Location: Bertram, Satin, Zhang, Smolen, Sherman, 2004 @ 69498d8092be / bertram_satin_zhang_smolen_sherman_2004_b.cellml

Author:
rcai987 <devnull@localhost>
Date:
2015-01-07 15:35:42+13:00
Desc:
Added annotations to bertram_satin_zhang_smolen_sherman_2004 models
Permanent Source URI:
https://models.cellml.org/workspace/bertram_satin_zhang_smolen_sherman_2004/rawfile/69498d8092be9d73dbc809aa9eb4794a8c00c5eb/bertram_satin_zhang_smolen_sherman_2004_b.cellml

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<article>
  <articleinfo>
  <title>Calcium and Glycolysis Mediate Multiple Bursting Modes in Pancreatic Islets</title>
  <author>
    <firstname>Catherine</firstname>
          <surname>Lloyd</surname>
    <affiliation>
      <shortaffil>Auckland Bioengineering Institute, University of Auckland</shortaffil>
    </affiliation>
  </author>
</articleinfo>
  <section id="sec_status">
    <title>Model Status</title>
    <para>
This model has been rebuilt and coded by translating the authors original XPPAUT.ode file, which can be found at http://www.math.fsu.edu/~bertram/software/islet/BJ_04a.ode. This file runs in PCEnv and COR and is able to produce the expected output. This model has been parameterised for the 'compound bursting' model.  Some equations have inconsistent magnitudes due to the fact that time is defined in milliseconds, yet flux is defined in micromolar per second.
</para>

  </section>
  <sect1 id="sec_structure">
<title>Model Structure</title>

<para>
ABSTRACT: Pancreatic islets of Langerhans produce bursts of electrical activity when exposed to stimulatory glucose levels. These bursts often have a regular repeating pattern, with a period of 10-60 s. In some cases, however, the bursts are episodic, clustered into bursts of bursts, which we call compound bursting. Consistent with this are recordings of free Ca2+ concentration, oxygen consumption, mitochondrial membrane potential, and intraislet glucose levels that exhibit very slow oscillations, with faster oscillations superimposed. We describe a new mathematical model of the pancreatic beta-cell that can account for these multimodal patterns. The model includes the feedback of cytosolic Ca2+ onto ion channels that can account for bursting, and a metabolic subsystem that is capable of producing slow oscillations driven by oscillations in glycolysis. This slow rhythm is responsible for the slow mode of compound bursting in the model. We also show that it is possible for glycolytic oscillations alone to drive a very slow form of bursting, which we call "glycolytic bursting." Finally, the model predicts that there is bistability between stationary and oscillatory glycolysis for a range of parameter values. We provide experimental support for this model prediction. Overall, the model can account for a diversity of islet behaviors described in the literature over the past 20 years.
</para>

<para>
Calcium and Glycolysis Mediate Multiple Bursting Modes in Pancreatic Islets, Richard Bertram, Leslie Satin, Min Zhang, Paul Smolen, and Arthur Sherman, 2004,
            <emphasis>Biophysical Journal</emphasis>, 87, 3074-3087. <ulink url="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;list_uids=15347584&amp;dopt=Abstract">PubMed ID: 15347584</ulink>
</para>

<informalfigure float="0" id="fig_cell_diagram">
<mediaobject>
  <imageobject>
    <objectinfo>
      <title>cell diagram</title>
    </objectinfo>
    <imagedata fileref="bertram_2004.png"/>
  </imageobject>
</mediaobject>
<caption>A schematic diagram of the ionic currents and fluxes across the ER and the cell surface membranes which are described by the mathematical model.</caption>
</informalfigure>
</sect1>
</article>
</documentation>
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                        <ci>bottom2</ci>
                        <apply>
                              <plus/>
                              <ci>bottom1</ci>
                              <ci>weight2</ci>
                        </apply>
                  </apply>
            </math>
            <math xmlns="http://www.w3.org/1998/Math/MathML" id="0010">
                  <apply>
                        <eq/>
                        <ci>weight3</ci>
                        <apply>
                              <divide/>
                              <apply>
                                    <power/>
                                    <ci>f6p</ci>
                                    <cn cellml:units="dimensionless">2</cn>
                              </apply>
                              <apply>
                                    <times/>
                                    <ci>k3</ci>
                                    <cn cellml:units="micromolar">1</cn>
                              </apply>
                        </apply>
                  </apply>
                  <apply>
                        <eq/>
                        <ci>topa3</ci>
                        <apply>
                              <plus/>
                              <ci>topa2</ci>
                              <ci>weight3</ci>
                        </apply>
                  </apply>
                  <apply>
                        <eq/>
                        <ci>bottom3</ci>
                        <apply>
                              <plus/>
                              <ci>bottom2</ci>
                              <ci>weight3</ci>
                        </apply>
                  </apply>
            </math>
            <math xmlns="http://www.w3.org/1998/Math/MathML" id="0011">
                  <apply>
                        <eq/>
                        <ci>weight4</ci>
                        <apply>
                              <divide/>
                              <apply>
                                    <power/>
                                    <apply>
                                          <times/>
                                          <ci>f6p</ci>
                                          <ci>atp</ci>
                                    </apply>
