Peter F. Drain Ph.D.

Our laboratory studies pancreatic β cell biology focused on insulin secretory granule proteins regulating trafficking and exocytic release, and β cell proliferation and anti-oxidant pathways underlying its adaption to oxidative stress in the setting of diabetes mellitus. In pancreatic β cells, the K_ATP channel brings insulin secretion under the control of blood glucose levels. Our major goal is to establish the molecular mechanisms underlying how ATP binding to the K_ATP channel signaling changes in glucose metabolism, in turn, signals commensurate changes in insulin granule trafficking and exocytosis. Normally, the fraction of time the K_ATP channel spends in the inhibited state determines insulin secretory rates. When this regulation goes awry, serious complications at the whole-organism level lead to diabetes and other diseases. (1) We have demonstrated how ATP binding to the Kir6.2 subunit of the K_ATP channel electrostatically couples to the transmembrane domain to cause gate closure. One of the positions of the K_ATPchannel required for this signaling is mutated in the conserved position of the human K_ATP channel in permanent neonatal diabetes (PNDM). (2) We have also combined confocal fluorescence microscopy and a novel molecular strategy to visualize insulin secretion in live β cells. The Ins-C-GFP reporter has exploded the ability to look inside live insulin secreting β cells to study glucose-stimulated insulin granule trafficking and exocytosis. Using this approach, we have localized K_ATP channels to insulin secretory granules. (3) Currently, we are using fluorescent reporters of oxidative stress to explore glucolipotoxicity and its reversal by anti-oxidant and proliferative pathways in pancreatic β cells. (4) Most recently, we are interrogating the role of granule K_ATP channels and its small molecule and protein ligands in regulating insulin secretion and β cell proliferation. Trainees in our laboratory are mentored in the exploration of scientific reasoning in health and disease by applying molecular genetics, confocal live-cell fluorescence imaging, native fluorescent protein gels, and western blotting, with insulin, stress, and cell proliferation ELISAs, to understand β cell biology in health and disease.