In vivo imaging of individual islets across the mouse pancreas reveals a heterogeneous insulin secretion response to glucose

While numerous techniques can be used to measure and analyze insulin secretion in isolated islets in culture, assessments of insulin secretion in vivo are typically indirect and only semiquantitative. The CpepSfGFP reporter mouse line allows the in vivo imaging of insulin secretion from individual islets after a glucose challenge, in live, anesthetized mice, addressing secretion from the pancreas as a whole. Imaging the whole pancreas at high resolution in live mice includes numerous technical challenges. Using rapid-fire imaging in high dynamic range and tiling combined with computer-assisted masked morphometry, we have developed a method to overcome motion blur, and the effects of anesthesia, to be able to monitor and quantify insulin (CpepSfGFP) content simultaneously and longitudinally for the first time in hundreds of individual islets, throughout a glucose challenge. Through this approach we demonstrate that while isolated islets respond homogeneously to glucose in culture, their response profile differs significantly in vivo. Independent of size or location, some islets respond sharply to a glucose stimulation while others barely secrete at all. This platform therefore provides a powerful approach to study the impact of disease, diet, surgery or pharmacological treatments on insulin secretion in the intact pancreas in vivo.