                                    <cn cellml:units="dimensionless">2</cn>
                              </apply>
                              <apply>
                                    <times/>
                                    <ci>fatp</ci>
                                    <ci>k3</ci>
                                    <ci>k4</ci>
                                    <apply>
                                          <power/>
                                          <cn cellml:units="micromolar">1</cn>
                                          <cn cellml:units="dimensionless">2</cn>
                                    </apply>
                              </apply>
                        </apply>
                  </apply>
                  <apply>
                        <eq/>
                        <ci>topa4</ci>
                        <apply>
                              <plus/>
                              <ci>topa3</ci>
                              <ci>weight4</ci>
                        </apply>
                  </apply>
                  <apply>
                        <eq/>
                        <ci>bottom4</ci>
                        <apply>
                              <plus/>
                              <ci>bottom3</ci>
                              <ci>weight4</ci>
                        </apply>
                  </apply>
            </math>
            <math xmlns="http://www.w3.org/1998/Math/MathML" id="0100">
                  <apply>
                        <eq/>
                        <ci>weight5</ci>
                        <apply>
                              <divide/>
                              <ci>fbp</ci>
                              <ci>k2</ci>
                        </apply>
                  </apply>
                  <apply>
                        <eq/>
                        <ci>topa5</ci>
                        <ci>topa4</ci>
                  </apply>
                  <apply>
                        <eq/>
                        <ci>bottom5</ci>
                        <apply>
                              <plus/>
                              <ci>bottom4</ci>
                              <ci>weight5</ci>
                        </apply>
                  </apply>
            </math>
            <math xmlns="http://www.w3.org/1998/Math/MathML" id="0101">
                  <apply>
                        <eq/>
                        <ci>weight6</ci>
                        <apply>
                              <divide/>
                              <apply>
                                    <times/>
                                    <ci>fbp</ci>
                                    <apply>
                                          <power/>
                                          <ci>atp</ci>
                                          <cn cellml:units="dimensionless">2</cn>
                                    </apply>
                              </apply>
                              <apply>
                                    <times/>
                                    <ci>k2</ci>
                                    <ci>k4</ci>
                                    <ci>fbt</ci>
                                    <cn cellml:units="micromolar">1</cn>
                              </apply>
                        </apply>
                  </apply>
                  <apply>
                        <eq/>
                        <ci>topa6</ci>
                        <ci>topa5</ci>
                  </apply>
                  <apply>
                        <eq/>
                        <ci>bottom6</ci>
                        <apply>
                              <plus/>
                              <ci>bottom5</ci>
                              <ci>weight6</ci>
                        </apply>
                  </apply>
            </math>
            <math xmlns="http://www.w3.org/1998/Math/MathML" id="0110">
                  <apply>
                        <eq/>
                        <ci>weight7</ci>
                        <apply>
                              <divide/>
                              <apply>
                                    <times/>
                                    <ci>fbp</ci>
                                    <apply>
                                          <power/>
                                          <ci>f6p</ci>
                                          <cn cellml:units="dimensionless">2</cn>
                                    </apply>
                              </apply>
                              <apply>
                                    <times/>
                                    <ci>k2</ci>
                                    <ci>k3</ci>
                                    <ci>ffbp</ci>
                                    <cn cellml:units="micromolar">1</cn>
                              </apply>
                        </apply>
                  </apply>
                  <apply>
                        <eq/>
                        <ci>topa7</ci>
                        <apply>
                              <plus/>
                              <ci>topa6</ci>
                              <ci>weight7</ci>
                        </apply>
                  </apply>
                  <apply>
                        <eq/>
                        <ci>bottom7</ci>
                        <apply>
                              <plus/>
                              <ci>bottom6</ci>
                              <ci>weight7</ci>
                        </apply>
                  </apply>
            </math>
            <math xmlns="http://www.w3.org/1998/Math/MathML" id="0111">
                  <apply>
                        <eq/>
                        <ci>weight8</ci>
                        <apply>
                              <divide/>
                              <apply>
                                    <times/>
                                    <ci>fbp</ci>
                                    <apply>
                                          <power/>
                                          <ci>f6p</ci>
