Role of islet amyloid in type 2 diabetes mellitus: consequence or cause?

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

“…Previous studies have shown that the N-terminal 1-19 region, rather than the amyloidogenic 20-29 region, is primarily responsible for the interaction of the IAPP peptide with membranes. Liposome leakage experiments presented in this study confirm that the pathological membrane disrupting activity of the full-length hIAPP is also shared by hIAPP [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19] . The hIAPP 1-19 fragment at a low concentration of peptide induces membrane disruption to a near identical extent as the full-length peptide.…”

“…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.…”

“…The hIAPP 20-29 peptide was synthesized as described above but with both an amidated C-terminus and an acetylated N-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]…”

“…Because of the high tissue visibility of the amyloid deposits and their prevalence in diabetic patients but not in nondiabetic individuals, it has been assumed that fibrillization of IAPP plays an important role in the pathogenic development of the disease. 1 The link between the formation of amyloid fibers by IAPP and loss of β-cell mass in type II diabetes has been further supported by in vitro studies which have shown that species which do not spontaneously develop type II diabetes, such as rats, have an IAPP variant which is nonamyloidogenic.2 The putative link between IAPP fiber formation and β-cell death has inspired numerous studies on the mechanism of amyloid fiber formation and the structures of fibers formed by IAPP and its fragments.3 However, the role of IAPP aggregation in the etiology of type II diabetes has been obscured by the apparent inertness of the fibers themselves; matured fibers formed from IAPP in solution exert only a minimal cytotoxic effect on pancreatic β-cells,4,5 a finding also reflected in studies of other diseases associated with amyloidogenic peptides.6,7…”

“…It has previously been shown through fluorescence anisotropy, infrared reflectionabsorption spectroscopy, and lipid monolayer expansion experiments that the N-terminal part of IAPP is the primary membrane binding site of IAPP.11,14,15 Indeed, the 1 -19 fragment of human IAPP (hIAPP [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19] ) inserts into lipid membranes with a higher efficiency than full-length IAPP.11 We report here that the N-terminal region of the peptide (residues 1 -19) can disrupt synthetic lipid vesicles to a similar extent as the full-length IAPP peptide without forming amyloid fibers and may therefore be an important model for the study of membrane disruption by IAPP and other amyloid proteins.…”