Amyloidogenicity and cytotoxicity of islet amyloid polypeptide

Abstract

Insoluble amyloid formation by islet amyloid polypeptide (IAPP) in the islets of Langerhans of the pancreas is a major pathophysiological feature of noninsulin dependent diabetes mellitus (NIDDM) or type II diabetes. Because in vivo formed amyloid colocalizes with areas of cell degeneration and IAPP amyloid aggregates are cytotoxic per se, the process of IAPP amyloid formation has been strongly associated with the progressive pancreatic cell degeneration and thus much of the pathology of type II diabetes. IAPP is a pancreatic polypeptide of 37 residues that, in its soluble form, is believed to play a role as a regulator of glucose homeostasis. The molecular cause and mechanism of the conversion of soluble IAPP into insoluble amyloid aggregates in vivo and its role in disease progress still remain to be clarified. Nevertheless, in the past few years significant progress has been made in understanding the amyloidogenesis pathway of IAPP in vitro and gaining insight into the structural and conformational “requirements” of IAPP amyloidogenesis and related cytotoxic effects. Importantly, several of the studies have revealed significant similarities of the above features of IAPP to other amyloidogenic polypeptides such as the β‐amyloid polypeptide Aβ. This suggests that, at the molecular level, amyloidogenesis, and possibly related cell degeneration and disease pathogenesis by completely different polypeptide sequences, may obey to common structural and conformational “rules” and follow similar molecular pathways. This review describes studies on the structural and conformational features of IAPP amyloid formation and cytotoxicity, and the application of the obtained knowledge for the understanding of the molecular mechanism of the IAPP amyloidogenesis pathway and the related cytotoxicity. © 2002 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 60: 438–459, 2001

Amyloid Fiber Formation and Membrane Disruption are Separate Processes Localized in Two Distinct Regions of IAPP, the Type-2-Diabetes-Related Peptide

“…A Thioflavin T fluorescence assay in the presence of POPG liposomes revealed a t 1/2 for amyloid fiber formation for the full-length peptide of 64 min, similar to previous reports in the literature ( Figure 5). 21 The hIAPP [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19] peptide did not induce any increase in the fluorescence of THT over the duration of the experiment indicating a lack of amyloid fiber formation for this peptide. Thioflavin T itself has been shown not to inhibit amyloid fiber formation by IAPP.…”

“…The hIAPP [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19] and hIAPP [20][21][22][23][24][25][26][27][28][29] peptides were synthesized using standard FMOC (9-fluornylmethoxycarbonyl) methods. A PAL-PEG resin was used to provide an amidated C-terminus.…”

“…After synthesis, the crude hIAPP [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19] peptide was subjected to air oxidation to form the disulfide bond. The identity of the hIAPP [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19] and hIAPP [20][21][22][23][24][25][26][27][28][29] sequences and formation of the disulfide bond for hIAPP [1][2][3][4][5][6]…”

RAGE binds preamyloid IAPP intermediates and mediates pancreatic β cell proteotoxicity

“…Postmortem histological studies of human subjects with T2D show predominantly extracellular pancreatic islet amyloid deposition (4,6,17). Rodents do not develop islet amyloidosis, as rodent IAPP is nonamyloidogenic and nontoxic (17,24,25), but a variety of Tg h-IAPP rodent models have been created that form either extracellular or intracellular islet amyloid, or both (26). Mice that overexpress h-IAPP demonstrate intracellular oligomer formation and defects in autophagy and/or ER stress (27)(28)(29)(30), while cultured Tg murine islets expressing physiological levels of h-IAPP do not display ER stress during islet amyloidosis (31).…”

Design of a mimic of nonamyloidogenic and bioactive human islet amyloid polypeptide (IAPP) as nanomolar affinity inhibitor of IAPP cytotoxic fibrillogenesis

“…The extremely high propensity of the pancreatic polypeptide human islet amyloid polypeptide (IAPP) to misfold into cytotoxic aggregates and fibrils is strongly associated with ␤-cell degeneration in type II diabetes (10,11). IAPP is a 37-residue polypeptide secreted by the ␤-cells that acts together with insulin as a regulator of glucose homeostasis (12,13).…”