Type II diabetes (T2D) is characterized by diminished insulin production and resistance of cells to insulin. Among others, endoplasmic reticulum (ER) stress is a principal factor contributing to T2D and induces a shift towards a more reducing cellular environment. At the same time, peripheral insulin resistance triggers the over-production of regulatory hormones such as insulin and human islet amyloid polypeptide (hIAPP). We show that the differential aggregation of reduced and oxidized hIAPP assists to maintain the redox equilibrium by restoring redox equivalents. Aggregation thus induces redox balancing which can assist initially to counteract ER stress. Failure of the protein degradation machinery might finally result in β-cell disruption and cell death. We further present a structural characterization of hIAPP in solution, demonstrating that the N-terminus of the oxidized peptide has a high propensity to form an α-helical structure which is lacking in the reduced state of hIAPP. In healthy cells, this residual structure prevents the conversion into amyloidogenic aggregates.

Central European Institute of Technology Masaryk University Kamenice 5 Brno 62500 Czech Republic

German Center for Diabetes Research Neuherberg 85764 Germany

Helmholtz Zentrum München Ingolstädter Landstr 1 Neuherberg 85764 Germany

Institute of Molecular Biology and Biochemistry Center of Molecular Medicine Medical University of Graz Austria

Max Delbrück Center Berlin Robert Rössle Str 10 Berlin 13125 Germany

Munich Center for Integrated Protein Science Germany

Synaptic Systems GmbH Rudolf Wissell Straße 28 Göttingen 37079 Germany

Technische Universität München Center of Life and Food Sciences Weihenstephan Freising 85354 Germany

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