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Insulin demand regulates β cell number via the unfolded protein response
Rohit B. Sharma, … , Peter Arvan, Laura C. Alonso
Rohit B. Sharma, … , Peter Arvan, Laura C. Alonso
Published September 21, 2015
Citation Information: J Clin Invest. 2015;125(10):3831-3846. https://doi.org/10.1172/JCI79264.
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Research Article Endocrinology Article has an altmetric score of 36

Insulin demand regulates β cell number via the unfolded protein response

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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

Rohit B. Sharma, Amy C. O’Donnell, Rachel E. Stamateris, Binh Ha, Karen M. McCloskey, Paul R. Reynolds, Peter Arvan, Laura C. Alonso

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Figure 7

UPR activation is required for insulin demand–induced β cell proliferation in vivo.

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UPR activation is required for insulin demand–induced β cell proliferati...
(A) Twice daily i.p. injections of TUDCA for 2 days prior to euthanasia reduced β cell ER stress marker BiP in Akita and db/db-BLKS ER load models. Images are representative of n = 3 biological replicates. (B–G) Two days of twice daily i.p. TUDCA reduced β cell proliferation in 2-week-old Akita mice (B and C; n = 3–5), in 4-week-old db/db mice (D and E; n = 5–13), and in HFD-fed mice (F and G; n = 5–8). Images were acquired at ×200 magnification. Arrowheads point to BrdU-positive β cells. Data are represented as mean ± SEM; *P < 0.05 and **P < 0.01 by ANOVA.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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