Paracrine regulation of glucagon secretion: the β/α/δ model.

The regulation of glucagon secretion in the pancreatic α-cell is not well understood. It has been proposed that glucose suppresses glucagon secretion either directly through an intrinsic mechanism within the α-cell or indirectly through an extrinsic mechanism. Previously, we described a mathematical model for isolated pancreatic α-cells and used it to investigate possible intrinsic mechanisms of regulating glucagon secretion. We demonstrated that glucose can suppress glucagon secretion through both ATP-dependent potassium channels (KATP) and a store-operated current (SOC). We have now developed an islet model that combines previously published mathematical models of α- and β-cells with a new model of δ-cells and use it to explore the effects of insulin and somatostatin on glucagon secretion. We show that the model can reproduce experimental observations that the inhibitory effect of glucose remains even when paracrine modulators are no longer acting on the α-cell. We demonstrate how paracrine interactions can either synchronize α- and δ-cells to produce pulsatile oscillations in glucagon and somatostatin secretion or fail to do so. The model can also account for the paradoxical observation that glucagon can be out of phase with insulin, whereas α-cell calcium is in phase with insulin. We conclude that both paracrine interactions and the α-cell's intrinsic mechanisms are needed to explain the response of glucagon secretion to glucose.

[1]  M. Rupnik,et al.  Unperturbed islet α‐cell function examined in mouse pancreas tissue slices , 2011, The Journal of physiology.

[2]  David W. Piston,et al.  Glucose Suppression of Glucagon Secretion , 2010, The Journal of Biological Chemistry.

[3]  A. Salehi,et al.  Glucose induces glucagon release pulses antisynchronous with insulin and sensitive to purinoceptor inhibition. , 2006, Endocrinology.

[4]  P. Rorsman,et al.  Somatostatin inhibits exocytosis in rat pancreatic α‐cells by Gi2‐dependent activation of calcineurin and depriming of secretory granules , 2001, The Journal of physiology.

[5]  Y. Horio,et al.  Somatostatin induces hyperpolarization in pancreatic islet α cells by activating a G protein‐gated K+ channel , 1999, FEBS letters.

[6]  F. Ashcroft,et al.  R-type Ca2+-channel-evoked CICR regulates glucose-induced somatostatin secretion , 2007, Nature Cell Biology.

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

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

[9]  E. Carneiro,et al.  Glucose induces opposite intracellular Ca2+ concentration oscillatory patterns in identified alpha- and beta-cells within intact human islets of Langerhans. , 2006, Diabetes.

[10]  P. Rorsman,et al.  Regulation of glucagon secretion by glucose: paracrine, intrinsic or both? , 2011, Diabetes, obesity & metabolism.

[11]  P. Rorsman,et al.  Glucose-inhibition of glucagon secretion involves activation of GABAA-receptor chloride channels , 1989, Nature.

[12]  V. Marks,et al.  PROMOTION OF INSULIN SECRETION BY GLUCAGON. , 1965, Lancet.

[13]  S. Theander,et al.  β-Cell Secretory Products Activate α-Cell ATP-Dependent Potassium Channels to Inhibit Glucagon Release , 2005 .

[14]  M. J. MacDonald,et al.  Perspective: emerging evidence for signaling roles of mitochondrial anaplerotic products in insulin secretion. , 2005, American journal of physiology. Endocrinology and metabolism.

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

[16]  J. Schaeffer,et al.  Somatostatin inhibits insulin and glucagon secretion via two receptors subtypes: an in vitro study of pancreatic islets from somatostatin receptor 2 knockout mice. , 2000, Endocrinology.

[17]  C. Wollheim,et al.  Islet β-cell secretion determines glucagon release from neighbouring α-cells , 2003, Nature Cell Biology.

[18]  F. Montefusco,et al.  Mathematical modelling of local calcium and regulated exocytosis during inhibition and stimulation of glucagon secretion from pancreatic alpha‐cells , 2015, The Journal of physiology.

