Disruption of the cellular membrane by the amyloidogenic peptide IAPP (or amylin) has been implicated in β-cell death during type 2 diabetes. While the structure of the mostly inert fibrillar form of IAPP has been investigated, the structural details of the highly toxic prefibrillar membrane-bound states of IAPP have been elusive. A recent study showed that a fragment of IAPP (residues 1-19) induces membrane disruption to a similar extent as the full-length peptide. However, unlike the full-length IAPP peptide, IAPP1-19 is conformationally stable in an α-helical conformation when bound to the membrane. In vivo and in vitro measurements of membrane disruption indicate the rat version of IAPP1-19, despite differing from hIAPP1-19 by the single substitution of Arg18 for His18, is significantly less toxic than hIAPP1-19, in agreement with the low toxicity of the full-length rat IAPP peptide. To investigate the origin of this difference at the atomic level, we have solved the structures of the human and rat IAPP1-19 peptides in DPC micelles. While both rat and human IAPP1-19 fold into similar mostly α-helical structures in micelles, paramagnetic quenching NMR experiments indicate a significant difference in the membrane orientation of hIAPP1-19 and rIAPP1-19. At pH 7.3, the more toxic hIAPP1-19 peptide is buried deeper within the micelle, while the less toxic rIAPP1-19 peptide is located at the surface of the micelle. Deprotonating H18 in hIAPP1-19 reorients the peptide to the surface of the micelle. This change in orientation is in agreement with the significantly reduced ability of hIAPP1-19 to cause membrane disruption at pH 6.0. This difference in peptide topology in the membrane may correspond to similar topology differences for the full-length human and rat IAPP peptides, with the toxic human IAPP peptide adopting a transmembrane orientation and the nontoxic rat IAPP peptide bound to the surface of the membrane.