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Functional connectivity in islets of Langerhans from mouse pancreas tissue slices.

Stožer A, Gosak M, Dolenšek J, Perc M, Marhl M, Rupnik MS, Korošak D - PLoS Comput. Biol. (2013)

Bottom Line: Moreover, we find that the range of interactions in networks during activity shows a clear dependence on the Euclidean distance, lending support to previous observations that beta cells are synchronized via calcium waves spreading throughout islets.Most interestingly, the functional connectivity patterns between beta cells exhibit small-world properties, suggesting that beta cells do not form a homogeneous geometric network but are connected in a functionally more efficient way.Presented results provide support for the existing knowledge of beta cell physiology from a network perspective and shed important new light on the functional organization of beta cell syncitia whose structural topology is probably not as trivial as believed so far.

View Article: PubMed Central - PubMed

Affiliation: Institute of Physiology, Faculty of Medicine, University of Maribor, Maribor, Slovenia.

ABSTRACT
We propose a network representation of electrically coupled beta cells in islets of Langerhans. Beta cells are functionally connected on the basis of correlations between calcium dynamics of individual cells, obtained by means of confocal laser-scanning calcium imaging in islets from acute mouse pancreas tissue slices. Obtained functional networks are analyzed in the light of known structural and physiological properties of islets. Focusing on the temporal evolution of the network under stimulation with glucose, we show that the dynamics are more correlated under stimulation than under non-stimulated conditions and that the highest overall correlation, largely independent of Euclidean distances between cells, is observed in the activation and deactivation phases when cells are driven by the external stimulus. Moreover, we find that the range of interactions in networks during activity shows a clear dependence on the Euclidean distance, lending support to previous observations that beta cells are synchronized via calcium waves spreading throughout islets. Most interestingly, the functional connectivity patterns between beta cells exhibit small-world properties, suggesting that beta cells do not form a homogeneous geometric network but are connected in a functionally more efficient way. Presented results provide support for the existing knowledge of beta cell physiology from a network perspective and shed important new light on the functional organization of beta cell syncitia whose structural topology is probably not as trivial as believed so far.

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Methodology used to extract functional connectivity patterns from cytosolic Ca2+ traces.A Image of an islet of Langerhans showing the relative intensity of fluorescence signal during sustained activity (HG). Red circles indicate two cells, i and j, which we regard in continuation. B Temporal evolution of global calcium activity characterized by the mean-field of all beta cells in the islet. In the intervals 0≤t≤150 and 754≤t≤1960 cells were exposed to 6 mM glucose, whereas for 150≤t≤754 a stimulating concentration of glucose (12 mM) was applied. Arrows above the temporal trace denote five different dynamical regimes considered in this study: low glucose prior to stimulation (LG1) – 0≤t<300, activation of beta cells (ON) – 300≤t<420, sustained activity in high glucose (HG) – 600≤t<1000, deactivation of beta cells (OFF) – 1080≤t<1200, and the low glucose after stimulation (LG2) – 1400≤t<1800. Note that the calcium activity pattern has been normalized to the unit interval. C Highlighted dynamical responses of cells i and j during the HG regime. D Correlation diagram for fluorescence signals of the i-th and j-th cell. E The correlation matrix for all pair wise determined Rij. F The corresponding connectivity matrix (thresholded matrix, Rth = 0.75). G Functional connectivity map in the islet for the HG regime. Red circles indicate cells i and j.
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pcbi-1002923-g001: Methodology used to extract functional connectivity patterns from cytosolic Ca2+ traces.A Image of an islet of Langerhans showing the relative intensity of fluorescence signal during sustained activity (HG). Red circles indicate two cells, i and j, which we regard in continuation. B Temporal evolution of global calcium activity characterized by the mean-field of all beta cells in the islet. In the intervals 0≤t≤150 and 754≤t≤1960 cells were exposed to 6 mM glucose, whereas for 150≤t≤754 a stimulating concentration of glucose (12 mM) was applied. Arrows above the temporal trace denote five different dynamical regimes considered in this study: low glucose prior to stimulation (LG1) – 0≤t<300, activation of beta cells (ON) – 300≤t<420, sustained activity in high glucose (HG) – 600≤t<1000, deactivation of beta cells (OFF) – 1080≤t<1200, and the low glucose after stimulation (LG2) – 1400≤t<1800. Note that the calcium activity pattern has been normalized to the unit interval. C Highlighted dynamical responses of cells i and j during the HG regime. D Correlation diagram for fluorescence signals of the i-th and j-th cell. E The correlation matrix for all pair wise determined Rij. F The corresponding connectivity matrix (thresholded matrix, Rth = 0.75). G Functional connectivity map in the islet for the HG regime. Red circles indicate cells i and j.

Mentions: Beta cells were distinguished from other cells on the basis of previous reports showing that cells within islets of Langerhans can reliably be identified by their type-specific calcium responses to stimulation with high glucose [46]–[48]. In cells identified as beta cells, intracellular concentration of calcium ([Ca2+]i) was low and rather stable under basal (6 mM) glucose. Upon stimulation with 12 mM glucose cells responded with a rapid increase in [Ca2+]i, followed by a sustained plateau of elevated [Ca2+]i with superimposed oscillations (Figure 1B). In different cells these oscillations had practically identical frequencies, but were slightly out of phase (Figure 1C). After the glucose was lowered back to 6 mM, [Ca2+]i rapidly returned to the prestimulatory level. In further analyses, five different regimes will be considered: low glucose prior to stimulation (LG1), activation of beta cells (ON), high glucose regime (HG), deactivation of beta cells (OFF), and the low glucose after stimulation (LG2) (Figure 1B). Video S1 features responses of all cells in the islet.


