Cellcell communication and the regulation of insulin secretion
The mechanisms through which pancreatic beta cells recognise and respond to external signals Type 2 diabetes is becoming increasing well understood, but we have less understanding of how the responses of individual cells are integrated within the islet of Langerhans. Islets are heterogenous organs containing a variety of endocrine cell types including beta, alpha, delta and PP cells which synthesise and secrete insulin, glucagon, somatostatin and pancreatic polypeptide, respectively. Disaggregation of islets results in impaired insulin secretion from the beta cells, suggesting that interactions between cells within islets are important in regulating normal islet function. Islet cells express a variety of cell adhesion molecules which confer the capacity for the spontaneous re-aggregation of dispersed islet cells into anatomically-correct, three-dimensional islet-like structures, and this is associated with a return to more appropriate patterns of insulin secretion. There are numerous possible mechanisms through which intercellular communication within the islet may modulate beta cell function, including gap junctions, paracrine signalling and direct cell-cell interactions through cell surface molecules. In vivo studies using transgenic mice and in vitro studies using isolated islets or hormone-secreting cells lines suggest that several different mechanisms act simultaneously to maintain appropriate insulin secretion by co-ordinating beta cell responses to external stimuli. Thus, gene ablation studies have identified an important role for connexin-36 gap junctions in the synchronous behaviour of adjacent beta cells. Interactions between cell surface molecules such as E-Cadherin, Ephs and Ephrins have been implicated in communication between adjacent islet cells to regulate insulin secretion, beta cell proliferation and apoptosis. Finally, beta cells express numerous cell surface receptors to islet hormones and other potential auto/paracrine regulators, and there is considerable evidence of multiple levels of regulation of beta cell function by intra-islet diffusible signals. Understanding these complex interactions between islet cells may offer novel insights into the causes and treatments of Type 2 diabetes.