                                          <cn cellml:units="dimensionless">2</cn>
                                    </apply>
                                    <apply>
                                          <power/>
                                          <ci>atp</ci>
                                          <cn cellml:units="dimensionless">2</cn>
                                    </apply>
                              </apply>
                              <apply>
                                    <times/>
                                    <ci>k2</ci>
                                    <ci>k3</ci>
                                    <ci>k4</ci>
                                    <ci>ffbp</ci>
                                    <ci>fbt</ci>
                                    <ci>fatp</ci>
                                    <apply>
                                          <power/>
                                          <cn cellml:units="micromolar">1</cn>
                                          <cn cellml:units="dimensionless">2</cn>
                                    </apply>
                              </apply>
                        </apply>
                  </apply>
                  <apply>
                        <eq/>
                        <ci>topa8</ci>
                        <apply>
                              <plus/>
                              <ci>topa7</ci>
                              <ci>weight8</ci>
                        </apply>
                  </apply>
                  <apply>
                        <eq/>
                        <ci>bottom8</ci>
                        <apply>
                              <plus/>
                              <ci>bottom7</ci>
                              <ci>weight8</ci>
                        </apply>
                  </apply>
            </math>
            <math xmlns="http://www.w3.org/1998/Math/MathML" id="1000">
                  <apply>
                        <eq/>
                        <ci>weight9</ci>
                        <apply>
                              <divide/>
                              <ci>amp</ci>
                              <ci>k1</ci>
                        </apply>
                  </apply>
                  <apply>
                        <eq/>
                        <ci>topa9</ci>
                        <ci>topa8</ci>
                  </apply>
                  <apply>
                        <eq/>
                        <ci>bottom9</ci>
                        <apply>
                              <plus/>
                              <ci>bottom8</ci>
                              <ci>weight9</ci>
                        </apply>
                  </apply>
            </math>
            <math xmlns="http://www.w3.org/1998/Math/MathML" id="1001">
                  <apply>
                        <eq/>
                        <ci>weight10</ci>
                        <apply>
                              <divide/>
                              <apply>
                                    <times/>
                                    <ci>amp</ci>
                                    <apply>
                                          <power/>
                                          <ci>atp</ci>
                                          <cn cellml:units="dimensionless">2</cn>
                                    </apply>
                              </apply>
                              <apply>
                                    <times/>
                                    <ci>k1</ci>
                                    <ci>k4</ci>
                                    <ci>fmt</ci>
                                    <cn cellml:units="micromolar">1</cn>
                              </apply>
                        </apply>
                  </apply>
                  <apply>
                        <eq/>
                        <ci>topa10</ci>
                        <ci>topa9</ci>
                  </apply>
                  <apply>
                        <eq/>
                        <ci>bottom10</ci>
                        <apply>
                              <plus/>
                              <ci>bottom9</ci>
                              <ci>weight10</ci>
                        </apply>
                  </apply>
            </math>
            <math xmlns="http://www.w3.org/1998/Math/MathML" id="1010">
                  <apply>
                        <eq/>
                        <ci>weight11</ci>
                        <apply>
                              <divide/>
                              <apply>
                                    <times/>
                                    <ci>amp</ci>
                                    <apply>
                                          <power/>
                                          <ci>f6p</ci>
                                          <cn cellml:units="dimensionless">2</cn>
                                    </apply>
                              </apply>
                              <apply>
                                    <times/>
                                    <ci>k1</ci>
                                    <ci>k3</ci>
                                    <ci>famp</ci>
                                    <cn cellml:units="micromolar">1</cn>
                              </apply>
                        </apply>
                  </apply>
                  <apply>
                        <eq/>
                        <ci>topa11</ci>
                        <apply>
                              <plus/>
                              <ci>topa10</ci>
                              <ci>weight11</ci>
                        </apply>
                  </apply>
                  <apply>
                        <eq/>
                        <ci>bottom11</ci>
                        <apply>
                              <plus/>
                              <ci>bottom10</ci>
                              <ci>weight11</ci>
                        </apply>
                  </apply>
