Interaction of glycolysis and mitochondrial respiration in metabolic oscillations of pancreatic islets
Catherine
Lloyd
Bioengineering Institute, University of Auckland
Model Status
This CellML model has been coded by translating the authors original XPPAUT.ode file, which can be found at http://www.math.fsu.edu/~bertram/software/islet/BJ_07/mitophan.ode. The model runs in PCEnv in COR and is able to produce the published results. The parameters have been chosen to recreate the bursting behaviour seen in figures 3 and 4 of the original paper. Some equations have inconsistent magnitudes due to the fact that some units are defined in milliseconds whereas others are defined in seconds.
Model Structure
Glucose metabolism plays a key signalling role in insulin-secreting pancreatic beta cells. In addition to generating ATP - the ubiquitous form of energy used to fuel many cellular processes - glucose metabolism in pancreatic beta cells is also the means by which blood glucose levels are monitored, ensuring an appropriate level of insulin secretion. ATP-sensitive potassium channels in the plasma membrane are activated by ADP and are inactivated by ATP, therefore a high ATP/ADP ratio results in a reduced number of open, ATP-sensitive, potassium channels. In turn, this results in membrane depolarisation and voltage-sensitive calcium channels open. The resulting influx of calcium ions into the cell cytosol induces insulin secretion, which in a healthy individual typically occurs in oscillatory waves. These can be fast with an oscillatory period of less than a minute, or slow with a duration of 2 to 7 minutes, or they can be a combination of fast and slow waves. This oscillatory pattern of insulin secretion appears to have a physiological function which is of particular interest since it is lost in patients with type II diabetes.
Although the definitive mechanisms underlying these insulin oscillations are unknown, in the paper described here, Richard Bertram et al. suggest that calcium feedback onto ATP production or consumption is responsible for the fast component of the insulin oscillations, while oscillations in the glycolytic pathway are responsible for the slow component. Furthermore, they build these phenomena into a mathematical model that combines a model of mitochondrial metabolism with models of glycolytic oscillations, plasma membrane electrical activity, and calcium handling in the cytosol and endoplasmic reticulum (summarised in the figure below).
model diagram
Schematic diagram of the model components and the variables which are exchanged between the components.
The original paper reference is cited below:
Interaction of glycolysis and mitochondrial respiration in metabolic oscillations of pancreatic islets, Richard Bertram, Leslie S. Satin, Morten Gram Pedersen, Dan S. Luciani, and Arthur Sherman, 2007, Biophysical Journal, 92, 1544-1555. PubMed ID: 17172305
The authors highlight that the original model code can be downloaded here.
JOrate of oxygen consumption at the final stage of the electron transport chain2007-03-01delta_psimitochondrial inner membrane potentialJunicalcium flux into the mitochondria through a calcium uniporterThe University of AucklandThe Bioengineering InstituteCammitochondrial calcium concentrationIntra- and inter-islet synchronization of metabolically driven insulin secretion9215441555ATPmmitochondrial ATPThis CellML model has been coded by translating the authors original XPPAUT .ode file, which can be found at http://www.math.fsu.edu/~bertram/software/islet/BJ_07/mitophan.ode . The model runs in PCEnv and is able to produce the published results. The parameters have been chosen to recreate the bursting behaviour seen in figures 3 and 4 of the original paper.nvoltage-dependent potassium current n gateJHatpJGKrate of the glucokinase reactionrate of ATP-driven proton fluxadpcytosolic ADP concentrationJHleakproton leakage into the mitochodria down the proton gradientMayCatherineLloydJPFKrate of the phosphofructokinase reactionSDanLucianiG6Pglucose 6-phosphateThe University of Auckland, Bioengineering InstituteFBPfructose 1-6-bisphosphateCatherine LloydJPDHrate of the pyruvate dehydrogenase reactionIcavoltage-dependent calcium currentMayCatherineLloydF6Pfructose 6-phosphateIkvoltage-dependent potassium currentSLeslieSatinJleakrate of calcium leakage out of the endoplasmic reticulumccytosolic calciumCaercalciumJGPDHrate of the glyceride 3-P dehydrogenase reactionJmemrate of calcium flux across the plasma membrane2009-05-15T16:19:11+12:00Biophysical JournalJerrate of calcium flux out of the endoplasmic reticulumatpcytosolic ATPJF1F0rate of the F1F0 ATP synthase catalysed reaction17172305Ikcacalcium-activated potassium current2007-08-08T00:00:00+00:00keywordNADHmmitochondrial NADH10000060000010c.lloyd@auckland.ac.nz Bertram et al.'s 2007 mathematical model of the interaction between glycolysis and mitochondrial respiration in metabolic oscillations of pancreatic islets. 2007-11-01T17:17:08+13:00Catherine LloydJHresflux through respiration-driven proton pumpsJSERCArate of calcium flux into the endoplasmic reticulum through the SERCA pumpsJhydcytosolic hydrolysis of ATPADPmmitochondrial ADPGramMortenPedersenUpdated curation statusModel has been fixed such that it now recreates the published results. This required a slight deviation from the equations in the published paper and the author's original .ODE code was used instead.NADmmitochondrial NADJNaCacalcium flux out of the mitochondria into the cytosol through the sodium-calcium ion exchangerRichardJamesLawsonArthurShermanThis is a CellML description of Bertram et al.'s 2007 mathematical model of the interaction between glycolysis and mitochondrial respiration in metabolic oscillations of pancreatic islets.RichardBertramJANTrate of ADP and ATP flux through the adenine nucleotide translocatormvoltage-dependent calcium current m gateIkatpATP-sensitive potassium currentglycolysisinsulinmitochondriapancreatic beta cellendocrinemetabolism