Newcomer insulin secretory granules as a highly calcium-sensitive pool

Abstract

Insulin secretion is biphasic in response to a step in glucose stimulation. Recent experiments suggest that 2 different mechanisms operate during the 2 phases, with transient first-phase secretion due to exocytosis of docked granules but the second sustained phase due largely to newcomer granules. Another line of research has shown that there exist 2 pools of releasable granules with different Ca(2+) sensitivities. An immediately releasable pool (IRP) is located in the vicinity of Ca(2+) channels, whereas a highly Ca(2+)-sensitive pool (HCSP) resides mainly away from Ca(2+) channels. We extend a previous model of exocytosis and insulin release by adding an HCSP and show that the inclusion of this pool naturally leads to insulin secretion mainly from newcomer granules during the second phase of secretion. We show that the model is compatible with data from single cells on the HCSP and from stimulation of islets by glucose, including L- and R-type Ca(2+) channel knockouts, as well as from Syntaxin-1A-deficient cells. We also use the model to investigate the relative contribution of calcium signaling and pool depletion in controlling biphasic secretion.