Proteostasis of Islet Amyloid Polypeptide: A Molecular Perspective of Risk Factors and Protective Strategies for Type II Diabetes.


Milardi D(1), Gazit E(2), Radford SE(3), Xu Y(3), Gallardo RU(3), Caflisch A(4), Westermark GT(5), Westermark P(6), Rosa C(7), Ramamoorthy A(8).
Author information:
(1)Istituto di Cristallografia, Consiglio Nazionale delle Ricerche, Via P. Gaifami 18, 95126 Catania, Italy.
(2)Department of Molecular Microbiology and Biotechnology, The Shmunis School of Biomedicine and Cancer Research, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 6997801, Israel.
(3)Astbury Centre for Structural Molecular Biology, School of Molecular and Cellular Biology, University of Leeds, Leeds LS2 9JT, United Kingdom.
(4)Department of Biochemistry, University of Zürich, Zürich CH-8057, Switzerland.
(5)Department of Medical Cell Biology, Uppsala University, SE-751 23 Uppsala, Sweden.
(6)Department of Immunology, Genetics and Pathology, Uppsala University, SE-751 85 Uppsala, Sweden.
(7)Dipartimento di Scienze Chimiche, Università degli Studi di Catania, Viale Andrea Doria 6, 95125 Catania, Italy.
(8)Biophysics, Department of Chemistry, Biomedical Engineering, Macromolecular Science and Engineering, University of Michigan, Ann Arbor, Michigan 41809-1055, United States.


The possible link between hIAPP accumulation and β-cell death in diabetic patients has inspired numerous studies focusing on amyloid structures and aggregation pathways of this hormone. Recent studies have reported on the importance of early oligomeric intermediates, the many roles of their interactions with lipid membrane, pH, insulin, and zinc on the mechanism of aggregation of hIAPP. The challenges posed by the transient nature of amyloid oligomers, their structural heterogeneity, and the complex nature of their interaction with lipid membranes have resulted in the development of a wide range of biophysical and chemical approaches to characterize the aggregation process. While the cellular processes and factors activating hIAPP-mediated cytotoxicity are still not clear, it has recently been suggested that its impaired turnover and cellular processing by proteasome and autophagy may contribute significantly toward toxic hIAPP accumulation and, eventually, β-cell death. Therefore, studies focusing on the restoration of hIAPP proteostasis may represent a promising arena for the design of effective therapies. In this review we discuss the current knowledge of the structures and pathology associated with hIAPP self-assembly and point out the opportunities for therapy that a detailed biochemical, biophysical, and cellular understanding of its aggregation may unveil.