TY - JOUR

T1 - The amylin peptide implicated in type 2 diabetes stimulates copper-mediated carbonyl group and ascorbate radical formation

AU - Masad, Atef

AU - Tabner, Brian J

AU - Mayes, Jennifer

AU - Allsop, David

N1 - Copyright © 2011 Elsevier Inc. All rights reserved.

PY - 2011/8/15

Y1 - 2011/8/15

N2 - 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.

AB - 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.

KW - Type 2 diabetes mellitus

KW - Human amylin

KW - Rodent amylin

KW - Reactive oxygen species

KW - Carbonyl group

KW - Copper ions

KW - Oxidation

KW - Free radicals

U2 - 10.1016/j.freeradbiomed.2011.05.033

DO - 10.1016/j.freeradbiomed.2011.05.033

M3 - Journal article

C2 - 21683137

VL - 51

SP - 869

EP - 875

JO - Free Radical Biology and Medicine

JF - Free Radical Biology and Medicine

SN - 1873-4596

IS - 4

ER -