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.␤-cells ͉ biphasic secretion ͉ exocytosis ͉ pancreatic islets ͉ vesicles

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

“…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. Other models describe the dynamics of granules as they move between different pools, and the control of exocytosis by Ca 2+ (Bertuzzi et al, 2007;Chen et al, 2008;Pedersen and Sherman, 2009). Using such a model it was suggested (Pedersen and Sherman, 2009) that a highly Ca 2+ -sensitive pool, described by capacitance measurements (Wan et al, 2004;Yang and Gillis, 2004) could correspond to newcomer granules seen in TIRF microscopy experiments (Ohara-Imaizumi et al, 2004), illustrating how mathematical models can be used to integrate data obtained with different techniques and on different timescales.…”

“…Other models describe the dynamics of granules as they move between different pools, and the control of exocytosis by Ca 2+ (Bertuzzi et al, 2007;Chen et al, 2008;Pedersen and Sherman, 2009). Using such a model it was suggested (Pedersen and Sherman, 2009) that a highly Ca 2+ -sensitive pool, described by capacitance measurements (Wan et al, 2004;Yang and Gillis, 2004) could correspond to newcomer granules seen in TIRF microscopy experiments (Ohara-Imaizumi et al, 2004), illustrating how mathematical models can be used to integrate data obtained with different techniques and on different timescales. This link between Ca 2+ -sensitivity and fusion mode was partly confirmed experimentally (Ohara-Imaizumi et al, 2009).…”

“…In this way, a behavior resembling TIRFM-imaging of [Ca 2+ ] mem (Hoppa et al, 2009) was obtained. The Ca 2+ -dynamics is described following (Chen et al, 2008;Pedersen and Sherman, 2009;Pedersen, 2010b), based on data from mouse β-cells (Chen et al, 2003). Exocytosis was assumed to be triggered from the submembrane Ca 2+ -compartment, and its rate was modelled as a Hillfunction of [Ca 2+ ] mem with relative high Ca 2+ -sensitivity (K D = 2 µM) and modest cooperativity (n = 3), mimicking the highly Ca 2+ -sensitive pool described in rat β-cells (Wan et al, 2004).…”

Multiscale modelling of insulin secretion during an intravenous glucose tolerance test

“…In particular, the model does not consider Ca 2þ dynamics, which is known to have complex temporal patterns with a first phase of raised cytosolic Ca 2þ concentrations followed by oscillations [22]. It is most likely that both granule pool dynamics and Ca 2þ patterns contribute to the typical biphasic secretion patterns seen after a rapid rise in glucose [23], such as following the glucose bolus in the IVGTT, as well as other secretion profiles. It will be interesting to investigate the relative contribution of Ca 2þ versus granule pool dynamics to IVGTT and OGTT insulin secretion profiles following the multiscale ideas presented in Pedersen et al [7] and in the present article.…”

Monoacylglycerol as a Metabolic Coupling Factor in Glucose-Stimulated Insulin Secretion

“…It is important to note that AMG9810 does not inhibit GSIS completely, even at high concentrations, which suggests that the TRPV1-R in -cells only partially contributes to the total Ca 2+ influx needed for exocytosis. It has been suggested that in islet -cells, while the 1 st phase insulin secretion is coupled to L-type Ca 2+ channels, the 2 nd phase secretion is probably coupled to R-type Ca 2+ channels (Jing et al, 2005;Pedersen and Sherman, 2009). …”