Title | Insulin demand regulates β cell number via the unfolded protein response. |
Publication Type | Journal Article |
Year of Publication | 2015 |
Authors | Sharma RB, O'Donnell AC, Stamateris RE, Ha B, McCloskey KM, Reynolds PR, Arvan P, Alonso LC |
Journal | J Clin Invest |
Volume | 125 |
Issue | 10 |
Pagination | 3831-46 |
Date Published | 2015 Oct 01 |
ISSN | 1558-8238 |
Keywords | Activating Transcription Factor 6, Adaptation, Physiological, Animals, Biomarkers, Calcium Signaling, Cell Division, Cells, Cultured, Endoplasmic Reticulum Stress, Endoplasmic Reticulum, Rough, Gene Expression Regulation, Glycosylation, Humans, Hyperglycemia, Insulin, Insulin-Secreting Cells, Male, Mice, Inbred C57BL, Mice, Mutant Strains, Models, Biological, Obesity, Proinsulin, Protein Processing, Post-Translational, Receptors, Leptin, Recombinant Fusion Proteins, 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. |
DOI | 10.1172/JCI79264 |
Alternate Journal | J. Clin. Invest. |
PubMed ID | 26389675 |
PubMed Central ID | PMC4607122 |
Grant List | U24-DK093000 / DK / NIDDK NIH HHS / United States R01 DK095140 / DK / NIDDK NIH HHS / United States R01 DK048280 / DK / NIDDK NIH HHS / United States K08 DK076562 / DK / NIDDK NIH HHS / United States U24 DK093000 / DK / NIDDK NIH HHS / United States DK095140 / DK / NIDDK NIH HHS / United States DK076562 / DK / NIDDK NIH HHS / United States P30 DK020572 / DK / NIDDK NIH HHS / United States DK48280 / DK / NIDDK NIH HHS / United States |