Journal
CELL REPORTS
Volume 41, Issue 1, Pages -Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2022.111436
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Funding
- MEXT of Japan [20K08866]
- Japan IDDM network
- Japan Diabetes Foundation
- Astellas Foundation for Research on Metabolic Disorders
- Naito Foundation
- Uehara Memorial Foundation
- Taiju Life Social Walfare Foundation
- A*STAR - AMED JOINT CALL for the Strategic International Collaborative Research Program (SICORP)
- Juvenile Diabetes Research Foundation Post-doctoral Fellowship [2-PDF-2020-435-A-N]
- Mary K. Iacocca Junior Postdoctoral Fellowship
- ADA Postdoctoral Fellowship [7-21-PDF-140]
- NIH [R01 DK067536, R01 DK105588, R01 DK117639]
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This study investigates the replication pathways of β cells under acute insulin resistance and identifies the involvement of insulin-independent factors CENP-A and transcription factor E2F1 in the multiplication of β cells induced by S961. Inhibition of E2F1 blocks β-cell proliferation in S961-injected mice. Furthermore, adipocytes activate E2F1 to promote β-cell replication.
Prevention or amelioration of declining 0 cell mass is a potential strategy to cure diabetes. Here, we report the pathways utilized by 0 cells to robustly replicate in response to acute insulin resistance induced by S961, a pharmacological insulin receptor antagonist. Interestingly, pathways that include CENP-A and the transcrip-tion factor E2F1 that are independent of insulin signaling and its substrates appeared to mediate S961 -induced 0 cell multiplication. Consistently, pharmacological inhibition of E2F1 blocks 0-cell proliferation in S961-injected mice. Serum from S961-treated mice recapitulates replication of 0 cells in mouse and human islets in an E2F1-dependent manner. Co-culture of islets with adipocytes isolated from S961-treated mice en-ables 0 cells to duplicate, while E2F1 inhibition limits their growth even in the presence of adipocytes. These data suggest insulin resistance-induced proliferative signals from adipocytes activate E2F1, a potential ther-apeutic target, to promote 0 cell compensation.
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