Cu(II) inhibits hIAPP fibrillation and promotes hIAPP-induced beta cell apoptosis through induction of ROS-mediated mitochondrial dysfunction.

Abstract

Human islet amyloid polypeptide (hIAPP), the major component of the amyloid deposits found in the pancreatic islets of patients with type 2 diabetes mellitus (T2DM), plays a central role in the loss of insulin-secreting pancreatic beta cells. Misfolded hIAPP fibrillating in islet beta cells may be one of the causations for T2DM. Studies have showed that fibrosis of hIAPP was inhibited by copper compounds while hIAPP-induced cytotoxicity was greatly stimulated. In this study, the suppression effects of three different forms of copper compounds CuCl2, CuSO4 and Cu(Gly)2 on amyloid fibril formation were examined in vitro. The results demonstrated that Cu(II) could interact with hIAPP to suppress the fibrosis without involvement of the anions. The fibrosis of hIAPP was inhibited by CuCl2, CuSO4 and Cu(Gly)2 with a similar degree. The particle size of hIAPP aggregates was decreased, which was further confirmed in atomic force microscopy (AFM) and transmission electron microscopy (TEM) images. Moreover, approximative cytotoxicity-enhancing levels between CuCl2, CuSO4 and Cu(Gly)2 on hIAPP were also observed in INS-1 cells. Studies on the action mechanisms displayed that copper compounds increased hIAPP-induced cytotoxicity by facilitating apoptosis-promoting effect of hIAPP, which was dominated mainly by cation. Furthermore, Cu(II)-promoted ROS overproduction and mitochondrial disruption might be the main reason for the enhanced apoptosis. Taken together, our studies demonstrate clear interaction mechanisms of Cu(II) and hIAPP in pancreatic beta cells, and provide useful information for our understanding and treatment of T2DM.

• Authors: Lijuan Ma, Xiaoling Li, Yi Wang, Wenjie Zheng, Tianfeng Chen
• Journal: Journal of inorganic biochemistry (J Inorg Biochem) Vol. 140 Pg. 143-52 (Nov 2014) ISSN: 1873-3344 [Electronic] United States
• PMID: 25108186 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Inc. All rights reserved.

Chemical References

• Islet Amyloid Polypeptide
• Reactive Oxygen Species
• Copper

Topics

• Animals
• Apoptosis (drug effects)
• Cell Line, Tumor
• Circular Dichroism
• Copper (pharmacology)
• Fluorescence
• Humans
• Islet Amyloid Polypeptide (antagonists & inhibitors, physiology)
• Islets of Langerhans (cytology, metabolism)
• Microscopy, Atomic Force
• Mitochondria (drug effects, physiology)
• Rats
• Reactive Oxygen Species (metabolism)