Interaction of glycolysis and mitochondrial respiration in metabolic oscillations of pancreatic islets

Insulin secretion from pancreatic beta-cells is oscillatory, with a typical period of 2-7 min, reflecting oscillations in membrane potential and the cytosolic Ca2+ concentration. Our central hypothesis is that the slow 2-7 min oscillations are due to glycolytic oscillations, whereas faster oscillations that are superimposed are due to Ca2+ feedback onto metabolism or ion channels. We extend a previous mathematical model based on this hypothesis to include a more detailed description of mitochondrial metabolism. We demonstrate that this model can account for typical oscillatory patterns of membrane potential and Ca2+ concentration in islets. It also accounts for temporal data on oxygen consumption in islets. A recent challenge to the notion that glycolyfic oscillations drive slow Ca2+ Oscillations in islets are data showing that oscillations in Ca2+, mitochondrial oxygen consumption, and NAD(P)H levels are all terminated by membrane hyperpolarization. We demonstrate that these data are in fact compatible with a model in which glycolytic oscillations are the key player in rhythmic islet activity. Finally, we use the model to address the recent finding that the activity of islets from some mice is uniformly fast, whereas that from islets of other mice is slow. We propose a mechanism for this dichotomy.