TY - JOUR
T1 - Amyloid-induced β-cell dysfunction and islet inflammation are ameliorated by 4-phenylbutyrate (PBA) treatment
AU - Montane, Joel
AU - De Pablo, Sara
AU - Castaño, Carlos
AU - Rodríguez-Comas, Júlia
AU - Cadavez, Lisa
AU - Obach, Mercè
AU - Visa, Montse
AU - Alcarraz-Vizán, Gema
AU - Sanchez-Martinez, Melchor
AU - Nonell-Canals, Alfons
AU - Parrizas, Marcelina
AU - Servitja, Joan Marc
AU - Novials, Anna
N1 - Funding Information:
The authors thank M. T. Bowers (University of California, Santa Barbara, Santa Barbara, CA, USA) and R. Tycko (National Institutes of Health, Bethesda, MD, USA) for kindly providing the crystal structures of hIAPP. The authors also thank L. Llorach-Pares (Mind the Byte) for assistance in the computational analysis of hIAPP-PBA complexes. The authors acknowledge K. Katte (CIBERDEM) for editorial work. J.M. is a recipient of an IDIBAPS Postdoctoral Fellowship-BioTrack, supported by the European Community's Seventh Framework Programme (ECFP7/2007-2013) under Grant 229673. L.C. is a recipient of Fundação da Ciência e Tecnologia (FCT-PhD) fellowship SFRH/BD/65645/2009, financed by POPH-QREN. This work was supported by Grants PI11/00679 and PI14/ 00447, integrated in the Plan Estatal I + D + I 2013-2016 from the Ministerio de Economía y Competitividad and cofinanced by the ISCIII-Subdirección General de Evaluación y Fomento de la investigación, Fondo Europeo de Desarrollo Regional (FEDER), the Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), and the CERCA Programme (Generalitat de Catalu-nya), as well as with the support of Project 2014_SGR_520 of the Department of Universities, Research and Information Society of the Government of Catalonia. J.-M.S. and A.N. are joint senior authors. The authors declare no conflicts of interest.
Funding Information:
The authors thank M. T. Bowers (University of California, Santa Barbara, Santa Barbara, CA, USA) and R. Tycko (National Institutes of Health, Bethesda, MD, USA) for kindly providing the crystal structures of hIAPP. The authors also thank L. Llorach-Pares (Mind the Byte) for assistance in the computational analysis of hIAPP-PBA complexes. The authors acknowledge K. Katte (CIBERDEM) for editorial work. J.M. is a recipient of an IDIBAPS Postdoctoral Fellowship-BioTrack, supported by the European Community’s Seventh Framework Programme (ECFP7/2007-2013) under Grant 229673. L.C. is a recipient of Fundação da Ciência e Tecnologia (FCT-PhD) fellowship SFRH/BD/65645/2009, financed by POPH-QREN. This work was supported by Grants PI11/00679 and PI14/ 00447, integrated in the Plan Estatal I + D + I 2013-2016 from the Ministerio de Economía y Competitividad and cofinanced by the ISCIII-Subdirección General de Evaluación y Fomento de la investigación, Fondo Europeo de Desarrollo Regional (FEDER), the Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBER-DEM), and the CERCA Programme (Generalitat de Catalu-nya), as well as with the support of Project 2014_SGR_520 of the Department of Universities, Research and Information Society of the Government of Catalonia. J.-M.S. and A.N. are joint senior authors. The authors declare no conflicts of interest.
Publisher Copyright:
© FASEB
PY - 2017
Y1 - 2017
N2 - Human islet amyloid polypeptide (hIAPP) aggregation is associated with b-cell dysfunction and death in type 2 diabetes (T2D). we aimed to determine whether in vivo treatment with chemical chaperone 4-phenylbutyrate (PBA) ameliorates hIAPP-induced b-cell dysfunction and islet amyloid formation. Oral administration of PBA in hIAPP transgenic (hIAPP Tg) mice expressing hIAPP in pancreatic b cells counteracted impaired glucose homeostasis and restored glucose-stimulated insulin secretion. Moreover, PBA treatment almost completely prevented the transcriptomic alterations observed in hIAPP Tg islets, including the induction of genes related to inflammation. PBA also increased b-cell viability and improved insulin secretion in hIAPP Tg islets cultured under glucolipotoxic conditions. Strikingly, PBA not only prevented but even reversed islet amyloid deposition, pointing to a direct effect of PBA on hIAPP. This was supported by in silico calculations uncovering potential binding sites of PBA to monomeric, dimeric, and pentameric fibrillar structures, and by in vitro assays showing inhibition of hIAPP fibril formation by PBA. Collectively, these results uncover a novel beneficial effect of PBA on glucose homeostasis by restoring b-cell function and preventing amyloid formation in mice expressing hIAPP in b cells, highlighting the therapeutic potential of PBA for the treatment of T2D.
AB - Human islet amyloid polypeptide (hIAPP) aggregation is associated with b-cell dysfunction and death in type 2 diabetes (T2D). we aimed to determine whether in vivo treatment with chemical chaperone 4-phenylbutyrate (PBA) ameliorates hIAPP-induced b-cell dysfunction and islet amyloid formation. Oral administration of PBA in hIAPP transgenic (hIAPP Tg) mice expressing hIAPP in pancreatic b cells counteracted impaired glucose homeostasis and restored glucose-stimulated insulin secretion. Moreover, PBA treatment almost completely prevented the transcriptomic alterations observed in hIAPP Tg islets, including the induction of genes related to inflammation. PBA also increased b-cell viability and improved insulin secretion in hIAPP Tg islets cultured under glucolipotoxic conditions. Strikingly, PBA not only prevented but even reversed islet amyloid deposition, pointing to a direct effect of PBA on hIAPP. This was supported by in silico calculations uncovering potential binding sites of PBA to monomeric, dimeric, and pentameric fibrillar structures, and by in vitro assays showing inhibition of hIAPP fibril formation by PBA. Collectively, these results uncover a novel beneficial effect of PBA on glucose homeostasis by restoring b-cell function and preventing amyloid formation in mice expressing hIAPP in b cells, highlighting the therapeutic potential of PBA for the treatment of T2D.
KW - Diabetes
KW - IAPP
KW - Insulin
KW - Pancreatic islets
UR - http://www.scopus.com/inward/record.url?scp=85036656970&partnerID=8YFLogxK
UR - https://www.webofscience.com/wos/woscc/full-record/WOS:000416588300015?SID=EUW1ED0D4DRkcjQK1cYSTxnT07r7i
U2 - 10.1096/fj.201700236R
DO - 10.1096/fj.201700236R
M3 - Article
C2 - 28821639
AN - SCOPUS:85036656970
SN - 0892-6638
VL - 31
SP - 5296
EP - 5306
JO - FASEB Journal
JF - FASEB Journal
IS - 12
ER -