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Metal Modulates Human Islet Amyloid Polypeptide Aggregation in Type 2 Diabetes

Author: YuYePing
Tutor: LiYanMei
School: Tsinghua University
Course: Chemistry
Keywords: Type 2 diabetes mellitus Human islet amyloid polypeptide ( hIAPP ) Cytotoxicity Gather Metal ion
CLC: R587.1
Type: Master's thesis
Year: 2010
Downloads: 57
Quote: 0
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Abstract


Islet amyloid deposition is an important pathological feature of type 2 diabetes. Human insulin polypeptide (hIAPP) is a major component of islet amyloid, composed of 37 amino acid residues. The study showed that hIAPP aggregation into filaments and β-cell function is missing, hIAPP induced cytotoxicity mechanism including the formation of soluble oligomers, cell membrane damage, cell membrane permeability increased oxidative stress. The latest evidence, metal plays an important role in the process of amyloid deposition. Metal ions such as Cu, Zn in the neurodegenerative diseases, of Alzheimer's disease is important, the metal ions can be combined with amyloid and changing the aggregation mechanism. However, the mechanism of interaction between metal and hIAPP still unclear. This work is mainly to study the impact of the of hIAPP aggregation process and cytotoxicity of metal ions of Cu, Ni, Zn, common in living systems, and Ta surface induced hIAPP aggregation mechanism. First, we found that a Cu-induced hIAPP formed spherical oligomers having cytotoxic mechanism. Cu hand inhibit the formation of aggregates of hIAPP fiber filamentous other hand, induced aggregation become a small size spherical oligomers, thereby enhancing β-cell toxicity induced by the hIAPP. This article further using Ni reproduce this effect of the Cu, Ni and Cu, and protein binding properties are very similar, but do not produce any oxidative stress. The study found that the Ni can also be increased by inducing the generation of toxic oligomers hIAPP cytotoxic. These data demonstrate that the main reason for Cu induced hIAPP greater cytotoxicity than oxidative stress, but more toxic spherical oligomers generated. Cu and Ni with different Zn via induction hIAPP into β-sheet conformation, thereby facilitating role in the process of aggregation against hIAPP. Since Zn hIAPP aggregation nucleation period is shortened, making hIAPP rapidly from monomer excessive cytotoxic small fibrous aggregate state, the toxic oligomers, and other forms of aggregation the presence of the intermediate time is greatly shortened, so Save small hIAPP induced cytotoxicity. This article also Ta metal surface to study the surface induced hIAPP aggregation mechanism. HIAPP aggregate into filaments in solution was found to have a three-dimensional nodular structures: filaments cross-linking between the wound and the formation of a thick mature filaments and further aggregation aggregates clusters of amyloid plaques. HIAPP mechanism induced by the surface of Ta contrast: the surface of the negatively charged first adsorbed the hIAPP monomer, and then aggregated into oligomers and continue to grow into the fibril strands, the oligomer further combined on the fibril strands, the extension of the fiber filaments length, thereby forming no nodular structure fiber filaments. These results demonstrate a new mechanism of the metal-induced cytotoxicity, reveals the important role of the metal in the type 2 diabetic pathologic pathway.

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CLC: > Medicine, health > Internal Medicine > Endocrine diseases and metabolic diseases > Islet disease > Diabetes
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