[19]  C. J. Goodner,et al.  Insulin, glucagon, and glucose exhibit synchronous, sustained oscillations in fasting monkeys. , 1977, Science.

[20]  S. Efendić,et al.  Studies on the mechanism of somatostatin action on insulin release in man. I. Effect of blockade of alpha-adrenergic receptors. , 1975, Acta endocrinologica.

[21]  Arthur Sherman,et al.  Identifying the targets of the amplifying pathway for insulin secretion in pancreatic beta-cells by kinetic modeling of granule exocytosis. , 2008, Biophysical journal.

[22]  A. Salehi,et al.  Pulses of somatostatin release are slightly delayed compared with insulin and antisynchronous to glucagon , 2007, Regulatory Peptides.

[23]  P. Rorsman,et al.  γ-Aminobutyric Acid (GABA) Is an Autocrine Excitatory Transmitter in Human Pancreatic β-Cells , 2010, Diabetes.

[24]  A. Tengholm,et al.  Neurotransmitter control of islet hormone pulsatility , 2014, Diabetes, obesity & metabolism.

[25]  G. Grodsky,et al.  Inhibition by somatostatin of glucagon and insulin release from the perfused rat pancreas in response to arginine, isoproterenol and theophylline: evidence for a preferential effect on glucagon secretion. , 1975, Endocrinology.

[26]  J. Walsh,et al.  Immunoneutralization of Somatostatin, Insulin, and Glucagon Causes Alterations in Islet Cell Secretion in the Isolated Perfused Human Pancreas , 2001, Pancreas.

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

[28]  A. Salehi,et al.  Glucose generates coincident insulin and somatostatin pulses and antisynchronous glucagon pulses from human pancreatic islets. , 2009, Endocrinology.

[29]  P. Berggren,et al.  Control of Insulin Secretion by Cholinergic Signaling in the Human Pancreatic Islet , 2014, Diabetes.

[30]  A. McCall,et al.  Pancreatic network control of glucagon secretion and counterregulation. , 2009, Methods in enzymology.

[31]  M. Vranic,et al.  Somatostatin Receptor Type 2 Antagonism Improves Glucagon Counterregulation in Biobreeding Diabetic Rats , 2013, Diabetes.

[32]  Amicia D Elliott,et al.  Somatostatin and insulin mediate glucose-inhibited glucagon secretion in the pancreatic α-cell by lowering cAMP. , 2015, American journal of physiology. Endocrinology and metabolism.

[33]  J. Gromada,et al.  α-Cells of the Endocrine Pancreas: 35 Years of Research but the Enigma Remains. , 2007, Endocrine reviews.

[34]  F. Ashcroft,et al.  Role of KATP Channels in Glucose-Regulated Glucagon Secretion and Impaired Counterregulation in Type 2 Diabetes , 2013, Cell metabolism.

[35]  Maciej J. Swat,et al.  The impact of mathematical modeling on the understanding of diabetes and related complications , 2013, CPT: pharmacometrics & systems pharmacology.

[36]  L. Eliasson,et al.  A KATP Channel-Dependent Pathway within α Cells Regulates Glucagon Release from Both Rodent and Human Islets of Langerhans , 2007, PLoS biology.

[37]  B. Soria,et al.  Homologous and heterologous asynchronicity between identified alpha-, beta- and delta-cells within intact islets of Langerhans in the mouse. , 1999, The Journal of physiology.

[38]  P. MacDonald,et al.  Corelease and Differential Exit via the Fusion Pore of GABA, Serotonin, and ATP from LDCV in Rat Pancreatic β Cells , 2007, The Journal of general physiology.

[39]  Junghyo Jo,et al.  Stable and flexible system for glucose homeostasis. , 2013, Physical review. E, Statistical, nonlinear, and soft matter physics.

