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Most endocrine cells secrete hormones as a result of Ca-regulated exocytosis, i.e., fusion of the membranes of hormone-containing secretory granules with the cell membrane, which allows the hormone molecules to escape to the extracellular space. As in neurons, electrical activity and cell depolarization open voltage-sensitive Ca channels, and the resulting Ca influx elevate the intracellular Ca concentration, which in turn causes exocytosis. Whereas the main molecular components involved in exocytosis are increasingly well understood, quantitative understanding of the dynamical aspects of exocytosis is still lacking. Due to the nontrivial spatiotemporal Ca dynamics, which depends on the particular pattern of electrical activity as well as Ca channel kinetics, exocytosis is dependent on the spatial arrangement of Ca channels and secretory granules. For example, the creation of local Ca microdomains, where the Ca concentration reaches tens of µM, are believed to be important for triggering exocytosis. Spatiotemporal simulations of buffered Ca diffusion have provided important insight into the interplay between electrical activity, Ca channel kinetics, and the location of granules and Ca channels. By confronting simulations with statistical time-to-event (or survival) regression analysis of single granule exocytosis monitored with TIRF microscopy, a direct connection between location and rate of exocytosis can be obtained at the local, single-granule level. To get insight into whole-cell secretion, simplifications of the full spatiotemporal dynamics have shown to be highly helpful. Here, we provide an overview of recent approaches and results for quantitative analysis of Ca regulated exocytosis of hormone-containing granules.

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“…These patterns were interpreted as the results of depletion of a small immediately releasable pool (IRP) of granules followed by slower release from a larger pool. Various mathematical models of granule pools and exocytosis were developed based on these and similar results, with the scope of reproducing and simulating typical behavior, in order to investigate the underlying biological mechanisms [25, 29–33]. However, the aim of such mathematical models is not to extract information from raw experimental data.…”

Section: Introductionmentioning

confidence: 99%

Statistical Frailty Modeling for Quantitative Analysis of Exocytotic Events Recorded by Live Cell Imaging: Rapid Release of Insulin-Containing Granules Is Impaired in Human Diabetic β-cells

et al. 2016

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Hormones and neurotransmitters are released when secretory granules or synaptic vesicles fuse with the cell membrane, a process denoted exocytosis. Modern imaging techniques, in particular total internal reflection fluorescence (TIRF) microscopy, allow the investigator to monitor secretory granules at the plasma membrane before and when they undergo exocytosis. However, rigorous statistical approaches for temporal analysis of such exocytosis data are still lacking. We propose here that statistical methods from time-to-event (also known as survival) analysis are well suited for the problem. These methods are typically used in clinical settings when individuals are followed over time to the occurrence of an event such as death, remission or conception. We model the rate of exocytosis in response to pulses of stimuli in insulin-secreting pancreatic β-cell from healthy and diabetic human donors using piecewise-constant hazard modeling. To study heterogeneity in the granule population we exploit frailty modeling, which describe unobserved differences in the propensity to exocytosis. In particular, we insert a discrete frailty in our statistical model to account for the higher rate of exocytosis in an immediately releasable pool (IRP) of insulin-containing granules. Estimates of parameters are obtained from maximum-likelihood methods. Since granules within the same cell are correlated, i.e., the data are clustered, a modified likelihood function is used for log-likelihood ratio tests in order to perform valid inference. Our approach allows us for example to estimate the size of the IRP in the cells, and we find that the IRP is deficient in diabetic cells. This novel application of time-to-event analysis and frailty modeling should be useful also for the study of other well-defined temporal events at the cellular level.

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Mathematical modelling of local calcium and regulated exocytosis during inhibition and stimulation of glucagon secretion from pancreatic alpha‐cells

Cited by 30 publications

References 54 publications

Modelling of dysregulated glucagon secretion in type 2 diabetes by considering mitochondrial alterations in pancreatic α-cells

Modelling of dysregulated glucagon secretion in type 2 diabetes by considering mitochondrial alterations in pancreatic α-cells

Recent advances in mathematical modeling and statistical analysis of exocytosis in endocrine cells

Statistical Frailty Modeling for Quantitative Analysis of Exocytotic Events Recorded by Live Cell Imaging: Rapid Release of Insulin-Containing Granules Is Impaired in Human Diabetic β-cells

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