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

Prevention or amelioration of declining β cell mass is a potential strategy to cure diabetes. Here, we report the pathways utilized by β 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 β cell multiplication. Consistently, pharmacological inhibition of E2F1 blocks β-cell proliferation in S961-injected mice. Serum from S961-treated mice recapitulates replication of β cells in mouse and human islets in an E2F1-dependent manner. Co-culture of islets with adipocytes isolated from S961-treated mice enables β 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 β cell compensation. [Display omitted] •Insulin receptor-independent pathways promote S961-induced β cell multiplication•β cell proliferation by S961 is mediated via E2F1 and CENP-A•Serum from S961-treated mice enhance β cell replication in mouse and human islets•Adipocytes isolated from S961-treated mice enable β cells to duplicate Adaptive β cell proliferation in response to insulin resistance is a compensatory pathway to increase functional β cell mass. Shirakawa et al. reveal that potential circulating factors from adipocytes drive β cell multiplication via insulin signaling-independent E2F1 and CENP-A pathways in response to S961-induced acute insulin resistance.