[40]  A. McCall,et al.  Amplification of pulsatile glucagon counterregulation by switch-off of alpha-cell-suppressing signals in streptozotocin-treated rats. , 2008, American journal of physiology. Endocrinology and metabolism.

[41]  P. MacDonald,et al.  SSTR2 is the functionally dominant somatostatin receptor in human pancreatic β- and α-cells. , 2012, American Journal of Physiology. Endocrinology and Metabolism.

[42]  K. Rother,et al.  Too Much Glucagon, Too Little Insulin , 2008, Diabetes Care.

[43]  A. Sherman,et al.  Modeling the pancreatic α-cell: dual mechanisms of glucose suppression of glucagon secretion. , 2014, Biophysical journal.

[44]  E. Samols,et al.  Intra-islet regulation. , 1988, The American journal of medicine.

[45]  D. Piston,et al.  Glucose Decouples Intracellular Ca2+ Activity from Glucagon Secretion in Mouse Pancreatic Islet Alpha-Cells , 2012, PloS one.

[46]  D. Piston,et al.  Connexin-36 Gap Junctions Regulate In Vivo First- and Second-Phase Insulin Secretion Dynamics and Glucose Tolerance in the Conscious Mouse , 2012, Diabetes.

[47]  D. Pipeleers,et al.  Regulation of adenosine 3',5'-monophosphate levels in the pancreatic B cell. , 1985, Endocrinology.

[48]  A. Berts,et al.  Ca2+ oscillations in pancreatic islet cells secreting glucagon and somatostatin. , 1995, Biochemical and biophysical research communications.

[49]  Bard Ermentrout,et al.  Simulating, analyzing, and animating dynamical systems - a guide to XPPAUT for researchers and students , 2002, Software, environments, tools.

[50]  J. Holst,et al.  Loss of Inverse Relationship Between Pulsatile Insulin and Glucagon Secretion in Patients With Type 2 Diabetes , 2011, Diabetes.

[51]  P. Rorsman,et al.  Gi2 proteins couple somatostatin receptors to low-conductance K+ channels in rat pancreatic α-cells , 2001, Pflügers Archiv.

[52]  Xiaosong Ma,et al.  ATP-Sensitive K+ Channel–Dependent Regulation of Glucagon Release and Electrical Activity by Glucose in Wild-Type and SUR1−/− Mouse α-Cells , 2004 .

[53]  C. Ricordi,et al.  Alpha cells secrete acetylcholine as a non-neuronal paracrine signal priming human beta cell function , 2011, Nature Medicine.

[54]  P. Rorsman,et al.  Patch‐clamp characterisation of somatostatin‐secreting δ‐cells in intact mouse pancreatic islets , 2000, The Journal of physiology.

[55]  C. C. Richardson,et al.  Somatostatin Secreted by Islet δ-Cells Fulfills Multiple Roles as a Paracrine Regulator of Islet Function , 2009, Diabetes.

[56]  P. Rorsman,et al.  Somatostatin release, electrical activity, membrane currents and exocytosis in human pancreatic delta cells , 2009, Diabetologia.

[57]  N. Diamant,et al.  Insulin regulates islet alpha-cell function by reducing KATP channel sensitivity to adenosine 5'-triphosphate inhibition. , 2006, Endocrinology.

[58]  P. Rorsman,et al.  Glucose inhibition of glucagon secretion from rat alpha-cells is mediated by GABA released from neighboring beta-cells. , 2004, Diabetes.

[59]  C. Wollheim,et al.  GABA in the Endocrine Pancreas , 2004, The Journal of general physiology.

[60]  D. Jacobson,et al.  TASK-1 Potassium Channels Limit Pancreatic α-Cell Calcium Influx and Glucagon Secretion. , 2015, Molecular endocrinology.

[61]  L. Velloso,et al.  Delta cell death in the islet of Langerhans and the progression from normal glucose tolerance to type 2 diabetes in non-human primates (baboon, Papio hamadryas) , 2015, Diabetologia.

