title: Time-resolved studies define the nature of toxic IAPP intermediates, providing insight for anti-amyloidosis therapeutics.
abstract: Islet amyloidosis by IAPP contributes to pancreatic β-cell death in diabetes, but the nature of toxic IAPP species remains elusive. Using concurrent time-resolved biophysical and biological measurements, we define the toxic species produced during IAPP amyloid formation and link their properties to induction of rat INS-1 β-cell and murine islet toxicity. These globally flexible, low order oligomers upregulate pro-inflammatory markers and induce reactive oxygen species. They do not bind 1-anilnonaphthalene-8-sulphonic acid and lack extensive β-sheet structure. Aromatic interactions modulate, but are not required for toxicity. Not all IAPP oligomers are toxic; toxicity depends on their partially structured conformational states. Some anti-amyloid agents paradoxically prolong cytotoxicity by prolonging the lifetime of the toxic species. The data highlight the distinguishing properties of toxic IAPP oligomers and the common features that they share with toxic species reported for other amyloidogenic polypeptides, providing information for rational drug design to treat IAPP induced β-cell death.
authors.affiliation: Diabetes Research Program, Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, New York University School of Medicine, New York, United States.
authors.forename: Andisheh
authors.initials: A
authors.lastname: Abedini
authors.affiliation: Child and Family Research Institute, Department of Pathology and Laboratory Medicine and Department of Surgery, University of British Columbia, Vancouver, Canada.
authors.forename: Annette
authors.initials: A
authors.lastname: Plesner
authors.affiliation: Department of Chemistry, Stony Brook University, Stony Brook, United States.
authors.forename: Ping
authors.initials: P
authors.lastname: Cao
authors.affiliation: Department of Chemistry, Stony Brook University, Stony Brook, United States.
authors.forename: Zachary
authors.initials: Z
authors.lastname: Ridgway
authors.affiliation: Diabetes Research Program, Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, New York University School of Medicine, New York, United States.
authors.forename: Jinghua
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Chemistry, Stony Brook University, Stony Brook, United States.
authors.forename: Ling-Hsien
authors.initials: LH
authors.lastname: Tu
authors.affiliation: Department of Chemistry, University of Wisconsin-Madison, Madison, United States.
authors.forename: Chris T
authors.initials: CT
authors.lastname: Middleton
authors.affiliation: Diabetes Research Program, Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, New York University School of Medicine, New York, United States.
authors.forename: Brian
authors.initials: B
authors.lastname: Chao
authors.affiliation: Diabetes Research Program, Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, New York University School of Medicine, New York, United States.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Sartori
authors.affiliation: Department of Chemistry, Stony Brook University, Stony Brook, United States.
authors.forename: Fanling
authors.initials: F
authors.lastname: Meng
authors.affiliation: Department of Chemistry, Stony Brook University, Stony Brook, United States.
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Chemistry, Stony Brook University, Stony Brook, United States.
authors.forename: Amy G
authors.initials: AG
authors.lastname: Wong
authors.affiliation: Department of Chemistry, University of Wisconsin-Madison, Madison, United States.
authors.forename: Martin T
authors.initials: MT
authors.lastname: Zanni
authors.affiliation: Child and Family Research Institute, Department of Pathology and Laboratory Medicine and Department of Surgery, University of British Columbia, Vancouver, Canada.
authors.forename: C Bruce
authors.initials: CB
authors.lastname: Verchere
authors.affiliation: Department of Chemistry, Stony Brook University, Stony Brook, United States.
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Raleigh
authors.affiliation: Diabetes Research Program, Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, New York University School of Medicine, New York, United States.
authors.forename: Ann Marie
authors.identifier: 0000-0001-8902-070X
authors.initials: AM
authors.lastname: Schmidt
mesh_terms: D058227:Amyloidogenic Proteins / Q000378:metabolism* / Q000633:toxicity*; D000686:Amyloidosis / Q000503:physiopathology* / Q000628:therapy; D000818:Animals; D002470:Cell Survival; D002478:Cells, Cultured; D007249:Inflammation / Q000473:pathology; D050417:Insulin-Secreting Cells / Q000502:physiology; D058228:Islet Amyloid Polypeptide / Q000378:metabolism* / Q000633:toxicity*; D007515:Islets of Langerhans / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D011487:Protein Conformation; D011489:Protein Denaturation; D055503:Protein Multimerization; D051381:Rats; D017382:Reactive Oxygen Species / Q000032:analysis; D013997:Time Factors
chemical_list: D058227:Amyloidogenic Proteins; D058228:Islet Amyloid Polypeptide; D017382:Reactive Oxygen Species
keywords: IAPP; amylin; amyloid; biochemistry; biophysics; diabetes; islet amyloid polypeptide; mouse; oligomer; rat; structural biology