title: Ionic mechanisms and Ca2+ dynamics underlying the glucose response of pancreatic β cells: a simulation study.
abstract: To clarify the mechanisms underlying the pancreatic β-cell response to varying glucose concentrations ([G]), electrophysiological findings were integrated into a mathematical cell model. The Ca(2+) dynamics of the endoplasmic reticulum (ER) were also improved. The model was validated by demonstrating quiescent potential, burst-interburst electrical events accompanied by Ca(2+) transients, and continuous firing of action potentials over [G] ranges of 0-6, 7-18, and >19 mM, respectively. These responses to glucose were completely reversible. The action potential, input impedance, and Ca(2+) transients were in good agreement with experimental measurements. The ionic mechanisms underlying the burst-interburst rhythm were investigated by lead potential analysis, which quantified the contributions of individual current components. This analysis demonstrated that slow potential changes during the interburst period were attributable to modifications of ion channels or transporters by intracellular ions and/or metabolites to different degrees depending on [G]. The predominant role of adenosine triphosphate-sensitive K(+) current in switching on and off the repetitive firing of action potentials at 8 mM [G] was taken over at a higher [G] by Ca(2+)- or Na(+)-dependent currents, which were generated by the plasma membrane Ca(2+) pump, Na(+)/K(+) pump, Na(+)/Ca(2+) exchanger, and TRPM channel. Accumulation and release of Ca(2+) by the ER also had a strong influence on the slow electrical rhythm. We conclude that the present mathematical model is useful for quantifying the role of individual functional components in the whole cell responses based on experimental findings.
authors.affiliation: Biosimulation Project, Ritsumeikan University, Kusatsu, Shiga, Japan.
authors.forename: Chae Young
authors.initials: CY
authors.lastname: Cha
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Himeno
authors.forename: Jianwu
authors.initials: J
authors.lastname: Wang
authors.forename: Shinpei
authors.initials: S
authors.lastname: Fujimoto
authors.forename: Nobuya
authors.initials: N
authors.lastname: Inagaki
authors.forename: Yung E
authors.initials: YE
authors.lastname: Earm
authors.forename: Akinori
authors.initials: A
authors.lastname: Noma
mesh_terms: D000200:Action Potentials; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D003198:Computer Simulation; D004594:Electrophysiology; D005947:Glucose / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D007473:Ion Channels / Q000378:metabolism; D051379:Mice; D050053:TRPM Cation Channels / Q000378:metabolism
chemical_list: D007473:Ion Channels; D050053:TRPM Cation Channels; D000255:Adenosine Triphosphate; D005947:Glucose; D002118:Calcium