Integrated multiscale mathematical modeling of insulin secretion reveals the role of islet network integrity for proper oscillatory glucose-dose response

Abstract

The integrated multiscale mathematical model we present in this paper is built on two of our previous ones: a model of electrical oscillation in β-cells connected to neighboring cells within a three-dimensional (3D) network, and a model of glucose-induced β-cell intracellular insulin granule trafficking and insulin secretion. In order to couple these two models, we assume that the rate at which primed and release-ready insulin granules fuse at the cell membrane increases with the intracellular calcium concentration. Moreover, by assuming that the fraction of free KATP-channels decreases with increasing glucose concentration, we take into account the effect of glucose dose on membrane potential and, indirectly via the effect on the potential, on intracellular calcium. Numerical analysis of our new model shows that a single step increase in glucose concentration yields the experimentally observed characteristic biphasic insulin release. We find that the biphasic response is typically oscillatory in nature for low and moderate glucose concentrations. The plateau fraction (the time that the β-cells spend in their active firing phase) increases with increasing glucose dose, as does the total insulin secretion. At high glucose concentrations, the oscillations tend to vanish due to a constantly elevated membrane potential of the β-cells. Our results also demonstrate how insulin secretion characteristics in various glucose protocols depend on the degree of β-cell loss, highlighting the potential impact from disease. In particular, both the secretory capacity (average insulin secretion rate per β-cell) and the oscillatory response diminish as the islet cell network becomes compromised.