Heterogeneity of the Pancreatic Beta Cell

The pancreatic beta cell functions as a key regulator of blood glucose levels by integrating a variety of signals in response to changing metabolic demands. Variations in beta cell identity that translate into functionally different subpopulations represent an interesting mechanism to allow beta cells to efficiently respond to diverse physiological and pathophysiological conditions. Recently, there is emerging evidence that morphological and functional differences between beta cells exist. Furthermore, the ability of novel single cell technologies to characterize the molecular identity of individual beta cells has created a new era in the beta cell field. These studies are providing important novel information about the origin of beta cell heterogeneity, the type and proportions of the different beta cell subpopulations, as well as their intrinsic properties. Furthermore, characterization of different beta cell subpopulations that could variably offer protection from or drive progression of diabetes has important clinical implications in diabetes prevention, beta cell regeneration and stem cell treatments. In this review, we will assess the evidence that supports the existence of heterogeneous populations of beta cells and the factors that could influence their formation. We will also address novel studies using islet single cell analysis that have provided important information toward understanding beta cell heterogeneity and discuss the caveats that may be associated with these new technologies.

[1]  Mauro J. Muraro,et al.  A Single-Cell Transcriptome Atlas of the Human Pancreas , 2016, Cell systems.

[2]  S. Leibler,et al.  Bacterial Persistence as a Phenotypic Switch , 2004, Science.

[3]  K. Kovács,et al.  Functional heterogeneity of the responses of histaminergic neuron subpopulations to various stress challenges , 2003, The European journal of neuroscience.

[4]  Samuel L. Wolock,et al.  A Single-Cell Transcriptomic Map of the Human and Mouse Pancreas Reveals Inter- and Intra-cell Population Structure. , 2016, Cell systems.

[5]  O. Soehnlein,et al.  Neutrophil heterogeneity: implications for homeostasis and pathogenesis. , 2016, Blood.

[6]  L Orci,et al.  Metabolic coupling between cultured pancreatic b-cells. , 1981, Experimental cell research.

[7]  K. Kaestner,et al.  Nkx6.1 Controls a Gene Regulatory Network Required for Establishing and Maintaining Pancreatic Beta Cell Identity , 2013, PLoS genetics.

[8]  J. Elmquist,et al.  PANIC-ATTAC: A Mouse Model for Inducible and Reversible β-Cell Ablation , 2008, Diabetes.

[9]  A. Clark,et al.  Alpha-, Delta- and PP-cells , 2015, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[10]  P. Halban,et al.  Functional differences between rat islets of ventral and dorsal pancreatic origin. , 1982, The Journal of clinical investigation.

[11]  S. Arber,et al.  Selective agenesis of the dorsal pancreas in mice lacking homeobox gene Hlxb9 , 1999, Nature Genetics.

[12]  D. van der Kooy,et al.  The adult mouse and human pancreas contain rare multipotent stem cells that express insulin. , 2011, Cell stem cell.

[13]  P. Meda,et al.  B-cell size influences glucose-stimulated insulin secretion. , 1993, The American journal of physiology.

[14]  T. Berney,et al.  Insulin secretion from human beta cells is heterogeneous and dependent on cell-to-cell contacts , 2008, Diabetologia.

[15]  Enric Llorens-Bobadilla,et al.  Single-Cell Transcriptomics Reveals a Population of Dormant Neural Stem Cells that Become Activated upon Brain Injury. , 2015, Cell stem cell.

[16]  D. Pipeleers,et al.  Pancreatic beta cell heterogeneity in glucose-induced insulin secretion. , 1992, The Journal of biological chemistry.

[17]  B. Petersson,et al.  Some properties of the B cells in the islet of Langerhans studied with regard to the position of the cells. , 1960, Acta endocrinologica.

[18]  J. Henquin,et al.  Measurements of cytoplasmic Ca2+ in islet cell clusters show that glucose rapidly recruits beta-cells and gradually increases the individual cell response. , 2001, Diabetes.

[19]  O. Chepurny,et al.  pancreatic b-cells , 2001 .

[20]  P. Halban,et al.  Differential expression of E-cadherin at the surface of rat beta-cells as a marker of functional heterogeneity. , 2007, The Journal of endocrinology.

[21]  A. Murphy,et al.  Single-Cell RNAseq Reveals That Pancreatic β-Cells From Very Old Male Mice Have a Young Gene Signature. , 2016, Endocrinology.

[22]  I. Nasir,et al.  Regeneration of pancreatic beta cells from intra-islet precursor cells in an experimental model of diabetes. , 2001, Endocrinology.

[23]  M. Hermann,et al.  Dickkopf-3 is expressed in a subset of adult human pancreatic beta cells , 2007, Histochemistry and Cell Biology.

