β Cells in the pancreatic islets are responsible for the regulation and release of insulin. Insulin demand increases in response to elevated blood glucose levels, and loss of β cell mass or function results in the development of diabetes. In mice, the pancreatic β cell population has recently been shown to expand from the proliferation of mature differentiated β cells in response to increased insulin demand; however, the factors that promote β cell expansion are unclear. Rohit Sharma and colleagues at the University of Massachusetts Medical School determined that modest activation of the unfolded protein response (UPR) mature β cells regulates proliferation. Using a proteomics screen, the authors identified UPR-related proteins, including BiP and ATF6, with altered expression levels in the islets of hyperglycemic mice compared to controls. Pancreatic tissue sections from hyperglycemic animals that were co-immunostained for insulin, BiP, and the proliferation marker PCNA revealed that the majority of proliferating β cells also exhibit UPR activation. Cultured murine β cells subjected to both moderate and high levels of ER stress showed that moderate ER stress increased β cell proliferation, while severe stress caused β cell loss, suggesting the presence of a delicate threshold that must be regulated by the UPR. Moreover, in murine models of late-onset diabetes, β cell proliferation increased early after the onset of ER stress; however, these cells ceased to proliferate and dedifferentiated as ER stress became severe. ATF6 was determined to provide the proliferative signal that drives this β cell proliferation, as ATF6 inhibition decreased β cell proliferation. Importantly, treatment of human islets with low-dose UPR-inducing agents increased β cell proliferation. Together, the results of this study suggest UPR modulation as a potential therapeutic strategy for increasing β cell populations in patients with diabetes. The accompanying image shows pancreatic sections from a hyperglycemic mouse. Left section stained for PCNA (red), insulin (green), and DAPI (blue). Right section stained for PCNA (red), BiP (green), and insulin (blue). Note that the majority of proliferating β cells exhibit ER stress.
Although stem cell populations mediate regeneration of rapid turnover tissues, such as skin, blood, and gut, a stem cell reservoir has not been identified for some slower turnover tissues, such as the pancreatic islet. Despite lacking identifiable stem cells, murine pancreatic β cell number expands in response to an increase in insulin demand. Lineage tracing shows that new β cells are generated from proliferation of mature, differentiated β cells; however, the mechanism by which these mature cells sense systemic insulin demand and initiate a proliferative response remains unknown. Here, we identified the β cell unfolded protein response (UPR), which senses insulin production, as a regulator of β cell proliferation. Using genetic and physiologic models, we determined that among the population of β cells, those with an active UPR are more likely to proliferate. Moreover, subthreshold endoplasmic reticulum stress (ER stress) drove insulin demand–induced β cell proliferation, through activation of ATF6. We also confirmed that the UPR regulates proliferation of human β cells, suggesting that therapeutic UPR modulation has potential to expand β cell mass in people at risk for diabetes. Together, this work defines a stem cell–independent model of tissue homeostasis, in which differentiated secretory cells use the UPR sensor to adapt organ size to meet demand.
Rohit B. Sharma, Amy C. O’Donnell, Rachel E. Stamateris, Binh Ha, Karen M. McCloskey, Paul R. Reynolds, Peter Arvan, Laura C. Alonso