Functional connectivity in islets of Langerhans from mouse pancreas tissue slices.

Stožer A, Gosak M, Dolenšek J, Perc M, Marhl M, Rupnik MS, Korošak D - PLoS Comput. Biol. (2013)

Methodology used to extract functional connectivity patterns from cytosolic Ca2+ traces.A Image of an islet of Langerhans showing the relative intensity of fluorescence signal during sustained activity (HG). Red circles indicate two cells, i and j, which we regard in continuation. B Temporal evolution of global calcium activity characterized by the mean-field of all beta cells in the islet. In the intervals 0≤t≤150 and 754≤t≤1960 cells were exposed to 6 mM glucose, whereas for 150≤t≤754 a stimulating concentration of glucose (12 mM) was applied. Arrows above the temporal trace denote five different dynamical regimes considered in this study: low glucose prior to stimulation (LG1) – 0≤t<300, activation of beta cells (ON) – 300≤t<420, sustained activity in high glucose (HG) – 600≤t<1000, deactivation of beta cells (OFF) – 1080≤t<1200, and the low glucose after stimulation (LG2) – 1400≤t<1800. Note that the calcium activity pattern has been normalized to the unit interval. C Highlighted dynamical responses of cells i and j during the HG regime. D Correlation diagram for fluorescence signals of the i-th and j-th cell. E The correlation matrix for all pair wise determined Rij. F The corresponding connectivity matrix (thresholded matrix, Rth = 0.75). G Functional connectivity map in the islet for the HG regime. Red circles indicate cells i and j.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3585390&req=5

pcbi-1002923-g001: Methodology used to extract functional connectivity patterns from cytosolic Ca2+ traces.A Image of an islet of Langerhans showing the relative intensity of fluorescence signal during sustained activity (HG). Red circles indicate two cells, i and j, which we regard in continuation. B Temporal evolution of global calcium activity characterized by the mean-field of all beta cells in the islet. In the intervals 0≤t≤150 and 754≤t≤1960 cells were exposed to 6 mM glucose, whereas for 150≤t≤754 a stimulating concentration of glucose (12 mM) was applied. Arrows above the temporal trace denote five different dynamical regimes considered in this study: low glucose prior to stimulation (LG1) – 0≤t<300, activation of beta cells (ON) – 300≤t<420, sustained activity in high glucose (HG) – 600≤t<1000, deactivation of beta cells (OFF) – 1080≤t<1200, and the low glucose after stimulation (LG2) – 1400≤t<1800. Note that the calcium activity pattern has been normalized to the unit interval. C Highlighted dynamical responses of cells i and j during the HG regime. D Correlation diagram for fluorescence signals of the i-th and j-th cell. E The correlation matrix for all pair wise determined Rij. F The corresponding connectivity matrix (thresholded matrix, Rth = 0.75). G Functional connectivity map in the islet for the HG regime. Red circles indicate cells i and j.
Mentions: Beta cells were distinguished from other cells on the basis of previous reports showing that cells within islets of Langerhans can reliably be identified by their type-specific calcium responses to stimulation with high glucose [46]–[48]. In cells identified as beta cells, intracellular concentration of calcium ([Ca2+]i) was low and rather stable under basal (6 mM) glucose. Upon stimulation with 12 mM glucose cells responded with a rapid increase in [Ca2+]i, followed by a sustained plateau of elevated [Ca2+]i with superimposed oscillations (Figure 1B). In different cells these oscillations had practically identical frequencies, but were slightly out of phase (Figure 1C). After the glucose was lowered back to 6 mM, [Ca2+]i rapidly returned to the prestimulatory level. In further analyses, five different regimes will be considered: low glucose prior to stimulation (LG1), activation of beta cells (ON), high glucose regime (HG), deactivation of beta cells (OFF), and the low glucose after stimulation (LG2) (Figure 1B). Video S1 features responses of all cells in the islet.

Bottom Line: Moreover, we find that the range of interactions in networks during activity shows a clear dependence on the Euclidean distance, lending support to previous observations that beta cells are synchronized via calcium waves spreading throughout islets.Most interestingly, the functional connectivity patterns between beta cells exhibit small-world properties, suggesting that beta cells do not form a homogeneous geometric network but are connected in a functionally more efficient way.Presented results provide support for the existing knowledge of beta cell physiology from a network perspective and shed important new light on the functional organization of beta cell syncitia whose structural topology is probably not as trivial as believed so far.

View Article: PubMed Central - PubMed

Affiliation: Institute of Physiology, Faculty of Medicine, University of Maribor, Maribor, Slovenia.

ABSTRACT
We propose a network representation of electrically coupled beta cells in islets of Langerhans. Beta cells are functionally connected on the basis of correlations between calcium dynamics of individual cells, obtained by means of confocal laser-scanning calcium imaging in islets from acute mouse pancreas tissue slices. Obtained functional networks are analyzed in the light of known structural and physiological properties of islets. Focusing on the temporal evolution of the network under stimulation with glucose, we show that the dynamics are more correlated under stimulation than under non-stimulated conditions and that the highest overall correlation, largely independent of Euclidean distances between cells, is observed in the activation and deactivation phases when cells are driven by the external stimulus. Moreover, we find that the range of interactions in networks during activity shows a clear dependence on the Euclidean distance, lending support to previous observations that beta cells are synchronized via calcium waves spreading throughout islets. Most interestingly, the functional connectivity patterns between beta cells exhibit small-world properties, suggesting that beta cells do not form a homogeneous geometric network but are connected in a functionally more efficient way. Presented results provide support for the existing knowledge of beta cell physiology from a network perspective and shed important new light on the functional organization of beta cell syncitia whose structural topology is probably not as trivial as believed so far.

Show MeSH
Related in: MedlinePlus