Identifying the targets of the amplifying pathway for insulin secretion in pancreatic beta-cells by kinetic modeling of granule exocytosis.
A kinetic model for insulin secretion in pancreatic beta-cells is adapted from a model for fast exocytosis in chromaffin cells. The fusion of primed granules with the plasma membrane is assumed to occur only in the "microdomain" near voltage-sensitive L-type Ca(2+)-channels, where [Ca(2+)] can reach micromolar levels. In contrast, resupply and priming of granules are assumed to depend on the cytosolic [Ca(2+)]. Adding a two-compartment model to handle the temporal distribution of Ca(2+) between the microdomain and the cytosol, we obtain a unified model that can generate both the fast granule fusion and the slow insulin secretion found experimentally in response to a step of membrane potential. The model can simulate the potentiation induced in islets by preincubation with glucose and the reduction in second-phase insulin secretion induced by blocking R-type Ca(2+)-channels (Ca(V)2.3). The model indicates that increased second-phase insulin secretion induced by the amplifying signal is controlled by the "resupply" step of the exocytosis cascade. In contrast, enhancement of priming is a good candidate for amplification of first-phase secretion by glucose, cyclic adenosine 3':5'-cyclic monophosphate, and protein kinase C. Finally, insulin secretion is enhanced when the amplifying signal oscillates in phase with the triggering Ca(2+)-signal.
Laboratory of Biological Modeling, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892-5621, USA.
Yi-der
YD
Chen
Shaokun
S
Wang
Arthur
A
Sherman
D000818:Animals; D002118:Calcium / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000378:metabolism; D020908:Calcium Channels, R-Type / Q000378:metabolism; D020013:Calcium Signaling / Q000502:physiology; D003594:Cytoplasmic Granules / Q000378:metabolism*; D005089:Exocytosis; D005947:Glucose / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism* / Q000648:ultrastructure; D007700:Kinetics; D021962:Membrane Microdomains / Q000378:metabolism; D008564:Membrane Potentials; D051379:Mice; D008954:Models, Biological; D051381:Rats
D020746:Calcium Channels, L-Type; D020908:Calcium Channels, R-Type; D007328:Insulin; D005947:Glucose; D002118:Calcium