Abstract
In this paper a first model is derived and applied which describes the transport of insulin granules through the cell interior and at the membrane of a beta cell. A special role is assigned to the actin network, which significantly influences the transport. For this purpose, microscopically measured actin networks are characterized and then further ones are artificially generated. In a Cellular Automaton model, phenomenological laws for granule movement are formulated and implemented. Simulation results are compared with experiments, primarily using TIRF images and secretion rates. In this respect, good similarities are already apparent. The model is a first useful approach to describe complex granule transport processes in beta cells, and offers great potential for future extensions. Furthermore, the model can be used as a tool to validate hypotheses and associated mechanisms regarding their effect on exocytosis or other processes. For this purpose, the source code for the model is provided online.
Highlights
It is obvious that such a stimulation pattern is nonphysiological, but the biphasic response is the hallmark of a healthy endocrine pancreas, which becomes blurred and diminished in human type 2 diabetes or in rodent models of this disease
Since diminished insulin secretion can be observed in metabolically healthy groups with a high risk of future development of type 2 diabetes, it can be regarded as an independent pathogenetic factor in the development of type 2 diabetes [6,7]
The course of the insulin output in the simulation is compared with the real beta cells, and it is determined whether the simulation ends in stationary states after a certain time
Summary
Glucose is the undisputed main stimulus for the release of insulin, the main glucoregulatory hormone, from pancreatic beta cells. The hypothesis that the biphasic kinetics of insulin secretion are due to two different pools of secretory granules seemed to be confirmed by the first measurements using total intern-reflection microscopy (TIRFM) In these investigations, the fusion rates of insulin granules which were pre-existent in the submembrane space, and those which only appeared during observation, were counted. In contrast to earlier models of granule transport, granules do move towards the plasma membrane and dock at release sites; rather, most of the granules which appear in the submembrane space return back into the cell interior after varying residence times [23,24] The latter observations raise the question of whether the traditional view of the cortical actin web, i.e., as a barrier which separates granules of the reserve pool from those which have reached the fusion sites at the plasma membrane, is correct. This complex seems to act as a physical and functional scaffold, and may define a pool of releasable granules beneath the plasma membrane [28]
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