            </math>
            <math xmlns="http://www.w3.org/1998/Math/MathML" id="1011">
                  <apply>
                        <eq/>
                        <ci>weight12</ci>
                        <apply>
                              <divide/>
                              <apply>
                                    <times/>
                                    <ci>amp</ci>
                                    <apply>
                                          <power/>
                                          <ci>f6p</ci>
                                          <cn cellml:units="dimensionless">2</cn>
                                    </apply>
                                    <apply>
                                          <power/>
                                          <ci>atp</ci>
                                          <cn cellml:units="dimensionless">2</cn>
                                    </apply>
                              </apply>
                              <apply>
                                    <times/>
                                    <ci>k1</ci>
                                    <ci>k3</ci>
                                    <ci>k4</ci>
                                    <ci>famp</ci>
                                    <ci>fmt</ci>
                                    <ci>fatp</ci>
                                    <apply>
                                          <power/>
                                          <cn cellml:units="micromolar">1</cn>
                                          <cn cellml:units="dimensionless">2</cn>
                                    </apply>
                              </apply>
                        </apply>
                  </apply>
                  <apply>
                        <eq/>
                        <ci>topa12</ci>
                        <apply>
                              <plus/>
                              <ci>topa11</ci>
                              <ci>weight12</ci>
                        </apply>
                  </apply>
                  <apply>
                        <eq/>
                        <ci>bottom12</ci>
                        <apply>
                              <plus/>
                              <ci>bottom11</ci>
                              <ci>weight12</ci>
                        </apply>
                  </apply>
            </math>
            <math xmlns="http://www.w3.org/1998/Math/MathML" id="1100">
                  <apply>
                        <eq/>
                        <ci>weight13</ci>
                        <apply>
                              <divide/>
                              <apply>
                                    <times/>
                                    <ci>amp</ci>
                                    <ci>fbp</ci>
                              </apply>
                              <apply>
                                    <times/>
                                    <ci>k1</ci>
                                    <ci>k2</ci>
                              </apply>
                        </apply>
                  </apply>
                  <apply>
                        <eq/>
                        <ci>topa13</ci>
                        <ci>topa12</ci>
                  </apply>
                  <apply>
                        <eq/>
                        <ci>bottom13</ci>
                        <apply>
                              <plus/>
                              <ci>bottom12</ci>
                              <ci>weight13</ci>
                        </apply>
                  </apply>
            </math>
            <math xmlns="http://www.w3.org/1998/Math/MathML" id="1101">
                  <apply>
                        <eq/>
                        <ci>weight14</ci>
                        <apply>
                              <divide/>
                              <apply>
                                    <times/>
                                    <ci>amp</ci>
                                    <ci>fbp</ci>
                                    <apply>
                                          <power/>
                                          <ci>atp</ci>
                                          <cn cellml:units="dimensionless">2</cn>
                                    </apply>
                              </apply>
                              <apply>
                                    <times/>
                                    <ci>k1</ci>
                                    <ci>k2</ci>
                                    <ci>k4</ci>
                                    <ci>fbt</ci>
                                    <ci>fmt</ci>
                                    <cn cellml:units="micromolar">1</cn>
                              </apply>
                        </apply>
                  </apply>
                  <apply>
                        <eq/>
                        <ci>topa14</ci>
                        <ci>topa13</ci>
                  </apply>
                  <apply>
                        <eq/>
                        <ci>bottom14</ci>
                        <apply>
                              <plus/>
                              <ci>bottom13</ci>
                              <ci>weight14</ci>
                        </apply>
                  </apply>
            </math>
            <math xmlns="http://www.w3.org/1998/Math/MathML" id="1110">
                  <apply>
                        <eq/>
                        <ci>weight15</ci>
                        <apply>
                              <divide/>
                              <apply>
                                    <times/>
                                    <ci>amp</ci>
                                    <ci>fbp</ci>
                                    <apply>
                                          <power/>
                                          <ci>f6p</ci>
                                          <cn cellml:units="dimensionless">2</cn>
                                    </apply>
