Islet amyloid: from fundamental biophysics to mechanisms of cytotoxicity

Abstract

Pancreatic islet amyloid is a characteristic feature of type 2 diabetes. The major protein component of islet amyloid is the polypeptide hormone known as islet amyloid polypeptide (IAPP, or amylin). IAPP is stored with insulin in the β-cell secretory granules and is released in response to the stimuli that lead to insulin secretion. IAPP is normally soluble and is natively unfolded in its monomeric state, but forms islet amyloid in type 2 diabetes. Islet amyloid is not the cause of type 2 diabetes, but it leads to β-cell dysfunction and cell death, and contributes to the failure of islet cell transplantation. The mechanism of IAPP amyloid formation is not understood and the mechanisms of cytotoxicity are not fully defined.

Figure 1. Processing of human PreProIAPP to form mature IAPP

(A) The primary sequence of human PreProIAPP, the peptide length is 89 residues. The 22 residue signal sequence is shown in black, the N- and C-terminal proIAPP flanking regions are shown in red, and the mature sequence in blue. (B) The primary sequence of the 67-residue human proIAPP. ProIAPP is cleaved by the prohormone convertases PC(1/3) and PC2 at the two dibasic sites, indicated by the arrows. Additional processing by CPE/PAM leads to an amidated C-terminus of IAPP. (C) The sequence of the mature 37-residue human IAPP. The biologically active peptide has an amidated C-terminus and a disulfide bridge between Cys-2 and Cys-7.

Figure 2. Primary sequences of human CGRP and IAPP from different species

Residues that differ from the human IAPP sequence are highlighted in blue. The biologically active mature sequences all have a disulfide bridge between Cys-2 and Cys-7 and an amidated C-terminus. Primates and cats have been reported to form islet amyloid while cows, rodents, and dogs do not. Ferret and porcine IAPP are reported to be significantly less amyloidogenic than human IAPP. Islet amyloid is found in the degu, but it is derived insulin, not IAPP. Only partial sequences are available for rabbit and hare.

Figure 3. Structural model of the hIAPP fibril derived from studies of steric zippers

(A) Ribbon diagram of the fibril structure. The two stacks of symmetry related monomers are shown. (B) Cross section of one fibril layer, looking down the fibril axis, showing several key residues. The aromatic residues Phe15, Phe23 and Tyr37 are shown in space filling format along with Arg11, His18 and Ser20. The color coding corresponds to that used in panel-A. (C) Cross section of one layer showing the tight “steric zipper” interface between two hIAPP monomers. Interdigitated residues Leu27, Ser29, Asn31 and Gly33 are shown in space filling representation.