Modeling KATP-Dependent Excitability in Pancreatic Islets

Abstract

In pancreatic beta cells, KATP channels respond to changes in blood glucose to regulate cell excitability and insulin release. Confirming this role, gain or loss of function mutations in KATP are linked to neonatal diabetes or hyperinsulinism, respectively. Compared to neurons or cardiac myocytes, cellular models of beta-cell electrical activity have remained relatively rudimentary, but a recent detailed computational model of single cell pancreatic beta cell excitability (Cha et al., J Gen Physiol. 2011 138:21-37) accurately reproduces the beta cell response to varying glucose concentrations. Our aim was to test whether the model could also reproduce experimentally observed changes in excitability when KATP conductance is altered by genetic manipulation. Since the experiments were conducted in islets, we extended the model from a single cell to a 3D model (10x10x10 cell) islet with 1000 cells. For each cell, the conductances of the major currents were allowed to vary as was the gap junction conductance between cells. Initial simulations showed that the model was unable to reproduce KATP conductance-dependent changes in glucose-responses of excitability. By altering the ATP dependence of the L-type Ca2+ channel and the Na+-K+ pump to better match experiment, appropriate KATP dependence was quantitatively reproduced. In extending and refining the previous model, these simulations highlight the criticality of these parameters and suggest further experiments to improve characterization of beta cell excitability.