                              </apply>
                              <apply>
                                    <times/>
                                    <ci>k1</ci>
                                    <ci>k2</ci>
                                    <ci>k3</ci>
                                    <ci>ffbp</ci>
                                    <ci>famp</ci>
                                    <cn cellml:units="micromolar">1</cn>
                              </apply>
                        </apply>
                  </apply>
                  <apply>
                        <eq/>
                        <ci>topa15</ci>
                        <ci>topa14</ci>
                  </apply>
                  <apply>
                        <eq/>
                        <ci>bottom15</ci>
                        <apply>
                              <plus/>
                              <ci>bottom14</ci>
                              <ci>weight15</ci>
                        </apply>
                  </apply>
                  <apply>
                        <eq/>
                        <ci>topb</ci>
                        <ci>weight15</ci>
                  </apply>
            </math>
            <math xmlns="http://www.w3.org/1998/Math/MathML" id="1111">
                  <apply>
                        <eq/>
                        <ci>weight16</ci>
                        <apply>
                              <divide/>
                              <apply>
                                    <times/>
                                    <ci>amp</ci>
                                    <ci>fbp</ci>
                                    <apply>
                                          <power/>
                                          <ci>f6p</ci>
                                          <cn cellml:units="dimensionless">2</cn>
                                    </apply>
                                    <apply>
                                          <power/>
                                          <ci>atp</ci>
                                          <cn cellml:units="dimensionless">2</cn>
                                    </apply>
                              </apply>
                              <apply>
                                    <times/>
                                    <ci>k1</ci>
                                    <ci>k2</ci>
                                    <ci>k3</ci>
                                    <ci>k4</ci>
                                    <ci>ffbp</ci>
                                    <ci>famp</ci>
                                    <ci>fbt</ci>
                                    <ci>fmt</ci>
                                    <ci>fatp</ci>
									<apply>
                                          <power/>
                                          <cn cellml:units="micromolar">1</cn>
                                          <cn cellml:units="dimensionless">2</cn>
                                    </apply>
                              </apply>
                        </apply>
                  </apply>
                  <apply>
                        <eq/>
                        <ci>topa16</ci>
                        <apply>
                              <plus/>
                              <ci>topa15</ci>
                              <ci>weight16</ci>
                        </apply>
                  </apply>
                  <apply>
                        <eq/>
                        <ci>bottom16</ci>
                        <apply>
                              <plus/>
                              <ci>bottom15</ci>
                              <ci>weight16</ci>
                        </apply>
                  </apply>
            </math>
            <variable name="topb" units="dimensionless"/>
            <variable name="fbp" public_interface="in" units="micromolar"/>
            <variable name="amp" public_interface="in" units="micromolar"/>
      </component>
      <component cmeta:id="id_00005" name="KATP">
            <variable name="time" public_interface="in" units="millisecond"/>
            <variable name="mgadp" units="micromolar"/>
            <variable name="adp3m" units="micromolar"/>
            <variable name="atp4m" units="micromolar"/>
            <variable name="topo" units="dimensionless"/>
            <variable name="bottomo" units="dimensionless"/>
            <variable cmeta:id="id_00013" name="katpo" units="dimensionless"/>
            <variable cmeta:id="id_00012" name="IKATP" public_interface="out" units="femtoA"/>
            <variable cmeta:id="id_00011" initial_value="-75" name="VK" public_interface="out" units="millivolt"/>
            <variable initial_value="25000" name="gkatpbar" units="picoS"/>
            <variable cmeta:id="id_00008" name="atp" public_interface="in" units="micromolar"/>
            <variable cmeta:id="id_00009" name="adp" public_interface="in" units="micromolar"/>
            <variable initial_value="17" name="kdd" units="dimensionless"/>
            <variable initial_value="26" name="ktd" units="dimensionless"/>
            <variable initial_value="1" name="ktt" units="dimensionless"/>
            <math xmlns="http://www.w3.org/1998/Math/MathML" id="mgadp">
                  <apply>
                        <eq/>
                        <ci>mgadp</ci>
                        <apply>
                              <times/>
                              <cn cellml:units="dimensionless">0.165</cn>
                              <ci>adp</ci>
                        </apply>
                  </apply>
            </math>
            <math xmlns="http://www.w3.org/1998/Math/MathML" id="adp3m">
                  <apply>
                        <eq/>
                        <ci>adp3m</ci>
                        <apply>
                              <times/>
                              <cn cellml:units="dimensionless">0.135</cn>
                              <ci>adp</ci>
                        </apply>
                  </apply>
            </math>
