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

ABSTRACT

Prevention or amelioration of declining ß cell mass is a potential strategy to cure diabetes. Here, we report the pathways utilized by ß 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 transcription factor E2F1 that are independent of insulin signaling and its substrates appeared to mediate S961-induced ß cell multiplication. Consistently, pharmacological inhibition of E2F1 blocks ß-cell proliferation in S961-injected mice. Serum from S961-treated mice recapitulates replication of ß cells in mouse and human islets in an E2F1-dependent manner. Co-culture of islets with adipocytes isolated from S961-treated mice enables ß 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 therapeutic target, to promote ß cell compensation.