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

Cell Rep. 2022 Oct 4;41(1):111436. doi: 10.1016/j.celrep.2022.111436.

Abstract

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.

Keywords: CP: Metabolism; E2F1; acute insulin resistance; adipocytes; compensation; human beta cells; insulin receptor; inter-organ communication; transcription factor; β cell proliferation.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cell Proliferation
  • Centromere Protein A / metabolism
  • E2F1 Transcription Factor / metabolism
  • Humans
  • Insulin / metabolism
  • Insulin Resistance*
  • Insulin-Secreting Cells* / metabolism
  • Mice
  • Mice, Knockout
  • Receptor, Insulin / metabolism

Substances

  • Centromere Protein A
  • E2F1 Transcription Factor
  • E2F1 protein, human
  • E2f1 protein, mouse
  • Insulin
  • Receptor, Insulin