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

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.
Jun Shirakawa 1,  Yu Togashi 2,  Giorgio Basile 3,  Tomoko Okuyama 2,  Ryota Inoue 4,  Megan Fernandez 3,  Mayu Kyohara 2,  Dario F De Jesus 3,  Nozomi Goto 2,  Wei Zhang 3,  Takahiro Tsuno 4,  Tatsuya Kin 5,  Hui Pan 6,  Jonathan M Dreyfuss 6,  A M James Shapiro 5,  Peng Yi 3,  Yasuo Terauchi 2,  Rohit N Kulkarni 7
Affiliations

Affiliations

  • 1 Islet Cell and Regenerative Biology, Joslin Diabetes Center, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02215, USA; Laboratory of Diabetes and Metabolic Disorders, Institute for Molecular and Cellular Regulation (IMCR), Gunma University, Maebashi 3718512, Japan; Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama-City University, Yokohama 2360004, Japan. Electronic address: [email protected].
  • 2 Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama-City University, Yokohama 2360004, Japan.
  • 3 Islet Cell and Regenerative Biology, Joslin Diabetes Center, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02215, USA.
  • 4 Laboratory of Diabetes and Metabolic Disorders, Institute for Molecular and Cellular Regulation (IMCR), Gunma University, Maebashi 3718512, Japan.
  • 5 Clinical Islet Laboratory and Clinical Islet Transplant Program, University of Alberta, Edmonton, AB, Canada.
  • 6 Bioinformatics Core, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215, USA.
  • 7 Islet Cell and Regenerative Biology, Joslin Diabetes Center, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02215, USA. Electronic address: [email protected].
PMID: 36198264 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.

Figures
Products