Experimental and theoretical investigations of the phantom bursting model for pancreatic beta-cell electrical activity

Pancreatic β-cells secrete insulin in response to stimulatory glucose levels through a stimulus-secretion coupling mechanism. A key step in this pathway is the generation of a characteristic pattern of electrical oscillations known as bursting. β-cell electrical oscillations encompass a wide range of frequencies that are separated into three categories: fast, medium, and slow. Although the medium oscillations have been well characterized since their discovery in 1968, the mechanism underlying these oscillations is not fully understood. A recent model, the Phantom Bursting Model (PBM), suggests that the medium oscillation is the result of interaction between the mechanisms that drive the fast and slow oscillation, such that no mechanism is directly responsible for driving the medium oscillation (hence the phantom oscillation). This model provides a new perspective on how and why medium oscillations occur in pancreatic β-cells. In this thesis, predictions of the PBM were compared to membrane potential oscillations recorded from β-cells in intact mouse islets of Langerhans. First, the property of bistability was explored and found to be present in slow membrane potential oscillations. This finding supports the modeling of slow oscillations in the PBM as bistable oscillations. Second, the glucose sensitivity of the fast, medium, and slow oscillations was explored by applying small changes in glucose concentration throughout the stimulatory regime. A relationship between β-cell electrical activity and oscillation frequency was obtained and imposed on the PBM to produce a more physiologically relevant model. Third, a theoretical islet study was performed to explain why a wide range of burst periods is experimentally observed in isolated β-cells, yet islets robustly oscillate in the medium regime. This study found that a Gaussian-like distribution of a single parameter within an islet can result in a bimodal single-cell period distribution, with very few single cells oscillating in the medium regime. Electrically coupling the cells produced model islets that robustly oscillated with medium frequency, suggesting that medium oscillations are an emergent property of islets. In summary, the results of this study both lend support to and refine the Phantom Bursting Model and deepen our understanding of β-cell oscillations.