| First Author | Sharma RB | Year | 2015 |
| Journal | J Clin Invest | Volume | 125 |
| Issue | 10 | Pages | 3831-46 |
| PubMed ID | 26389675 | Mgi Jnum | J:226393 |
| Mgi Id | MGI:5697216 | Doi | 10.1172/JCI79264 |
| Citation | Sharma RB, et al. (2015) Insulin demand regulates beta cell number via the unfolded protein response. J Clin Invest 125(10):3831-46 |
| abstractText | 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 beta cell number expands in response to an increase in insulin demand. Lineage tracing shows that new beta cells are generated from proliferation of mature, differentiated beta cells; however, the mechanism by which these mature cells sense systemic insulin demand and initiate a proliferative response remains unknown. Here, we identified the beta cell unfolded protein response (UPR), which senses insulin production, as a regulator of beta cell proliferation. Using genetic and physiologic models, we determined that among the population of beta cells, those with an active UPR are more likely to proliferate. Moreover, subthreshold endoplasmic reticulum stress (ER stress) drove insulin demand-induced beta cell proliferation, through activation of ATF6. We also confirmed that the UPR regulates proliferation of human beta cells, suggesting that therapeutic UPR modulation has potential to expand beta 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. |
