| Abstract | Pancreatic beta-cells sense the ambient blood-glucose concentration and secrete insulin to signal other tissues to take up glucose. Mitochondria play a key role in this response as they metabolize nutrients to produce ATP and reactive oxygen species (ROS), both of which are involved in insulin secretion signaling. We have developed a model of beta-cell mitochondrial respiration, ATP synthesis, and ROS production in response to glucose and fatty acid stimulation, based on available data in the literature and mathematical models derived from first principles. The model is consistent with a number of experimental observations reported in the literature. Most notably, it explains the non-ohmic rise in the passive proton-leak rate at high membrane potential and its dependence on increased ROS production. Results from our model suggest increasing mitochondrial density while decreasing uncoupling protein activity may be an effective way to increase glucose-stimulated insulin secretion while decreasing oxidative stress. It also predicts that glucose-stimulated insulin secretion may be inhibited by long-term fatty acid exposure. Using glucose and fatty acid profiles from individuals in a diet study, we find a negative correlation between the amount of ROS produced per ATP, as predicted by the model, and the individual insulin sensitivities. The model can also be applied in a clinical setting to predict the insulin secretion rate and quantify beta-cell function for a single individual. |
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