[62]  A. Salehi,et al.  Glucose inhibits glucagon secretion by a direct effect on mouse pancreatic alpha cells , 2007, Diabetologia.

[63]  A. Salehi,et al.  Isolated mouse islets respond to glucose with an initial peak of glucagon release followed by pulses of insulin and somatostatin in antisynchrony with glucagon. , 2012, Biochemical and biophysical research communications.

[64]  M. Ravier,et al.  Tolbutamide Controls Glucagon Release From Mouse Islets Differently Than Glucose , 2013, Diabetes.

[65]  Frank Reimann,et al.  Submembrane ATP and Ca2+ kinetics in α-cells: unexpected signaling for glucagon secretion , 2015, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[66]  Leslie S Satin,et al.  Pulsatile insulin secretion, impaired glucose tolerance and type 2 diabetes. , 2015, Molecular aspects of medicine.

[67]  L. Orci,et al.  The role of glucagon in the endogenous hyperglycemia of diabetes mellitus. , 1977, Annual review of medicine.

[68]  L. Orci,et al.  Insulin within islets is a physiologic glucagon release inhibitor. , 1984, The Journal of clinical investigation.

[69]  Min Zhang,et al.  Calcium and glycolysis mediate multiple bursting modes in pancreatic islets. , 2004, Biophysical journal.

[70]  Arthur Sherman,et al.  Newcomer insulin secretory granules as a highly calcium-sensitive pool , 2009, Proceedings of the National Academy of Sciences.

[71]  J. Holst,et al.  Meal-stimulated glucagon release is associated with postprandial blood glucose level and does not interfere with glycemic control in children and adolescents with new-onset type 1 diabetes. , 2007, The Journal of clinical endocrinology and metabolism.

[72]  D. Cook,et al.  Glucagon and forskolin have dual effects upon islet cell electrical activity. , 1984, Life sciences.

[73]  Min Zhang,et al.  Gap junctions and other mechanisms of cell–cell communication regulate basal insulin secretion in the pancreatic islet , 2011, The Journal of physiology.

[74]  Richard Bertram,et al.  Interaction of glycolysis and mitochondrial respiration in metabolic oscillations of pancreatic islets. , 2007, Biophysical journal.

[75]  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.

[76]  A. Salehi,et al.  Paradoxical Stimulation of Glucagon Secretion by High Glucose Concentrations , 2006, Diabetes.

[77]  V. Grill,et al.  Studies on the mechanisms of somatostatin action on insulin release. IV. effect of somatostatin on cyclic AMP levels and phosphodiesterase activity in isolated rat pancreatic islets. , 1977, Acta endocrinologica.

[78]  A. Berts,et al.  Suppression of Ca2+ oscillations in glucagon-producing alpha 2-cells by insulin/glucose and amino acids. , 1996, Biochimica et biophysica acta.

[79]  M. Strowski,et al.  Function and expression of somatostatin receptors of the endocrine pancreas , 2008, Molecular and Cellular Endocrinology.

[80]  P. Rorsman,et al.  Glucose Inhibition of Glucagon Secretion From Rat-Cells Is Mediated by GABA Released From Neighboring-Cells , 2004 .

[81]  R. Turner,et al.  Pulsatile, Synchronous Basal Insulin and Glucagon Secretion in Man , 1982, Diabetes.

[82]  K. Tornheim.  Are Metabolic Oscillations Responsible for Normal Oscillatory Insulin Secretion? , 1997, Diabetes.

[83]  E. Vieira,et al.  A store-operated mechanism determines the activity of the electrically excitable glucagon-secreting pancreatic alpha-cell. , 2004, Cell calcium.

[84]  P. Gilon,et al.  Glucose and Pharmacological Modulators of ATP-Sensitive K+ Channels Control [Ca2+]c by Different Mechanisms in Isolated Mouse α-Cells , 2009, Diabetes.