Glucose Oscillations Can Activate an Endogenous Oscillator in Pancreatic Islets

Pancreatic islets manage elevations in blood glucose level by secreting insulin into the bloodstream in a pulsatile manner. Pulsatile insulin secretion is governed by islet oscillations such as bursting electrical activity and periodic Ca2+ entry in β-cells. In this report, we demonstrate that although islet oscillations are lost by fixing a glucose stimulus at a high concentration, they may be recovered by subsequently converting the glucose stimulus to a sinusoidal wave. We predict with mathematical modeling that the sinusoidal glucose signal’s ability to recover islet oscillations depends on its amplitude and period, and we confirm our predictions by conducting experiments with islets using a microfluidics platform. Our results suggest a mechanism whereby oscillatory blood glucose levels recruit non-oscillating islets to enhance pulsatile insulin output from the pancreas. Our results also provide support for the main hypothesis of the Dual Oscillator Model, that a glycolytic oscillator endogenous to islet β-cells drives pulsatile insulin secretion.

胰岛（pancreatic islets）通过以脉冲方式向血液循环中分泌胰岛素，以调控血糖水平的升高。脉冲式胰岛素分泌受胰岛振荡的调控，包括β细胞（β-cells）内的爆发性电活动与周期性Ca²+内流。本研究证实，尽管将葡萄糖刺激固定于高浓度时会使胰岛振荡消失，但后续将葡萄糖刺激转换为正弦波后，振荡可得以恢复。我们通过数学建模预测，正弦葡萄糖信号恢复胰岛振荡的能力取决于其振幅与周期，并借助微流控平台（microfluidics platform）开展胰岛实验验证了上述预测。本研究结果揭示了一种机制：振荡性血糖水平可募集非振荡性胰岛，以增强胰腺的脉冲式胰岛素输出；同时也为双振荡器模型（Dual Oscillator Model）的核心假说提供了实验支持——该假说认为，胰岛β细胞内源性的糖酵解振荡器驱动脉冲式胰岛素分泌。