Functional Connectivity in Islets of Langerhans from Mouse Pancreas Tissue Slices

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.

[1]  C. J. Stam,et al.  Functional connectivity patterns of human magnetoencephalographic recordings: a ‘small-world’ network? , 2004, Neuroscience Letters.

[2]  B. Soria,et al.  Glucoseminduced [Ca2+]i oscillations in single human pancreatic islets , 1996 .

[3]  L Orci,et al.  Rapid and reversible secretion changes during uncoupling of rat insulin-producing cells. , 1990, The Journal of clinical investigation.

[4]  A. Barabasi,et al.  The human disease network , 2007, Proceedings of the National Academy of Sciences.

[5]  H. Berendse,et al.  The application of graph theoretical analysis to complex networks in the brain , 2007, Clinical Neurophysiology.

[6]  Junghyo Jo,et al.  Islet architecture: A comparative study , 2009, Islets.

[7]  M. Ravier,et al.  Disorganization of cytoplasmic Ca2+ oscillations and pulsatile insulin secretion in islets from ob/ob mice , 2002, Diabetologia.

[8]  S. Oliver,et al.  Chance and necessity in the evolution of minimal metabolic networks , 2006, Nature.

[9]  Patrice Mollard,et al.  Coordination of calcium signals by pituitary endocrine cells in situ. , 2012, Cell calcium.

[10]  D. Hodson,et al.  Investigating and Modelling Pituitary Endocrine Network Function , 2010, Journal of neuroendocrinology.

[11]  A. Barabasi,et al.  Lethality and centrality in protein networks , 2001, Nature.

[12]  Duncan J. Watts,et al.  Collective dynamics of ‘small-world’ networks , 1998, Nature.

[13]  Helen Christian,et al.  Existence of long-lasting experience-dependent plasticity in endocrine cell networks , 2012, Nature Communications.

[14]  A. Barabasi,et al.  Network biology: understanding the cell's functional organization , 2004, Nature Reviews Genetics.

[15]  U. Bhalla,et al.  Complexity in biological signaling systems. , 1999, Science.

[16]  L Orci,et al.  Cell contacts in human islets of Langerhans. , 1975, The Journal of clinical endocrinology and metabolism.

[17]  Paolo Meda,et al.  Cx36-Mediated Coupling Reduces β-Cell Heterogeneity, Confines the Stimulating Glucose Concentration Range, and Affects Insulin Release Kinetics , 2007, Diabetes.

[18]  T. Prescott,et al.  The brainstem reticular formation is a small-world, not scale-free, network , 2006, Proceedings of the Royal Society B: Biological Sciences.

[19]  Cornelis J Stam,et al.  Graph theoretical analysis of complex networks in the brain , 2007, Nonlinear biomedical physics.

[20]  H E Stanley,et al.  Classes of small-world networks. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[21]  A. Barabasi,et al.  The network takeover , 2011, Nature Physics.

[22]  Morten Gram Pedersen,et al.  Homogenization of Heterogeneously Coupled Bistable ODE's—Applied to Excitation Waves in Pancreatic Islets of Langerhans , 2004, Journal of biological physics.

[23]  E. Kinney Primer of Biostatistics , 1987 .

[24]  R. Albert,et al.  The large-scale organization of metabolic networks , 2000, Nature.

[25]  E. Rojas,et al.  Magnitude and modulation of pancreatic β-cell gap junction electrical conductance in situ , 1995, The Journal of Membrane Biology.

[26]  K. Sneppen,et al.  Specificity and Stability in Topology of Protein Networks , 2002, Science.

[27]  C. Stam,et al.  The organization of physiological brain networks , 2012, Clinical Neurophysiology.

[28]  Daniel Eberhard,et al.  ‘Giving and taking’: endothelial and β-cells in the islets of Langerhans , 2010, Trends in Endocrinology & Metabolism.

[29]  J. Rinzel,et al.  Model for synchronization of pancreatic beta-cells by gap junction coupling. , 1991, Biophysical journal.

[30]  M. Newman Communities, modules and large-scale structure in networks , 2011, Nature Physics.