            <math xmlns="http://www.w3.org/1998/Math/MathML" id="atp4m">
                  <apply>
                        <eq/>
                        <ci>atp4m</ci>
                        <apply>
                              <times/>
                              <cn cellml:units="dimensionless">0.05</cn>
                              <ci>atp</ci>
                        </apply>
                  </apply>
            </math>
            <math xmlns="http://www.w3.org/1998/Math/MathML" id="topo">
                  <apply>
                        <eq/>
                        <ci>topo</ci>
                        <apply>
                              <plus/>
                              <apply>
                                    <times/>
                                    <cn cellml:units="dimensionless">0.08</cn>
                                    <apply>
                                          <plus/>
                                          <cn cellml:units="dimensionless">1</cn>
                                          <apply>
                                                <divide/>
                                                <apply>
                                                      <times/>
                                                      <cn cellml:units="dimensionless">2</cn>
                                                      <ci>mgadp</ci>
                                                </apply>
                                                <apply>
                                                      <times/>
                                                      <ci>kdd</ci>
                                                      <cn cellml:units="micromolar">1</cn>
                                                </apply>
                                          </apply>
                                    </apply>
                              </apply>
                              <apply>
                                    <times/>
                                    <cn cellml:units="dimensionless">0.89</cn>
                                    <apply>
                                          <power/>
                                          <apply>
                                                <divide/>
                                                <ci>mgadp</ci>
                                                <apply>
                                                      <times/>
                                                      <ci>kdd</ci>
                                                      <cn cellml:units="micromolar">1</cn>
                                                </apply>
                                          </apply>
                                          <cn cellml:units="dimensionless">2</cn>
                                    </apply>
                              </apply>
                        </apply>
                  </apply>
            </math>
            <math xmlns="http://www.w3.org/1998/Math/MathML" id="bottomo">
                  <apply>
                        <eq/>
                        <ci>bottomo</ci>
                        <apply>
                              <times/>
                              <apply>
                                    <power/>
                                    <apply>
                                          <plus/>
                                          <cn cellml:units="dimensionless">1</cn>
                                          <apply>
                                                <divide/>
                                                <ci>mgadp</ci>
                                                <apply>
                                                      <times/>
                                                      <ci>kdd</ci>
                                                      <cn cellml:units="micromolar">1</cn>
                                                </apply>
                                          </apply>
                                    </apply>
                                    <cn cellml:units="dimensionless">2</cn>
                              </apply>
                              <apply>
                                    <plus/>
                                    <cn cellml:units="dimensionless">1</cn>
                                    <apply>
                                          <divide/>
                                          <ci>adp3m</ci>
                                          <apply>
                                                <times/>
                                                <ci>ktd</ci>
                                                <cn cellml:units="micromolar">1</cn>
                                          </apply>
                                    </apply>
                                    <apply>
                                          <divide/>
                                          <ci>atp4m</ci>
                                          <apply>
                                                <times/>
                                                <ci>ktt</ci>
                                                <cn cellml:units="micromolar">1</cn>
                                          </apply>
                                    </apply>
                              </apply>
                        </apply>
                  </apply>
            </math>
            <math xmlns="http://www.w3.org/1998/Math/MathML" id="katpo">
                  <apply>
                        <eq/>
                        <ci>katpo</ci>
                        <apply>
                              <divide/>
                              <ci>topo</ci>
                              <ci>bottomo</ci>
                        </apply>
                  </apply>
            </math>
            <math xmlns="http://www.w3.org/1998/Math/MathML" id="ikatp">
                  <apply>
                        <eq/>
                        <ci>IKATP</ci>
                        <apply>
                              <times/>
