Insulin secretion chip (InS-chip) reveals two peaks within first-phase that temporally coincide with a transition in glucose metabolism

Abstract

First-phase glucose-stimulated insulin secretion is mechanistically linked to type 2 diabetes yet the underlying metabolism driving this early stage of secretion is difficult to discern due to significant islet-to-islet variability. Here, we miniaturize a fluorescence anisotropy immunoassay onto a microfluidic device to measure C-peptide secretion from individual islets as a surrogate for insulin (InS-chip). This method measures secretion from up to four islets at a time with ~7 s resolution while providing an optical window for real-time live cell imaging. Using the InS-chip, we reveal for the first time two glucose-dependent peaks of insulin secretion (i.e., a double peak) within the first phase (<10 min). By combining real-time secretion and live cell imaging, we show that islets transition from glycolytic to OxPhos-driven metabolism at the nadir of the peaks. Overall, these data validate the InS-chip to measure glucose-stimulated insulin secretion while revealing the first-phase secretion contains two peaks defined by a shift in glucose metabolism.