The IGFBP3/TMEM219 pathway regulates beta cell homeostasis

Francesca D’Addio, Anna Maestroni, Emma Assi, Moufida Ben Nasr, Giovanni Amabile, Vera Usuelli, Cristian Loretelli, Federico Bertuzzi, Barbara Antonioli, Francesco Cardarelli, Basset El Essawy, Anna Solini, Ivan C. Gerling, Cristina Bianchi, Gabriella Becchi, Serena Mazzucchelli, Domenico Corradi, Gian Paolo Fadini, Diego Foschi, James F. Markmann, Emanuela Orsi, Jan Škrha, Maria Gabriella Camboni, Reza Abdi, A. M. James Shapiro, Franco Folli, Johnny Ludvigsson, Stefano Del Prato, Gianvincenzo Zuccotti and Paolo Fiorina ()
Additional contact information
Francesca D’Addio: Università di Milano
Anna Maestroni: Università di Milano
Emma Assi: Università di Milano
Moufida Ben Nasr: Università di Milano
Giovanni Amabile: Enthera S.r.l.
Vera Usuelli: Università di Milano
Cristian Loretelli: Università di Milano
Federico Bertuzzi: ASST Grande Ospedale Metropolitano Niguarda
Barbara Antonioli: ASST Grande Ospedale Metropolitano Niguarda
Francesco Cardarelli: NEST-Scuola Normale Superiore
Basset El Essawy: Brigham and Women’s Hospital
Anna Solini: University of Pisa
Ivan C. Gerling: University of Tennessee
Cristina Bianchi: University of Pisa and Azienda Ospedaliero-Universitaria Pisana
Gabriella Becchi: University of Parma
Serena Mazzucchelli: Università di Milano
Domenico Corradi: University of Parma
Gian Paolo Fadini: University of Padua
Diego Foschi: Università di Milano
James F. Markmann: Harvard Medical School
Emanuela Orsi: IRCCS Cà Granda - Ospedale Maggiore Policlinico Foundation
Jan Škrha: Charles University, First Faculty of Medicine
Maria Gabriella Camboni: Enthera S.r.l.
Reza Abdi: Brigham and Women’s Hospital
A. M. James Shapiro: University of Alberta
Franco Folli: Università di Milano, ASST Santi Paolo e Carlo
Johnny Ludvigsson: Linköping University
Stefano Del Prato: University of Pisa and Azienda Ospedaliero-Universitaria Pisana
Gianvincenzo Zuccotti: Buzzi Children’s Hospital
Paolo Fiorina: Università di Milano

Nature Communications, 2022, vol. 13, issue 1, 1-14

Abstract: Abstract Loss of pancreatic beta cells is a central feature of type 1 (T1D) and type 2 (T2D) diabetes, but a therapeutic strategy to preserve beta cell mass remains to be established. Here we show that the death receptor TMEM219 is expressed on pancreatic beta cells and that signaling through its ligand insulin-like growth factor binding protein 3 (IGFBP3) leads to beta cell loss and dysfunction. Increased peripheral IGFBP3 was observed in established and at-risk T1D/T2D patients and was confirmed in T1D/T2D preclinical models, suggesting that dysfunctional IGFBP3/TMEM219 signaling is associated with abnormalities in beta cells homeostasis. In vitro and in vivo short-term IGFBP3/TMEM219 inhibition and TMEM219 genetic ablation preserved beta cells and prevented/delayed diabetes onset, while long-term IGFBP3/TMEM219 blockade allowed for beta cell expansion. Interestingly, in several patients’ cohorts restoration of appropriate IGFBP3 levels was associated with improved beta cell function. The IGFBP3/TMEM219 pathway is thus shown to be a physiological regulator of beta cell homeostasis and is also demonstrated to be disrupted in T1D/T2D. IGFBP3/TMEM219 targeting may therefore serve as a therapeutic option in diabetes.

Date: 2022
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DOI: 10.1038/s41467-022-28360-2

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