                              <ci>gkatpbar</ci>
                              <ci>katpo</ci>
                              <apply>
                                    <minus/>
                                    <ci>V</ci>
                                    <ci>VK</ci>
                              </apply>
                        </apply>
                  </apply>
            </math>
            <variable name="V" public_interface="in" units="millivolt"/>
      </component>
      <component cmeta:id="id_00006" name="nucleotides">
            <variable name="time" public_interface="in" units="millisecond"/>
            <variable cmeta:id="id_00007" name="atp" public_interface="out" units="micromolar"/>
            <variable cmeta:id="id_00010" initial_value="780" name="adp" public_interface="out" units="micromolar"/>
            <variable name="fback" units="dimensionless"/>
            <variable initial_value="300000" name="taua" units="dimensionless"/>
            <variable initial_value="0.35" name="r1" units="micromolar"/>
            <variable name="c" public_interface="in" units="micromolar"/>
            <variable initial_value="1" name="r" units="dimensionless"/>
            <variable name="y" units="dimensionless"/>
            <variable initial_value="2.2" name="vg" units="dimensionless"/>
            <variable name="rgpdh" public_interface="in" units="flux"/>
            <variable initial_value="10" name="kg" units="flux"/>
            <math xmlns="http://www.w3.org/1998/Math/MathML" id="d(adp)/d(time)">
                  <apply>
                        <eq/>
                        <apply>
                              <diff/>
                              <bvar>
                                    <ci>time</ci>
                              </bvar>
                              <ci>adp</ci>
                        </apply>
                        <apply>
                              <divide/>
                              <apply>
                                    <minus/>
                                    <ci>atp</ci>
                                    <apply>
                                          <times/>
                                          <ci>adp</ci>
                                          <apply>
                                                <exp/>
                                                <apply>
                                                      <times/>
                                                      <ci>fback</ci>
                                                      <apply>
                                                            <minus/>
                                                            <cn cellml:units="dimensionless">1</cn>
                                                            <apply>
                                                                  <divide/>
                                                                  <ci>c</ci>
                                                                  <ci>r1</ci>
                                                            </apply>
                                                      </apply>
                                                </apply>
                                          </apply>
                                    </apply>
                              </apply>
                              <apply>
                                    <times/>
                                    <ci>taua</ci>
                                    <cn cellml:units="millisecond">1</cn>
                              </apply>
                        </apply>
                  </apply>
            </math>
            <math xmlns="http://www.w3.org/1998/Math/MathML" id="fback">
                  <apply>
                        <eq/>
                        <ci>fback</ci>
                        <apply>
                              <plus/>
                              <ci>r</ci>
                              <ci>y</ci>
                        </apply>
                  </apply>
            </math>
            <math xmlns="http://www.w3.org/1998/Math/MathML" id="y">
                  <apply>
                        <eq/>
                        <ci>y</ci>
                        <apply>
                              <times/>
                              <ci>vg</ci>
                              <apply>
                                    <divide/>
                                    <ci>rgpdh</ci>
                                    <apply>
                                          <plus/>
                                          <ci>kg</ci>
                                          <ci>rgpdh</ci>
                                    </apply>
                              </apply>
                        </apply>
                  </apply>
            </math>
            <math xmlns="http://www.w3.org/1998/Math/MathML" id="atp">
                  <apply>
                        <eq/>
                        <ci>atp</ci>
                        <apply>
                              <times/>
                              <cn cellml:units="dimensionless">0.5</cn>
                              <apply>
                                    <plus/>
                                    <apply>
                                          <minus/>
                                          <ci>atot</ci>
                                          <ci>adp</ci>
                                    </apply>
                                    <apply>
                                          <times/>
                                          <ci>rad</ci>
                                          <cn cellml:units="micromolar">1</cn>
                                    </apply>
                              </apply>
                        </apply>
                  </apply>
            </math>
            <math xmlns="http://www.w3.org/1998/Math/MathML" id="amp">
                  <apply>
                        <eq/>
                        <ci>amp</ci>
                        <apply>
