Description:

The emphasis of this project is on the mechanism of pancreatic islet coordination. We have pursued a series of experiments designed to assess the overall hypothesis that regulated insulin secretion, from primary, reconstituted or ductal cell derived islets, depends on the intra-islet organization, inclusive of coordinated cell function, cell-cell communication and the balance of heterogeneous cell types. The research outlined tests this hypothesis using primary, reconstituted, and engineered islets. This forms the overall aim. We address this hypothesis by combining new and established procedures for generating islets with novel and established experimental procedures to monitor the islet metabolic state, insulin secretion and cellular connectivity within the islets.

The pulsatile release of insulin is achieved through coordinated activity of hundreds of beta cells within the islet. This periodic release is important for the efficiency of action on organs targeted. A lack of coordination in the activity of insulin secreting beta cells, and the other cells present in the islet, will affect the periodicity of insulin release and consequently the activity of the target organs. The periodic pattern of insulin secretion is altered in type-II diabetes patients.

Progress:

We have developed an electrophysiological recording technique, and data analysis methods, to probe the electrical activity of cell populations in the intact islet. Spatiotemporal changes in population spikes synchrony within cell population and between cell populations have been studied, revealing glucose dependent linkages within the islet that break down at both high and low levels. The breakdown at high glucose levels has clear implications for the diabetic condition where blood glucose regulation fails. These results imply that in some conditions the pathosphysiology will be exacerbated by a subsequent disruption in beta cell function, for example insulin resistance in type-II diabetes.