Insulin demand regulates β cell number via the unfolded protein response
Rohit B. Sharma, Amy C. O’Donnell, Rachel E. Stamateris, Binh Ha, Karen M. McCloskey, Paul R. Reynolds, Peter Arvan, Laura C. Alonso
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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Research Article Endocrinology

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

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 4

Activating mild UPR ex vivo increases β cell proliferation and β cell number.

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Activating mild UPR ex vivo increases β cell proliferation and β cell nu...
(A and B) In primary mouse islet cells, PCNA induced by 15 mM glucose was further increased by low-dose Tg (2–20 nM) or Tm (10–100 ng/ml). A marked drug-dose threshold was apparent; at higher doses of Tg or Tm, PCNA was abruptly lost and decompensation markers CHOP (A) and activated caspase 3 (B) were induced. Numbers below bands are average band intensity quantification of n = 5–7 immunoblots; plots of averages are found in Supplemental Figure 4. *P < 0.05 vs. 15 mM vehicle. (C–E) Mouse islet cells treated with low-dose Tg or Tm increased proliferation in high glucose (n = 3). (F and G) Proliferation was confirmed by phospho-Histone H3 (n = 3). (H) Expression of Akita proinsulin increased β cell proliferation (n = 5). (I–L) Quantitative cell counting using flow cytometry showed increased β cell number in cultures treated with low-dose Tg and Tm (n = 5–7). (J and K) Low-dose Tg did not induce cell death (n = 4). (C and F) Images acquired at ×200 magnification. Data are represented as mean ± SEM; *P < 0.05, **P < 0.01, ***P < 0.001, and †P < 0.0001 by ANOVA. P values in A, B, G, and I–L are vs. 15 mM vehicle.