                              <divide/>
                              <apply>
                                    <times/>
                                    <ci>adp</ci>
                                    <ci>adp</ci>
                              </apply>
                              <ci>atp</ci>
                        </apply>
                  </apply>
            </math>
            <math xmlns="http://www.w3.org/1998/Math/MathML" id="ratio">
                  <apply>
                        <eq/>
                        <ci>ratio</ci>
                        <apply>
                              <divide/>
                              <ci>atp</ci>
                              <ci>adp</ci>
                        </apply>
                  </apply>
            </math>
            <math xmlns="http://www.w3.org/1998/Math/MathML" id="rad">
                  <apply>
                        <eq/>
                        <ci>rad</ci>
                        <apply>
                              <divide/>
                              <apply>
                                    <root/>
                                    <apply>
                                          <abs/>
                                          <apply>
                                                <minus/>
                                                <apply>
                                                      <power/>
                                                      <apply>
                                                            <minus/>
                                                            <ci>adp</ci>
                                                            <ci>atot</ci>
                                                      </apply>
                                                      <cn cellml:units="dimensionless">2</cn>
                                                </apply>
                                                <apply>
                                                      <times/>
                                                      <cn cellml:units="dimensionless">4</cn>
                                                      <apply>
                                                            <power/>
                                                            <ci>adp</ci>
                                                            <cn cellml:units="dimensionless">2</cn>
                                                      </apply>
                                                </apply>
                                          </apply>
                                    </apply>
                              </apply>
                              <cn cellml:units="micromolar">1</cn>
                        </apply>
                  </apply>
            </math>
            <variable name="amp" public_interface="out" units="micromolar"/>
            <variable name="rad" units="dimensionless"/>
            <variable name="ratio" units="dimensionless"/>
            <variable name="atot" public_interface="in" units="micromolar"/>
      </component>
      <connection>
            <map_components component_1="environment" component_2="membrane"/>
            <map_variables variable_1="time" variable_2="time"/>
      </connection>
      <connection>
            <map_components component_1="KATP" component_2="membrane"/>
            <map_variables variable_1="IKATP" variable_2="IKATP"/>
            <map_variables variable_1="VK" variable_2="VK"/>
            <map_variables variable_1="V" variable_2="V"/>
      </connection>
      <connection>
            <map_components component_1="environment" component_2="calcium_handling"/>
            <map_variables variable_1="time" variable_2="time"/>
      </connection>
      <connection>
            <map_components component_1="membrane" component_2="calcium_handling"/>
            <map_variables variable_1="ICa" variable_2="ICa"/>
            <map_variables variable_1="c" variable_2="c"/>
      </connection>
      <connection>
            <map_components component_1="environment" component_2="glycolysis"/>
            <map_variables variable_1="time" variable_2="time"/>
      </connection>
      <connection>
            <map_components component_1="environment" component_2="pfk"/>
            <map_variables variable_1="time" variable_2="time"/>
      </connection>
      <connection>
            <map_components component_1="glycolysis" component_2="pfk"/>
            <map_variables variable_1="pfkbas" variable_2="pfkbas"/>
            <map_variables variable_1="f6p" variable_2="f6p"/>
            <map_variables variable_1="fbp" variable_2="fbp"/>
            <map_variables variable_1="pfk" variable_2="pfk"/>
      </connection>
      <connection>
            <map_components component_1="nucleotides" component_2="pfk"/>
            <map_variables variable_1="atp" variable_2="atp"/>
            <map_variables variable_1="amp" variable_2="amp"/>
      </connection>
      <connection>
            <map_components component_1="environment" component_2="KATP"/>
            <map_variables variable_1="time" variable_2="time"/>
      </connection>
      <connection>
            <map_components component_1="nucleotides" component_2="KATP"/>
            <map_variables variable_1="atp" variable_2="atp"/>
            <map_variables variable_1="adp" variable_2="adp"/>
      </connection>
      <connection>
            <map_components component_1="environment" component_2="nucleotides"/>
            <map_variables variable_1="time" variable_2="time"/>
      </connection>
      <connection>
            <map_components component_1="calcium_handling" component_2="nucleotides"/>
            <map_variables variable_1="c" variable_2="c"/>
      </connection>
      <connection>
            <map_components component_1="glycolysis" component_2="nucleotides"/>
            <map_variables variable_1="rgpdh" variable_2="rgpdh"/>
            <map_variables variable_1="atot" variable_2="atot"/>
      </connection>
      
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