[31]  Changsong Zhou,et al.  Hierarchical organization unveiled by functional connectivity in complex brain networks. , 2006, Physical review letters.

[32]  L F Lago-Fernández,et al.  Fast response and temporal coherent oscillations in small-world networks. , 1999, Physical review letters.

[33]  Paloma Alonso-Magdalena,et al.  Glucose Induces Opposite Intracellular Ca2+ Concentration Oscillatory Patterns in Identified α- and β-Cells Within Intact Human Islets of Langerhans , 2006, Diabetes.

[34]  B. Soria,et al.  Different effects of tolbutamide and diazoxide in alpha, beta-, and delta-cells within intact islets of Langerhans. , 1999, Diabetes.

[35]  Morten Gram Pedersen,et al.  Wave-Block Due to a Threshold Gradient Underlies Limited Coordination in Pancreatic Islets , 2008, Journal of biological physics.

[36]  A. Moreno,et al.  Biophysical evidence that connexin-36 forms functional gap junction channels between pancreatic mouse beta-cells. , 2005, American journal of physiology. Endocrinology and metabolism.

[37]  D C Spray,et al.  Biophysical properties of gap junctions between freshly dispersed pairs of mouse pancreatic beta cells. , 1991, Biophysical journal.

[38]  Santo Fortunato,et al.  Community detection in graphs , 2009, ArXiv.

[39]  G. Cecchi,et al.  Scale-free brain functional networks. , 2003, Physical review letters.

[40]  Edouard Machery,et al.  The Heterogeneity Hypothesis , 2009 .

[41]  J. Henquin,et al.  The dual control of insulin secretion by glucose involves triggering and amplifying pathways in β-cells. , 2011, Diabetes research and clinical practice.

[42]  B. Soria,et al.  Oscillation of gap junction electrical coupling in the mouse pancreatic islets of Langerhans. , 1997, The Journal of physiology.

[43]  Mark E. J. Newman,et al.  Structure and Dynamics of Networks , 2009 .

[44]  Albert,et al.  Emergence of scaling in random networks , 1999, Science.

[45]  R. Bertram,et al.  Metabolic and electrical oscillations: partners in controlling pulsatile insulin secretion. , 2007, American journal of physiology. Endocrinology and metabolism.

[46]  Patrice Mollard,et al.  Endocrine cells and blood vessels work in tandem to generate hormone pulses. , 2011, Journal of molecular endocrinology.

[47]  J. Urry Complexity , 2006, Interpreting Art.

[48]  Lena Eliasson,et al.  Cell coupling in mouse pancreatic β-cells measured in intact islets of Langerhans , 2008, Philosophical Transactions of the Royal Society A: Mathematical, Physical and Engineering Sciences.

[49]  S. Havlin,et al.  Dimension of spatially embedded networks , 2011 .

[50]  F. Sommer,et al.  Global Relationship between Anatomical Connectivity and Activity Propagation in the Cerebral Cortex , 2022 .

[51]  O. Sporns,et al.  Complex brain networks: graph theoretical analysis of structural and functional systems , 2009, Nature Reviews Neuroscience.

[52]  H. Agrawal Extreme self-organization in networks constructed from gene expression data. , 2002, Physical review letters.

[53]  M. Ravier,et al.  Disorganization of cytoplasmic Ca(2+) oscillations and pulsatile insulin secretion in islets from ob/ obmice. , 2002, Diabetologia.

[54]  R Nano,et al.  Mechanisms of coordination of Ca2+ signals in pancreatic islet cells. , 1999, Diabetes.

[55]  L. Rosário,et al.  Glucose‐induced oscillations of intracellular Ca2+ concentration resembling bursting electrical activity in single mouse islets of Langerhans , 1989, FEBS letters.

[56]  P. Gilon,et al.  Influence of membrane potential changes on cytoplasmic Ca2+ concentration in an electrically excitable cell, the insulin-secreting pancreatic B-cell. , 1992, The Journal of biological chemistry.

