title: The amylin peptide implicated in type 2 diabetes stimulates copper-mediated carbonyl group and ascorbate radical formation.
abstract: Human amylin (hA), which is toxic to islet β-cells, can self-generate H(2)O(2), and this process is greatly enhanced in the presence of Cu(II) ions. Here we show that carbonyl groups, a marker of oxidative modification, were formed in hA incubated in the presence of Cu(II) ions or Cu(II) ions plus H(2)O(2), but not in the presence of H(2)O(2) alone. Furthermore, under similar conditions (i.e., in the presence of both Cu(II) ions and H(2)O(2)), hA also stimulated ascorbate radical formation. The same observations concerning carbonyl group formation were made when the histidine residue (at position 18) in hA was replaced by alanine, indicating that this residue does not play a key role. In complete contrast to hA, rodent amylin, which is nontoxic, does not generate H(2)O(2), and binds Cu(II) ions only weakly, showed none of these properties. We conclude that the hA-Cu(II)/Cu(I) complex is redox active, with electron donation from the peptide reducing the oxidation state of the copper ions. The complex is capable of forming H(2)O(2) from O(2) and can also generate (•)OH via Fenton chemistry. These redox properties of hA can explain its ability to stimulate copper-mediated carbonyl group and ascorbate radical formation. The formation of reactive oxygen species from hA in this way could hold the key to a better understanding of the damaging consequences of amyloid formation within the pancreatic islets of patients with type 2 diabetes mellitus.
authors.affiliation: Division of Biomedical and Life Sciences, School of Health and Medicine, Lancaster University, Lancaster LA1 4YQ, UK.
authors.forename: Atef
authors.initials: A
authors.lastname: Masad
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Tabner
authors.forename: Jennifer
authors.initials: J
authors.lastname: Mayes
authors.forename: David
authors.initials: D
authors.lastname: Allsop
mesh_terms: D000682:Amyloid / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D001205:Ascorbic Acid / Q000737:chemistry / Q000378:metabolism*; D003300:Copper / Q000737:chemistry / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D004578:Electron Spin Resonance Spectroscopy; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000378:metabolism* / Q000473:pathology; D058228:Islet Amyloid Polypeptide / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D010084:Oxidation-Reduction; D050050:Protein Carbonylation; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000682:Amyloid; D058228:Islet Amyloid Polypeptide; D017382:Reactive Oxygen Species; D003300:Copper; D006861:Hydrogen Peroxide; D001205:Ascorbic Acid