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The standard model for Ca 2+ oscillations in insulin-secreting pancreatic β cells centers on Ca 2+ entry through voltage-activated Ca 2+ channels. These work in combination with ATP-dependent K + channels, which are the bridge between the metabolic state of the cells and plasma membrane potential. This partnership underlies the ability of the β cells to secrete insulin appropriately on a minute-to-minute time scale to control whole body plasma glucose. Though this model, developed over more than 40 years through many cycles of experimentation and mathematical modeling, has been very successful, it has been challenged by a hypothesis that calcium-induced calcium release from the endoplasmic reticulum through ryanodine or inositol trisphosphate (IP3) receptors is instead the key driver of islet oscillations. We show here that the alternative model is in fact incompatible with a large body of established experimental data and that the new observations offered in support of it can be better explained by the standard model. 

Insulin is secreted in a pulsatile pattern, with important physiological ramifications. In pancreatic β-cells, which are the cells that synthesize insulin, insulin exocytosis is elicited by pulses of elevated intracellular Ca 2+ initiated by bursts of electrical activity. In parallel with these electrical and Ca 2+ oscillations are oscillations in metabolism, and the periods of all of these oscillatory processes are similar. A key question that remains unresolved is whether the electrical oscillations are responsible for the metabolic oscillations via the effects of Ca 2+ , or whether the metabolic oscillations are responsible for the electrical oscillations due to the effects of ATP on ATP-sensitive ion channels? Mathematical modeling is a useful tool for addressing this and related questions as modeling can aid in the design of well-focused experiments that can test the predictions of particular models and subsequently be used to improve the models in an iterative fashion. In this article, we discuss a recent mathematical model, the Integrated Oscillator Model (IOM), that was the product of many years of development. We use the model to demonstrate that the relationship between calcium and metabolism in beta cells is symbiotic: in some contexts, the electrical oscillations drive the metabolic oscillations, while in other contexts it is the opposite. We provide new insights regarding these results and illustrate that what might at first appear to be contradictory data are actually compatible when viewed holistically with the IOM.