[57]  A. Tengholm,et al.  Origin of slow and fast oscillations of Ca2+ in mouse pancreatic islets , 1998, The Journal of physiology.

[58]  M. DePamphilis,et al.  HUMAN DISEASE , 1957, The Ulster Medical Journal.

[59]  Marjan Rupnik,et al.  A novel approach to in situ characterization of pancreatic β-cells , 2003, Pflügers Archiv.

[60]  Angel Nadal,et al.  Homologous and heterologous asynchronicity between identified α‐, β‐ and δ‐cells within intact islets of Langerhans in the mouse , 1999 .

[61]  Min Zhang,et al.  Gap junction coupling and calcium waves in the pancreatic islet. , 2008, Biophysical journal.

[62]  M. Young,et al.  Computational analysis of functional connectivity between areas of primate cerebral cortex. , 2000, Philosophical transactions of the Royal Society of London. Series B, Biological sciences.

[63]  Camillo Ricordi,et al.  The unique cytoarchitecture of human pancreatic islets has implications for islet cell function , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[64]  J Rinzel,et al.  Why pancreatic islets burst but single beta cells do not. The heterogeneity hypothesis. , 1993, Biophysical journal.

[65]  Dinggang Shen,et al.  Development Trends of White Matter Connectivity in the First Years of Life , 2011, PloS one.

[66]  Olaf Sporns,et al.  Complex network measures of brain connectivity: Uses and interpretations , 2010, NeuroImage.

[67]  Gipsi Lima-Mendez,et al.  The powerful law of the power law and other myths in network biology. , 2009, Molecular bioSystems.

[68]  G. Nikolova,et al.  The vascular niche and its basement membrane. , 2007, Trends in cell biology.

[69]  H P Meissner,et al.  Electrophysiological evidence for coupling between beta cells of pancreatic islets. , 1976, Nature.

[70]  Angel Nadal,et al.  Widespread synchronous [Ca2+]i oscillations due to bursting electrical activity in single pancreatic islets , 1991, Pflügers Archiv.

[71]  T. Iwanaga,et al.  Identification of alpha- and beta-cells in intact isolated islets of Langerhans by their characteristic cytoplasmic Ca2+ concentration dynamics and immunocytochemical staining. , 1998, Diabetes.

[72]  L Orci,et al.  Nonrandom distribution of gap junctions between pancreatic beta-cells. , 1980, The American journal of physiology.

[73]  J. Rapoport,et al.  Simple models of human brain functional networks , 2012, Proceedings of the National Academy of Sciences.

[74]  A. Scott,et al.  Excitation wave propagation as a possible mechanism for signal transmission in pancreatic islets of Langerhans. , 2001, Biophysical journal.

[75]  Shilpa Chakravartula,et al.  Complex Networks: Structure and Dynamics , 2014 .

[76]  Péter Csermely,et al.  The efficiency of multi-target drugs: the network approach might help drug design. , 2004, Trends in pharmacological sciences.

[77]  U. Bhalla,et al.  Emergent properties of networks of biological signaling pathways. , 1999, Science.

[78]  M. Valdeolmillos,et al.  In vivo synchronous membrane potential oscillations in mouse pancreatic beta‐cells: lack of co‐ordination between islets. , 1996, The Journal of physiology.

[79]  Marjan Rupnik,et al.  All together now: Exocytose or fail , 2009, Islets.

[80]  Soumitra Ghosh,et al.  Investigating the Role of Islet Cytoarchitecture in Its Oscillation Using a New β-Cell Cluster Model , 2007, PloS one.

[81]  Arturo Hernández-Cruz,et al.  GnRH-Induced [Ca2+]i-Signalling Patterns in Mouse Gonadotrophs Recorded from Acute Pituitary Slices in vitro , 2010, Neuroendocrinology.

[82]  Paolo Meda,et al.  Loss of connexin36 channels alters beta-cell coupling, islet synchronization of glucose-induced Ca2+ and insulin oscillations, and basal insulin release. , 2005, Diabetes.

[83]  S. Strogatz Exploring complex networks , 2001, Nature.