title: 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.affiliation: Department of Chemistry, Jinan University, Guangzhou 510632, PR China.
authors.forename: Lijuan
authors.initials: L
authors.lastname: Ma
authors.affiliation: Department of Chemistry, Jinan University, Guangzhou 510632, PR China.
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Chemistry, Jinan University, Guangzhou 510632, PR China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Chemistry, Jinan University, Guangzhou 510632, PR China.
authors.forename: Wenjie
authors.initials: W
authors.lastname: Zheng
authors.affiliation: Department of Chemistry, Jinan University, Guangzhou 510632, PR China. Electronic address: tchentf@jnu.edu.cn.
authors.forename: Tianfeng
authors.initials: T
authors.lastname: Chen
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D002942:Circular Dichroism; D003300:Copper / Q000494:pharmacology*; D005453:Fluorescence; D006801:Humans; D058228:Islet Amyloid Polypeptide / Q000037:antagonists & inhibitors* / Q000502:physiology; D007515:Islets of Langerhans / Q000166:cytology* / Q000378:metabolism; D018625:Microscopy, Atomic Force; D008928:Mitochondria / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: D058228:Islet Amyloid Polypeptide; D017382:Reactive Oxygen Species; D003300:Copper
keywords: Apoptosis; Copper compound; Fibrosis; hIAPP