Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 81, Issue -, Pages 442-455Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2014.05.038
Keywords
Spectroscopy; Type 2 diabetes; Confocal microscopy; Mitochondria; Amyloid; Model membranes
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Funding
- MIUR FIRB-MERIT [RBNE08HWLZ]
- PRIN [WCNS5C]
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The human islet polypeptide (hIAPP) or amylin is a 37-residue peptide hormone secreted by beta-cells of the islet of Langerhans in the pancreas. Unlike the rat variant of IAPP (rIAPP), human amylin is highly amyloidogenic and is found as amyloid deposits in nearly 95% of patients afflicted with type 2 diabetes mellitus (T2DM). Human and rat IAPP have nearly identical primary sequence differing at only six positions which are encompassed within the 17-29 aminoacid region. Using Circular Dichroism (CD), Dynamic Light Scattering (DLS) and ThT-fluorescence (Th-T), we examined the aggregation properties of both full-length hIAPP1-37 and the related peptide fragment hIAPP17-29. For the sake of comparison, similar experiments were carried out on the respective rat variants rIAPP1-37 and rIAPP17-29. These studies were conducted at physiological pH in buffered solution not containing fluorinated co-solvents as well as in the presence of model membranes (LUV). In addition, the cytotoxic activity of the investigated peptides was determined toward different pancreatic beta-cell lines. All the peptide studied in this work resulted cytotoxic despite beta-sheet structure being observed, in vitro, for the hIAPP1-37 only. This suggests that beta-sheet conformational transition that generally precedes the fibril formation, is not a prerequisite for toxicity towards beta-cells. Interestingly, confocal microscopy indicated that the IAPP peptides can enter the cell and might exert their toxic action at an intracellular level. (C) 2014 Elsevier Masson SAS. All rights reserved.
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