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

Figures & data

Figure 1 Schematic diagram of the primary sequence of IAPP.

Notes: Black circles indicate the cysteine amino acid C2–C7 disulfide bond. Gray circles indicate amino acid sequences for the hydrophobic regions, with the three aromatic amino acids (F15, F23, and Y37) shown in red. Dashed-circled amino acids are those responsible for amyloid formation.
Abbreviation: IAPP, islet amyloid polypeptide.

Figure 2 List of genetic mutations of IAPP determined from in silico studies, and naturally occurring (eg, S20G) mutations.

Notes: Sequence alignment between mutants and wild-type IAPP revealed the effect of single-point mutations (S20G, F15L, Y37L, F23L, G24P, and I26P). The S20G and F15L mutations result in higher rates of amyloid formation and amyloidogenesis. In contrast, the Y37L, F23L, G24P, and I26P mutations result in a reduction in the amyloidogenic property. Dots indicate identical residues, and blue letters indicate aromatic regions (F15, F23, and Y37).
Abbreviation: IAPP, islet amyloid polypeptide.

Figure 3 Alignment of IAPP amino acid sequences from different species.

Notes: Amino acid sequences of the N-terminus and C-terminus are conserved, but region 20–29 is species specific. Amino acid alignment of IAPP identified slight differences between human, rat, mouse, cat, monkey, and dog sequences. Dots represent the conserved amino acids compared with human IAPP. Red letters denote the amyloidogenic regions.
Abbreviation: IAPP, islet amyloid polypeptide.

Figure 4 Causative factors of toxic oligomer formation.

Notes: Mechanistic factors that result in the generation of oligomers from pro-IAPP include the absence of PC2 enzyme, deamidation, reduction of the disulfide bond, environmental factors in the cell, genetic mutations, copper metal ions, and heparin-induced cell apoptosis. The barrel-stave model and carpet model demonstrate known methods by which amyloidogenic peptides can trigger membrane destabilization and disruption. In addition, both intra- and extracellular aggregation may be involved in these cytotoxic processes, although they most likely occur intracellularly. The mechanisms contributing to inhibitory effects such as copper ion chelators and rifampicin are indicated.
Abbreviations: IAPP, islet amyloid polypeptide; PARP, poly (ADP-ribose) polymerase; ROS, reactive oxygen species; PC1/3, proprotein convertase 1/3; PC2, proprotein convertase 2; PAM, peptidylglycine α-amidating monooxygenase; Cu(II), copper (II) ion.