E2F1 transcription factor mediates a link between fat and islets to promote ? cell proliferation in response to acute insulin resistance

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.

Automated summary

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.