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.

The IGFBP3/TMEM219 pathway regulates beta cell homeostasis / F. D'Addio, A. Maestroni, E. Assi, M. Ben Nasr, G. Amabile, V. Usuelli, C. Loretelli, F. Bertuzzi, B. Antonioli, F. Cardarelli, B. El Essawy, A. Solini, I.C. Gerling, C. Bianchi, G. Becchi, S. Mazzucchelli, D. Corradi, G.P. Fadini, D. Foschi, J.F. Markmann, E. Orsi, J. Škrha, M.G. Camboni, R. Abdi, A.M. James Shapiro, F. Folli, J. Ludvigsson, S. Del Prato, G.V. Zuccotti, P. Fiorina. - In: NATURE COMMUNICATIONS. - ISSN 2041-1723. - 13:1(2022 Feb 03), pp. 684.1-684.14. [10.1038/s41467-022-28360-2]

The IGFBP3/TMEM219 pathway regulates beta cell homeostasis

F. D'Addio
Primo
;
A. Maestroni
Secondo
;
E. Assi;M. Ben Nasr;V. Usuelli;C. Loretelli;B. Antonioli;C. Bianchi;S. Mazzucchelli;D. Foschi;E. Orsi;F. Folli;G.V. Zuccotti
Penultimo
;
P. Fiorina
Ultimo
2022

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.
Settore MED/13 - Endocrinologia
Settore MED/50 - Scienze Tecniche Mediche Applicate
Settore MED/49 - Scienze Tecniche Dietetiche Applicate
PSR2015-1716MMARI_M - PIANO DI SOSTEGNO ALLA RICERCA 2015-2017 - LINEA 2 "DOTAZIONE ANNUALE PER ATTIVITA' ISTITUZIONALE" - MARIOTTI, MAURIZIO - PSR2015-17 - Piano di sviluppo di ricerca 2015-17 - 2015
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/903167
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