A subcellular model of glucose-stimulated pancreatic insulin secretion

Abstract

When glucose is raised from a basal to stimulating level, the pancreatic islets respond with a typical biphasic insulin secretion pattern. Moreover, the pancreas is able to recognize the rate of change of the glucose concentration. We present a relatively simple model of insulin secretion from pancreatic b-cells, yet founded on solid physiological grounds and capable of reproducing a series of secretion patterns from perfused pancreases as well as from stimulated islets. The model includes the notion of distinct pools of granules as well as mechanisms such as mobilization, priming, exocytosis and kiss-and-run. Based on experimental data, we suggest that the individual b-cells activate at different glucose concentrations. The model reproduces most of the data it was tested against very well, and can therefore serve as a general model of glucose-stimulated insulin secretion. Simulations predict that the effect of an increased frequency of kissand-run exocytotic events is a reduction in insulin secretion without modification of the qualitative pattern. Our model also appears to be the first physiology-based one to reproduce the staircase experiment, which underlies 'derivative control', i.e. the pancreatic capacity of measuring the rate of change of the glucose concentration.

Mathematical modeling and statistical analysis of calcium-regulated insulin granule exocytosis in β-cells from mice and humans

“…The assumption of granules having different glucose thresholds has not been confirmed experimentally. Recently, it was argued using an update of Grodsky's model that threshold behavior on the cellular level (Jonkers and Henquin, 2001), rather than on the levels of granules, can explain the staircase experiments (Pedersen et al, 2008). This model was used (Pedersen et al, 2010) to show how cell heterogeneity might underlie the fact that the pancreas senses not only the plasma glucose concentration, but also how rapid the glucose concentration increases (Breda et al, 2001(Breda et al, , 2002.…”

Multiscale modelling of insulin secretion during an intravenous glucose tolerance test

“…Granules are assumed to be mobilized to a pool of granules docked to the plasma membrane (D) from which they become primed and enter a readily releasable pool (RRP). (Note that the pool D corresponds to the pool denoted 'intermediate pool' in the original publication [15].) In response to calcium influx the RRP granules undergo exocytosis, i.e.…”

“…The mechanistic model [15] describes the dynamics of granule pools in a heterogeneous b-cell population as outlined in figure 1. Granules are assumed to be mobilized to a pool of granules docked to the plasma membrane (D) from which they become primed and enter a readily releasable pool (RRP).…”

“…Inspired by the earlier phenomenological model by Grodsky [14], we developed a mathematical model of insulin granule dynamics that incorporated cell-to-cell heterogeneity in the glucose threshold for cell activation and secretion [15]. By analysing this model with a multiscale approach, we showed that the cell-activation threshold distribution underlies the fact that the pancreas senses not only the glucose concentration but also its rate of change, so-called derivative control in OGTT secretion models [7].…”

“…Here, we follow the multiscale strategy to investigate how the various dynamical steps of our mechanistic model [15] relate to the minimal model description of IVGTT insulin secretion [5]. We find that the IVGTT model can be derived from the cellular model, and in particular that derivative control is negligible during an IVGTT.…”