[24]  E. Flores,et al.  Compartmentalized function through cell differentiation in filamentous cyanobacteria , 2010, Nature Reviews Microbiology.

[25]  J. Sweedler,et al.  Single Cell Peptide Heterogeneity of Rat Islets of Langerhans. , 2016, ACS chemical biology.

[26]  Camillo Ricordi,et al.  Innervation patterns of autonomic axons in the human endocrine pancreas. , 2011, Cell metabolism.

[27]  A. Renold,et al.  Ventral and dorsal areas of rat pancreas: islet hormone content and secretion. , 1981, The American journal of physiology.

[28]  Qidi Wang,et al.  Glibenclamide treatment recruits beta-cell subpopulation into elevated and sustained basal insulin synthetic activity. , 2006, Diabetes.

[29]  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.

[30]  M. Magnuson,et al.  Heterogeneous expression of glucokinase among pancreatic beta cells. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[31]  Dirk Trauner,et al.  Beta Cell Hubs Dictate Pancreatic Islet Responses to Glucose , 2016, Cell metabolism.

[32]  R. Evans,et al.  ERRγ Is Required for the Metabolic Maturation of Therapeutically Functional Glucose-Responsive β Cells. , 2016, Cell metabolism.

[33]  B. Strutt,et al.  Insulin-positive, Glut2-low cells present within mouse pancreas exhibit lineage plasticity and are enriched within extra-islet endocrine cell clusters , 2016, Islets.

[34]  K. Willecke,et al.  In vivo modulation of connexin 43 gene expression and junctional coupling of pancreatic B-cells. , 1991, Experimental cell research.

[35]  L. Orci,et al.  In Vivo Modulation of Gap Junctions and Dye Coupling Between B-Cells of the Intact Pancreatic Islet , 1983, Diabetes.

[36]  F. Brunicardi,et al.  Islet Vasculature as a Regulator of Endocrine Pancreas Function , 2007, World Journal of Surgery.

[37]  S. Pfaff,et al.  Pancreas dorsal lobe agenesis and abnormal islets of Langerhans in Hlxb9-deficient mice , 1999, Nature Genetics.

[38]  H. Vrolijk,et al.  Topologically Heterogeneous Beta Cell Adaptation in Response to High-Fat Diet in Mice , 2013, PloS one.

[39]  L. Orci,et al.  Quantitation of Endocrine Cell Content in the Pancreas of Nondiabetic and Diabetic Humans , 1982, Diabetes.

[40]  S. Lenzen,et al.  Nutrient-dependent distribution of insulin and glucokinase immunoreactivities in rat pancreatic beta cells , 1999, Virchows Archiv.

[41]  J. Habener,et al.  Pancreatic beta-cells are rendered glucose-competent by the insulinotropic hormone glucagon-like peptide-1(7-37) , 1993, Nature.

[42]  M. Hara,et al.  Quantitative Analysis of Pancreatic Polypeptide Cell Distribution in the Human Pancreas , 2013, PloS one.

[43]  S. Bonner-Weir,et al.  Subpopulations of GFP-marked mouse pancreatic β-cells differ in size, granularity, and insulin secretion. , 2012, Endocrinology.

[44]  I. Artner,et al.  MafB is required for islet β cell maturation , 2007, Proceedings of the National Academy of Sciences.

[45]  D. Pipeleers,et al.  The biosociology of pancreatic B cells , 1987, Diabetologia.

[46]  D Pipeleers,et al.  Glucose-induced insulin release depends on functional cooperation between islet cells. , 1982, Proceedings of the National Academy of Sciences of the United States of America.

[47]  Hsin C. Lin,et al.  Use of the Fluidigm C1 platform for RNA sequencing of single mouse pancreatic islet cells , 2016, Proceedings of the National Academy of Sciences.

[48]  Frans,et al.  Differences in glucose recognition by individual rat pancreatic B cells are associated with intercellular differences in glucose-induced biosynthetic activity. , 1992, The Journal of clinical investigation.

[49]  A. Herchuelz,et al.  Heterogeneous changes in [Ca2+]i induced by glucose, tolbutamide and K+ in single rat pancreatic B cells. , 1991, Cell calcium.

[50]  Olle Korsgren,et al.  Identification of proliferative and mature β-cells in the islets of Langerhans , 2016, Nature.

[51]  L. Orci,et al.  Stimulation of insulin secretion reveals heterogeneity of pancreatic B cells in vivo. , 1987, The Journal of clinical investigation.

[52]  Richard K. P. Benninger,et al.  Cellular communication and heterogeneity in pancreatic islet insulin secretion dynamics , 2014, Trends in Endocrinology & Metabolism.

[53]  S. Ku,et al.  An immunohistochemical study of the pancreatic endocrine cells of the ddN mouse. , 2010, Folia histochemica et cytobiologica.

