Signal transduction pathways controlling Ins2 gene activity and beta cell state transitions.

Pancreatic β cells exist in low and high insulin gene activity states that are dynamic on a scale of hours to days. Here, we used live 3D imaging, mass spectrometry proteomics, and targeted perturbations of β cell signaling to comprehensively investigate Ins2(GFP)(HIGH) and Ins2(GFP)(LOW) β cell states. We identified the two Ins2 gene activity states in intact isolated islets and showed that cells in the same state were more likely to be nearer to each other. We report the proteomes of pure β cells to a depth of 5555 proteins and show that β cells with high Ins2 gene activity had reduced β cell immaturity factors, as well as increased translation. We identified activators of cAMP signaling (GLP1, IBMX) as powerful drivers of Ins2(GFP)(LOW) to Ins2(GFP)(HIGH) transitions. Okadaic acid and cyclosporine A had the opposite effects. This study provides new insight into the proteomic profiles and regulation of β cell states.