Identifying the targets of the amplifying pathway for insulin secretion in pancreatic beta-cells by kinetic modeling of granule exocytosis

Biophys J. 2008 Sep;95(5):2226-41. doi: 10.1529/biophysj.107.124990. Epub 2008 May 30.


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.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • Calcium / metabolism
  • Calcium Channels, L-Type / metabolism
  • Calcium Channels, R-Type / metabolism
  • Calcium Signaling / physiology
  • Cytoplasmic Granules / metabolism*
  • Exocytosis*
  • Glucose / metabolism
  • Insulin / metabolism*
  • Insulin Secretion
  • Insulin-Secreting Cells / metabolism*
  • Insulin-Secreting Cells / ultrastructure
  • Kinetics
  • Membrane Microdomains / metabolism
  • Membrane Potentials
  • Mice
  • Models, Biological*
  • Rats


  • Calcium Channels, L-Type
  • Calcium Channels, R-Type
  • Insulin
  • Glucose
  • Calcium