Oscillations in K(ATP) conductance drive slow calcium oscillations in pancreatic β-cells

ATP-sensitive K+ (K(ATP)) channels were first reported in the beta-cells of pancreatic islets in 1984, and it was soon established that they are the primary means by which the blood glucose level is transduced to cellular electrical activity and consequently insulin secretion. However, the role that the K(ATP) channels play in driving the bursting electrical activity of islet beta-cells, which drives pulsatile insulin secretion, remains unclear. One difficulty is that bursting is abolished when several different ion channel types are blocked pharmacologically or genetically, making it challenging to distinguish causation from correlation. Here, we demonstrate a means for determining whether activity-dependent oscillations in K(ATP) conductance play the primary role in driving electrical bursting in beta-cells. We use mathematical models to predict that if K(ATP) is the driver, then contrary to intuition, the mean, peak, and nadir levels of ATP/ADP should be invariant to changes in glucose within the concentration range that supports bursting. We test this in islets using Perceval-HR to image oscillations in ATP/ADP. We find that mean, peak, and nadir levels are indeed approximately invariant, supporting the hypothesis that oscillations in K(ATP) conductance are the main drivers of the slow bursting oscillations typically seen at stimulatory glucose levels in mouse islets. In conclusion, we provide, for the first time to our knowledge, causal evidence for the role of K(ATP) channels not only as the primary target for glucose regulation but also for their role in driving bursting electrical activity and pulsatile insulin secretion.

Automated summary

ATP-sensitive K+ channels in pancreatic islet beta-cells have been found to play a primary role in transducing blood glucose levels to cellular electrical activity and insulin secretion. In this study, researchers used mathematical models and experimental techniques to investigate the role of K(ATP) conductance oscillations in driving electrical bursting in beta-cells. They found that ATP/ADP levels remain relatively constant despite changes in glucose levels, supporting the hypothesis that oscillations in K(ATP) conductance are the main drivers of bursting electrical activity in mouse islets.