title: Insulin demand regulates β cell number via the unfolded protein response.
abstract: 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.
authors.forename: Rohit B
authors.initials: RB
authors.lastname: Sharma
authors.forename: Amy C
authors.initials: AC
authors.lastname: O'Donnell
authors.forename: Rachel E
authors.initials: RE
authors.lastname: Stamateris
authors.forename: Binh
authors.initials: B
authors.lastname: Ha
authors.forename: Karen M
authors.initials: KM
authors.lastname: McCloskey
authors.forename: Paul R
authors.initials: PR
authors.lastname: Reynolds
authors.forename: Peter
authors.initials: P
authors.lastname: Arvan
authors.forename: Laura C
authors.initials: LC
authors.lastname: Alonso
mesh_terms: D051702:Activating Transcription Factor 6 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D000222:Adaptation, Physiological; D000818:Animals; D015415:Biomarkers; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology; D002455:Cell Division; D002478:Cells, Cultured; D059865:Endoplasmic Reticulum Stress / Q000502:physiology; D018870:Endoplasmic Reticulum, Rough / Q000648:ultrastructure; D005786:Gene Expression Regulation; D006031:Glycosylation; D006801:Humans; D006943:Hyperglycemia / Q000503:physiopathology; D007328:Insulin / Q000235:genetics / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008954:Models, Biological; D009765:Obesity / Q000235:genetics / Q000503:physiopathology; D011384:Proinsulin / Q000235:genetics; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D054411:Receptors, Leptin / Q000172:deficiency; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D056811:Unfolded Protein Response / Q000502:physiology*
chemical_list: C497111:ATF6 protein, human; D051702:Activating Transcription Factor 6; C497112:Atf6 protein, mouse; D015415:Biomarkers; D007328:Insulin; D054411:Receptors, Leptin; D011993:Recombinant Fusion Proteins; C515447:leptin receptor, mouse; D011384:Proinsulin