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The IGFBP3/TMEM219 pathway regulates beta cell homeostasis.
D'Addio, Francesca; Maestroni, Anna; Assi, Emma; Ben Nasr, Moufida; Amabile, Giovanni; Usuelli, Vera; Loretelli, Cristian; Bertuzzi, Federico; Antonioli, Barbara; Cardarelli, Francesco; El Essawy, Basset; Solini, Anna; Gerling, Ivan C; Bianchi, Cristina; Becchi, Gabriella; Mazzucchelli, Serena; Corradi, Domenico; Fadini, Gian Paolo; Foschi, Diego; Markmann, James F; Orsi, Emanuela; Skrha, Jan; Camboni, Maria Gabriella; Abdi, Reza; James Shapiro, A M; Folli, Franco; Ludvigsson, Johnny; Del Prato, Stefano; Zuccotti, Gianvincenzo; Fiorina, Paolo.
Afiliación
  • D'Addio F; International Center for T1D, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, DIBIC, Università di Milano, Milan, Italy.
  • Maestroni A; International Center for T1D, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, DIBIC, Università di Milano, Milan, Italy.
  • Assi E; International Center for T1D, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, DIBIC, Università di Milano, Milan, Italy.
  • Ben Nasr M; International Center for T1D, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, DIBIC, Università di Milano, Milan, Italy.
  • Amabile G; Nephrology Division, Boston Children's Hospital and Transplantation Research Center, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
  • Usuelli V; Enthera S.r.l., Milano, Italy.
  • Loretelli C; International Center for T1D, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, DIBIC, Università di Milano, Milan, Italy.
  • Bertuzzi F; Nephrology Division, Boston Children's Hospital and Transplantation Research Center, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
  • Antonioli B; International Center for T1D, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, DIBIC, Università di Milano, Milan, Italy.
  • Cardarelli F; Diabetology Unit, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy.
  • El Essawy B; Diabetology Unit, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy.
  • Solini A; NEST-Scuola Normale Superiore, Pisa, Italy.
  • Gerling IC; Transplantation Research Center, Nephrology Division, Brigham and Women's Hospital, Boston, MA, USA.
  • Bianchi C; Medicine, Al-Azhar University, Cairo, Egypt.
  • Becchi G; Department of Surgical, Medical and Molecular Pathology and Critical Care Medicine, University of Pisa, Pisa, Italy.
  • Mazzucchelli S; Department of Medicine, University of Tennessee, Memphis, TN, USA.
  • Corradi D; Section of Diabetes and Metabolic Disease, Department of Clinical and Experimental Medicine, University of Pisa and Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy.
  • Fadini GP; Department of Medicine and Surgery, Unit of Pathology, University of Parma, Parma, Italy.
  • Foschi D; International Center for T1D, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, DIBIC, Università di Milano, Milan, Italy.
  • Markmann JF; Department of Medicine and Surgery, Unit of Pathology, University of Parma, Parma, Italy.
  • Orsi E; Department of Medicine, University of Padua, Padua, Italy.
  • Skrha J; General Surgery, DIBIC, L. Sacco Hospital, Università di Milano, Milan, Italy.
  • Camboni MG; Division of Transplantation, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
  • Abdi R; Diabetes Service, Endocrinology and Metabolic Diseases Unit, IRCCS Cà Granda - Ospedale Maggiore Policlinico Foundation, Milan, Italy.
  • James Shapiro AM; 3rd Department of Internal Medicine, Charles University, First Faculty of Medicine, Prague, Czech Republic.
  • Folli F; Enthera S.r.l., Milano, Italy.
  • Ludvigsson J; Transplantation Research Center, Nephrology Division, Brigham and Women's Hospital, Boston, MA, USA.
  • Del Prato S; Clinical Islet Transplant Program, Alberta Diabetes Institute, University of Alberta, Edmonton, AB, Canada.
  • Zuccotti G; Endocrinology and Metabolism, Department of Health Science, Università di Milano, ASST Santi Paolo e Carlo, Milan, Italy.
  • Fiorina P; Crown Princess Victoria Children´s Hospital and Div of Pediatrics, Dept of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.
Nat Commun ; 13(1): 684, 2022 02 03.
Article en En | MEDLINE | ID: mdl-35115561
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Transducción de Señal / Regulación de la Expresión Génica / Proteína 3 de Unión a Factor de Crecimiento Similar a la Insulina / Células Secretoras de Insulina / Homeostasis / Proteínas de la Membrana Tipo de estudio: Prognostic_studies Límite: Adult / Animals / Female / Humans / Male / Middle aged Idioma: En Revista: Nat Commun Asunto de la revista: BIOLOGIA / CIENCIA Año: 2022 Tipo del documento: Article País de afiliación: Italia Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Transducción de Señal / Regulación de la Expresión Génica / Proteína 3 de Unión a Factor de Crecimiento Similar a la Insulina / Células Secretoras de Insulina / Homeostasis / Proteínas de la Membrana Tipo de estudio: Prognostic_studies Límite: Adult / Animals / Female / Humans / Male / Middle aged Idioma: En Revista: Nat Commun Asunto de la revista: BIOLOGIA / CIENCIA Año: 2022 Tipo del documento: Article País de afiliación: Italia Pais de publicación: Reino Unido