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Causative factors for formation of toxic islet amyloid polypeptide oligomer in type 2 diabetes mellitus

Authors Jeong HR, An SSA

Received 31 August 2015

Accepted for publication 6 October 2015

Published 19 November 2015 Volume 2015:10 Pages 1873—1879

DOI https://doi.org/10.2147/CIA.S95297

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Supriya Swarnkar

Peer reviewer comments 2

Editor who approved publication: Dr Richard Walker

Hye Rin Jeong, Seong Soo A An

Department of Bionano Technology, Gachon Medical Research Institute, Gachon University, Gyeonggi-do, Republic of Korea

Abstract: Human islet amyloid polypeptide (h-IAPP) is a peptide hormone that is synthesized and cosecreted with insulin from insulin-secreting pancreatic β-cells. Recently, h-IAPP was proposed to be the main component responsible for the cytotoxic pancreatic amyloid deposits in patients with type 2 diabetes mellitus (T2DM). Since the causative factors of IAPP (or amylin) oligomer aggregation are not fully understood, this review will discuss the various forms of h-IAPP aggregation. Not all forms of IAPP aggregates trigger the destruction of β-cell function and loss of β-cell mass; however, toxic oligomers do trigger these events. Once these toxic oligomers form under abnormal metabolic conditions in T2DM, they can lead to cell disruption by inducing cell membrane destabilization. In this review, the various factors that have been shown to induce toxic IAPP oligomer formation will be presented, as well as the potential mechanism of oligomer and fibril formation from pro-IAPPs. Initially, pro-IAPPs undergo enzymatic reactions to produce the IAPP monomers, which can then develop into oligomers and fibrils. By this mechanism, toxic oligomers could be generated by diverse pathway components. Thus, the interconnections between factors that influence amyloid aggregation (eg, absence of PC2 enzyme, deamidation, reduction of disulfide bonds, environmental factors in the cell, genetic mutations, copper metal ions, and heparin) will be presented. Hence, this review will aid in understanding the fundamental causative factors contributing to IAPP oligomer formation and support studies for investigating novel T2DM therapeutic approaches, such as the development of inhibitory agents for preventing oligomerization at the early stages of diabetic pathology.

Keywords: amyloid aggregation, causative factor, IAPP, islet amyloid polypeptide, toxic oligomer, T2DM, type 2 diabetes mellitus

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