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.

3rd Department of Internal Medicine Charles University 1st Faculty of Medicine Prague Czech Republic

Clinical Islet Transplant Program Alberta Diabetes Institute University of Alberta Edmonton AB Canada

Crown Princess Victoria Children´s Hospital and Div of Pediatrics Dept of Biomedical and Clinical Sciences Linköping University Linköping Sweden

Department of Medicine and Surgery Unit of Pathology University of Parma Parma Italy

Department of Medicine University of Padua Padua Italy

Department of Medicine University of Tennessee Memphis TN USA

Department of Surgical Medical and Molecular Pathology and Critical Care Medicine University of Pisa Pisa Italy

Diabetes Service Endocrinology and Metabolic Diseases Unit IRCCS Cà Granda Ospedale Maggiore Policlinico Foundation Milan Italy

Diabetology Unit ASST Grande Ospedale Metropolitano Niguarda Milan Italy

Division of Endocrinology ASST Fatebenefratelli Sacco Milan Italy

Division of Transplantation Department of Surgery Massachusetts General Hospital Harvard Medical School Boston MA USA

Endocrinology and Metabolism Department of Health Science Università di Milano ASST Santi Paolo e Carlo Milan Italy

Enthera S r l Milano Italy

General Surgery DIBIC L Sacco Hospital Università di Milano Milan Italy

International Center for T1D Pediatric Clinical Research Center Romeo ed Enrica Invernizzi DIBIC Università di Milano Milan Italy

Medicine Al Azhar University Cairo Egypt

Nephrology Division Boston Children's Hospital and Transplantation Research Center Brigham and Women's Hospital Harvard Medical School Boston MA USA

NEST Scuola Normale Superiore Pisa Italy

Pediatric Clinical Research Center Romeo ed Enrica Invernizzi DIBIC Università di Milano and Department of Pediatrics Buzzi Children's Hospital Milan Italy

Section of Diabetes and Metabolic Disease Department of Clinical and Experimental Medicine University of Pisa and Azienda Ospedaliero Universitaria Pisana Pisa Italy

Transplantation Research Center Nephrology Division Brigham and Women's Hospital Boston MA USA

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