[54]  S. Luquet,et al.  Exploring Functional β-Cell Heterogeneity In Vivo Using PSA-NCAM as a Specific Marker , 2009, PloS one.

[55]  Dave T. Gerrard,et al.  Human pancreas development , 2015, Development.

[56]  D. M. Smith,et al.  Single-Cell Transcriptome Profiling of Human Pancreatic Islets in Health and Type 2 Diabetes , 2016, Cell metabolism.

[57]  P. Rorsman,et al.  Glucagon-like peptide I increases cytoplasmic calcium in insulin-secreting beta TC3-cells by enhancement of intracellular calcium mobilization. , 1995, Diabetes.

[58]  P. Meda,et al.  Ion channels of glucose-responsive and -unresponsive beta-cells. , 1991, Diabetes.

[59]  A. Bennett The Origin of Species by means of Natural Selection; or the Preservation of Favoured Races in the Struggle for Life , 1872, Nature.

[60]  L M Wahl,et al.  Evolving the division of labour: generalists, specialists and task allocation. , 2002, Journal of theoretical biology.

[61]  James D. Johnson,et al.  Insulin protects islets from apoptosis via Pdx1 and specific changes in the human islet proteome , 2006, Proceedings of the National Academy of Sciences.

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

[63]  J. Schug,et al.  Single-Cell Mass Cytometry Analysis of the Human Endocrine Pancreas. , 2016, Cell metabolism.

[64]  Jonathan Schug,et al.  Human islets contain four distinct subtypes of β cells , 2016, Nature Communications.

[65]  P. Meda,et al.  Repeated glucose stimulation reveals distinct and lasting secretion patterns of individual rat pancreatic B cells. , 1991, The Journal of clinical investigation.

[66]  D. Pipeleers,et al.  Intercellular differences in interleukin 1beta-induced suppression of insulin synthesis and stimulation of noninsulin protein synthesis by rat pancreatic beta-cells. , 1998, Endocrinology.

[67]  Edward R Sumner,et al.  Phenotypic heterogeneity can enhance rare‐cell survival in ‘stress‐sensitive’ yeast populations , 2007, Molecular microbiology.

[68]  E. Schaftingen,et al.  Heterogeneity in glucose sensitivity among pancreatic beta‐cells is correlated to differences in glucose phosphorylation rather than glucose transport. , 1993, The EMBO journal.

[69]  P. Liberali,et al.  Population context determines cell-to-cell variability in endocytosis and virus infection , 2009, Nature.

[70]  L. Orci,et al.  THE TOPOGRAPHY OF ELECTRICAL SYNCHRONY AMONG β‐CELLS IN THE MOUSE ISLET OF LANGERHANS , 1984 .

[71]  C. Donaldson,et al.  Urocortin3 mediates somatostatin-dependent negative feedback control of insulin secretion , 2015, Nature Medicine.

[72]  R.,et al.  Ion Channels , 1996, Ion Channels.

[73]  I. Nasir,et al.  Regeneration of Pancreatic β Cells from Intra-Islet Precursor Cells in an Experimental Model of Diabetes. , 2001, Endocrinology.

[74]  James D. Johnson,et al.  Reversal of diabetes with insulin-producing cells derived in vitro from human pluripotent stem cells , 2014, Nature Biotechnology.

[75]  M. Zabel,et al.  Polyhormonal aspect of the endocrine cells of the human fetal pancreas , 1999, Histochemistry and Cell Biology.

[76]  Christoph Bock,et al.  Single‐cell transcriptomes reveal characteristic features of human pancreatic islet cell types , 2015, EMBO reports.

[77]  James D. Johnson,et al.  Maturation of adult beta-cells revealed using a Pdx1/insulin dual-reporter lentivirus. , 2009, Endocrinology.

[78]  P. Dean,et al.  Electrical Activity in Pancreatic Islet Cells , 1968, Nature.

[79]  D. Melton,et al.  Generation of Functional Human Pancreatic β Cells In Vitro , 2014, Cell.

[80]  J. Rahier,et al.  The pancreatic polypeptide cells in the human pancreas: the effects of age and diabetes. , 1983, The Journal of clinical endocrinology and metabolism.

[81]  S. Bonner-Weir Morphological Evidence for Pancreatic Polarity of β-Cell Within Islets of Langerhans , 1988, Diabetes.

[82]  R. Rizza,et al.  Relationship between pancreatic vesicular monoamine transporter 2 (VMAT2) and insulin expression in human pancreas , 2008, Journal of Molecular Histology.

[83]  S. Efendić,et al.  Studies on the inhibitory effect of somatostatin on glucose induced insulin release in the isolated perfused rat pancreas. , 1975, Acta endocrinologica.