Modeling the Effect of Neonatal Diabetes Mutations on Electrical Activity and Insulin Secretion in Pancreatic Beta Cell

Diabetes is caused by dysfunctional beta (beta) cells found in the multicellular pancreatic islet of Langerhans, an essential micro-organ to maintaining glucose homeostasis via the secretion of insulin. beta cells are highly coupled within the islet, functioning to coordinate a global response to elevated glucose levels and suppressing insulin secretion at basal glucose levels. Despite intrinsic heterogeneity in beta cells, the islet displays network behavior where global activation and suppression are a result of the intracellular coupling between beta cells by means of gap junctions. Previous work has shown that under the influence of gap junction coupling there exists a critical number of inexcitable cells (~15%) that can act as a dominate negative to the system, and suppress activity in stimulatory glucose conditions. This was done by using an inducible mutation that renders specific cells inexcitable, producing a functional form of Neonatal Diabetes Mellitus (NDM), and was simulated by a multi-cellular model for beta cell electrophysiology. We explore this critical behavior further by altering the level of cell-cell coupling by removing gap junction expression in mice and simulating an uncoupled multi-cellular islet with multiple forms of the inactivating (NDM) mutation. We find that critical behavior is diminished when coupling is removed, and islet electrical activity can persist into the realm of severe NDM mutation. Further, we add completeness to the model of the beta cell by accounting for stochastic channel noise and insulin secretion. We show that critical behavior in physiological parameters, e.g. insulin secretion, and electrical activity as measured by real time and simulated calcium dynamics and can be rescued when cell-cell coupling is removed. We present these results as further characterization of the emergent critical behavior in the islet and uncover possible treatment methods for Neonatal Diabetes Mellitus, and other monogenic forms of diabetes.