文章基本信息

标题：Inhibition of IAPP aggregation by insulin depends on the insulin oligomeric state regulated by zinc ion concentration
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作者：Praveen Nedumpully-Govindan ; Feng Ding
期刊名称：Scientific Reports
电子版ISSN：2045-2322
出版年度：2015
卷号：5
期号：1
DOI：10.1038/srep08240
语种：English
出版社：Springer Nature
摘要：While islet amyloid polypeptide (IAPP) aggregation is associated with β-cell death in type-II diabetes (T2D), environmental elements of β-cell granules — e.g. high concentrations of insulin and Zn²⁺ — inhibit IAPP aggregation in healthy individuals. The inhibition by insulin is experimentally known, but the role of Zn²⁺ is controversial as both correlations and anti-correlations at the population level are observed between T2D risk and the activity of a β-cell specific zinc ion transporter, ZnT8. Since Zn²⁺ concentration determines insulin oligomer equilibrium, we computationally investigated interactions of IAPP with different insulin oligomers and compared with IAPP homodimer formation. We found that IAPP binding with insulin oligomers competes with the formation of both higher-molecular-weight insulin oligomers and IAPP homodimers. Therefore, zinc deficiency due to loss-of-function ZnT8 mutations shifts insulin oligomer equilibrium toward zinc-free monomers and dimers, which bind IAPP monomers more efficiently compared to zinc-bound hexamers. The hetero-molecular complex formation prevents IAPP from self-association and subsequent aggregation, reducing T2D risk.