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Modeling K,ATP--dependent excitability in pancreatic islets.

ABSTRACT: In pancreatic ?-cells, K,ATP channels respond to changes in glucose to regulate cell excitability and insulin release. Confirming a high sensitivity of electrical activity to K,ATP activity, mutations that cause gain of K,ATP function cause neonatal diabetes. Our aim was to quantitatively assess the contribution of K,ATP current to the regulation of glucose-dependent bursting by reproducing experimentally observed changes in excitability when K,ATP conductance is altered by genetic manipulation. A recent detailed computational model of single cell pancreatic ?-cell excitability reproduces the ?-cell response to varying glucose concentrations. However, initial simulations showed that the model underrepresents the significance of K,ATP activity and was unable to reproduce K,ATP conductance-dependent changes in excitability. By altering the ATP and glucose dependence of the L-type Ca(2+) channel and the Na-K ATPase to better fit experiment, appropriate dependence of excitability on K,ATP conductance was reproduced. Because experiments were conducted in islets, which contain cell-to-cell variability, we extended the model from a single cell to a three-dimensional model (10×10×10 cell) islet with 1000 cells. For each cell, the conductance of the major currents was allowed to vary as was the gap junction conductance between cells. This showed that single cell glucose-dependent behavior was then highly variable, but was uniform in coupled islets. The study highlights the importance of parameterization of detailed models of ?-cell excitability and suggests future experiments that will lead to improved characterization of ?-cell excitability and the control of insulin secretion.

SUBMITTER: Silva JR

PROVIDER: S-EPMC4223185 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature

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Modeling K,ATP--dependent excitability in pancreatic islets.

Silva Jonathan R JR Cooper Paige P Nichols Colin G CG

Biophysical journal 20141101 9

In pancreatic ?-cells, K,ATP channels respond to changes in glucose to regulate cell excitability and insulin release. Confirming a high sensitivity of electrical activity to K,ATP activity, mutations that cause gain of K,ATP function cause neonatal diabetes. Our aim was to quantitatively assess the contribution of K,ATP current to the regulation of glucose-dependent bursting by reproducing experimentally observed changes in excitability when K,ATP conductance is altered by genetic manipulation. ...[more]

PMID: 25418087

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Project description:The pancreas became one of the first objects of regenerative medicine, since other possibilities of dealing with the pancreatic endocrine insufficiency were clearly exhausted. The number of people living with diabetes mellitus is currently approaching half a billion, hence the crucial relevance of new methods to stimulate regeneration of the insulin-secreting β-cells of the islets of Langerhans. Natural restrictions on the islet regeneration are very tight; nevertheless, the islets are capable of physiological regeneration via β-cell self-replication, direct differentiation of multipotent progenitor cells and spontaneous α- to β- or δ- to β-cell conversion (trans-differentiation). The existing preclinical models of β-cell dysfunction or ablation (induced surgically, chemically or genetically) have significantly expanded our understanding of reparative regeneration of the islets and possible ways of its stimulation. The ultimate goal, sufficient level of functional activity of β-cells or their substitutes can be achieved by two prospective broad strategies: β-cell replacement and β-cell regeneration. The "regeneration" strategy aims to maintain a preserved population of β-cells through in situ exposure to biologically active substances that improve β-cell survival, replication and insulin secretion, or to evoke the intrinsic adaptive mechanisms triggering the spontaneous non-β- to β-cell conversion. The "replacement" strategy implies transplantation of β-cells (as non-disintegrated pancreatic material or isolated donor islets) or β-like cells obtained ex vivo from progenitors or mature somatic cells (for example, hepatocytes or α-cells) under the action of small-molecule inducers or by genetic modification. We believe that the huge volume of experimental and clinical studies will finally allow a safe and effective solution to a seemingly simple goal-restoration of the functionally active β-cells, the innermost hope of millions of people globally.

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Modeling K,ATP--dependent excitability in pancreatic islets.

Publications

Modeling K,ATP--dependent excitability in pancreatic islets.

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