The insulin-secreting p-cells of the pancreas play a crucial role in blood glucose homeostasis. An elevation in blood glucose triggers the release of insulin into the systemic circulation, restoring euglycaemia. Diabetes mellitus arises when there is no longer an adequate supply of insulin available to regulate the concentration of blood glucose effectively. Beta-cells reside within cellular aggregates called the islets of Langerhans, the three-dimensional anatomy of which is crucial to their secretory function. It is well established that increased cell proximity augments glucose-evoked insulin secretion and several studies have highlighted the importance of homologous p-cell contacts within the islet configuration. It has been suggested that the improved secretory function is the result of communication via gap junctions and/or paracrine mediators between adjacent p-cells. However, there may be other molecules that are capable of modulating p-cell function in response to cell contact and recent work has provided evidence for a role for the Ca2+-dependent cell adhesion protein, E-cadherin. Using MIN6 pseudoislets as a model system, this study demonstrates that E-cadherin is a key regulator of p-cell function and is more than just an adhesion molecule, holding the three-dimensional islet together. It is not only important for the homotypic coupling of p-cells but also affects their secretory activity. Insulin secretion experiments demonstrate that the treatment of pre-formed pseudoislets with an immuno-neutralising E-cadherin antibody markedly reduces glucose-evoked insulin release. Furthermore, Fura-2 microfluorimtery shows that the synchronous glucoseinduced [Ca21i oscillations characteristic of pseudoislets are lost in the absence of Ecadherin- based cell contacts. Attenuation of fluorescent dye transfer between cells in the absence of cadherin ligation indicates a lack of functional gap junctions under such conditions providing evidence for an interaction between gap junctions and Ecadherin in p-cells. Overall these findings imply that E-cadherin has an important role in the regulation of intercellular communication between p-cells within the islet, an effect which appears to be gap junction dependent. The results of this study have potential implications for the in vitro generation of islets for future transplantation therapy.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:504819 |
| Date | January 2007 |
| Creators | Rogers, Gareth James |
| Publisher | University of Warwick |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
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