Transitions between bursting modes in the integrated oscillator model for pancreatic β-cells

Insulin-secreting beta-cells of pancreatic islets of Langerhans produce bursts of electrical impulses, resulting in intracellular Ca2+ oscillations and pulsatile insulin secretion. The mechanism for this bursting activity has been the focus of mathematical modeling for more than three decades, and as new data are acquired old models are modified and new models are developed. Comprehensive models must now account for the various modes of bursting observed in islet beta-cells, which include fast bursting, slow bursting, and compound bursting. One such model is the Integrated Oscillator Model (IOM), in which beta-cell electrical activity, intracellular Ca2+, and glucose metabolism interact via numerous feedforward and feedback pathways. These interactions can produce metabolic oscillations with a sawtooth time course or a pulsatile time course, reflecting very different oscillation mechanisms. In this report, we determine conditions favorable to one form of oscillations or the other, and examine the transitions between modes of bursting and the relationship of the transitions to the patterns of metabolic oscillations. Importantly, this work clarifies what can be expected in experimental measurements of beta-cell oscillatory activity, and suggests pathways through which oscillations of one type can be converted to oscillations of another type. (C) 2018 Elsevier Ltd. All rights reserved.