Coordination of pancreatic islet rhythmic activity by delayed negative feedback

Secretion of insulin from the pancreas is pulsatile, driven by intrinsic oscillations within individual islets of Langerhans. The secretions are coordinated among the many islets distributed throughout the pancreas producing a synchronized rhythm in vivo that is essential for maintaining normal glucose levels. One hypothesized mechanism for the coordination of islet activity is negative feedback, whereby sequestration of glucose in response to elevated insulin leads to a reduction in the blood glucose level that is sensed by the islet population. This global signal of glucose then coordinates the individual islets. In this study, we tested how this coordination mechanism is affected by time delays in the negative feedback, using a microfluidic system to monitor Ca²⁺ levels in a small population of islets and implementing glucose control through a negative feedback system. We found that islet synchronization occurs even with time delays in the feedback of up to 7 min. We also found that a second, slower closed-loop oscillation period is produced during delayed feedback in which islet oscillations are clustered into episodes. The period of this second oscillatory mode increases with the time delay and appears to be a second stable behavior that coexists with the faster synchronized oscillation. The general conclusion is that islet coordination through negative feedback is a viable means of islet coordination that is robust to delays in the timing of the feedback, and could complement other potential coordination mechanisms such as entrainment by pancreatic ganglia.NEW & NOTEWORTHY Insulin secretion from islets of Langerhans is rhythmic, and these rhythms are coordinated to produce oscillatory plasma insulin levels. Using a combination of microfluidics and computational modeling, we demonstrate that coordination can occur through negative feedback of the type provided by the liver, even if that feedback is delayed by several minutes. We also demonstrate that a second, slower, mode of oscillations can occur when feedback is delayed where faster oscillations are grouped into episodes.