Co-ordinated Ca2+-signalling within pancreatic islets: does β-cell entrainment require a secreted messenger

Loss of Connexin36 Channels Alters β-Cell Coupling, Islet Synchronization of Glucose-Induced Ca2+ and Insulin Oscillations, and Basal Insulin Release

“…The residual oscillations of insulin secretion that are observed under such conditions (29,30) are irregular and of small amplitude compared with those accompanying the normal [Ca 2ϩ ] i oscillations (31). The fluctuations of insulin secretion that we observed in a few Cx36 Ϫ/Ϫ islets during stimulation with glucose and forskolin also paralleled the transient [Ca 2ϩ ] i increases, suggesting that a weak synchronization among some ␤-cells may persist after the loss of Cx36, presumably as a result of the signaling achieved by diffusible factors (27,28,32). The absence of insulin pulsatility observed in glucose-stimulated Cx36 Ϫ/Ϫ islets cannot be attributed to defects in the action of Ca 2ϩ on exocytosis, because oscillations of [Ca 2ϩ ] i imposed by KCl pulses were able to trigger synchronized pulses of insulin secretion.…”

“…Several studies measuring [Ca 2ϩ ] i in whole islets or clusters of islet cells have indirectly supported this interpretation (5,17,24,25) but could not conclusively prove it, mainly because specific inhibitors of connexin channels are not yet available (26). Alternative explanations attributing synchronization to extracellular signals have thus been put forward (27,28). Our data provide the first direct evidence that gap junctions made of Cx36 channels are essential to ensure the synchronization of glucose-induced [Ca 2ϩ ] i oscillations within intact islets.…”

Configuration of electrofusion-derived human insulin-secreting cell line as pseudoislets enhances functionality and therapeutic utility

“…By contrast, dispersed islet cells have also been reaggregated in culture into islet-like structures with restoration of cellular architecture and the original insulin secretory properties of intact islets (Hopcroft et al 1985, Halban et al 1987, Squires et al 2000. Thus, the normal b-cell secretory response in islets depends on intra-islet coordinated signaling cross talk and communication with adjacent cells (Meda et al 1979, Halban et al 1987, Palti et al 1996, Vozzi et al 1995, Squires et al 2000, Serre-Beinier et al 2002. This has prompted much research into the formation of functional islet-like structures, termed 'pseudoislets', aimed to better understand islet function and provide artificial islets that will function normally when transplanted to an in vivo environment (Kelly et al 2011).…”

“…This is supported by recent studies using heterotypic pseudoislets comprising murine MIN6, alphaTC, and TGP52, which showed that the presence of a-and d-cells in the heterogeneous pseudoislets did not potentiate insulin release in response to established secretagogues compared with pseudoislets comprising MIN6 cells alone (Kelly et al 2010c). Although various mechanisms and signaling pathways contribute to cell communication, these studies suggest that E-Cadherin and gap junction proteins connexin 36 and 43 are prominent in maintaining secretory function and islet architecture (Meda et al 1979, Vozzi et al 1995, Squires et al 2000, Calabrese et al 2004, Luther et al 2005, Brereton et al 2006, Kelly et al 2010b.…”

The calcium-sensing receptor and insulin secretion: a role outside systemic control 15 years on

“…Several theories have been proposed to explain the synchronous and cooperative activity of islets when compared with non-cooperative events in isolated individual b-cells including direct communication via gap junctions (Moreno et al 2005, Rogers et al 2007, the presence of other endocrine cells (Ishihara et al 2003), as well as the existence of extracellular diffusible mediators (Squires et al 2002, Hellman et al 2004. The possibility that local changes in extracellular Ca 2C , resulting from the efflux of mobilised Ca 2C , in one cell are sufficient to activate the CaR on an adjacent cell was elegantly demonstrated in a HEK293 model system (Hofer et al 2000).…”