Phase Transitions in the Multi-cellular Regulatory Behavior of Pancreatic Islet Excitability

The pancreatic islets of Langerhans are multicellular micro-organs integral to maintaining glucose homeostasis through secretion of the hormone insulin. β-cells within the islet exist as a highly coupled electrical network which coordinates electrical activity and insulin release at high glucose, but leads to global suppression at basal glucose. Despite its importance, how network dynamics generate this emergent binary on/off behavior remains to be elucidated. Previous work has suggested that a small threshold of quiescent cells is able to suppress the entire network. By modeling the islet as a Boolean network, we predicted a phase-transition between globally active and inactive states would emerge near this threshold number of cells, indicative of critical behavior. This was tested using islets with an inducible-expression mutation which renders defined numbers of cells electrically inactive, together with pharmacological modulation of electrical activity. This was combined with real-time imaging of intracellular free-calcium activity [Ca2+]i and measurement of physiological parameters in mice. As the number of inexcitable cells was increased beyond ∼15%, a phase-transition in islet activity occurred, switching from globally active wild-type behavior to global quiescence. This phase-transition was also seen in insulin secretion and blood glucose, indicating physiological impact. This behavior was reproduced in a multicellular dynamical model suggesting critical behavior in the islet may obey general properties of coupled heterogeneous networks. This study represents the first detailed explanation for how the islet facilitates inhibitory activity in spite of a heterogeneous cell population, as well as the role this plays in diabetes and its reversal. We further explain how islets utilize this critical behavior to leverage cellular heterogeneity and coordinate a robust insulin response with high dynamic range. These findings also give new insight into emergent multicellular dynamics in general which are applicable to many coupled physiological systems, specifically where inhibitory dynamics result from coupled networks.Author Summary: As science has successfully broken down the elements of many biological systems, the network dynamics of large-scale cellular interactions has emerged as a new frontier. One way to understand how dynamical elements within large networks behave collectively is via mathematical modeling. Diabetes, which is of increasing international concern, is commonly caused by a deterioration of these complex dynamics in a highly coupled micro-organ called the islet of Langerhans. Therefore, if we are to understand diabetes and how to treat it, we must understand how coupling affects ensemble dynamics. While the role of network connectivity in islet excitation under stimulatory conditions has been well studied, how connectivity also suppresses activity under fasting conditions remains to be elucidated. Here we use two network models of islet connectivity to investigate this process. Using genetically altered islets and pharmacological treatments, we show how suppression of islet activity is solely dependent on a threshold number of inactive cells. We found that the islet exhibits critical behavior in the threshold region, rapidly transitioning from global activity to inactivity. We therefore propose how the islet and multicellular systems in general can generate a robust stimulated response from a heterogeneous cell population.