title: Graphene oxide inhibits hIAPP amyloid fibrillation and toxicity in insulin-producing NIT-1 cells.
abstract: Human islet amyloid polypeptide (hIAPP or amylin) aggregation is directly associated with pancreatic β-cell death and subsequent insulin deficiency in type 2 diabetes (T2D). Since no cure is currently available for T2D, it is of great benefit to devise new anti-aggregation molecules, which protect β-cells against hIAPP aggregation-induced toxicity. Engineered nanoparticles have been recently exploited as anti-aggregation nanomedicines. In this work, we studied graphene oxide (GO) nanosheets for their potential for hIAPP aggregation inhibition by combining computational modeling, biophysical characterization and cell toxicity measurements. Using discrete molecular dynamics (DMD) simulations and in vitro studies, we showed that GO exhibited an inhibitory effect on hIAPP aggregation. DMD simulations indicated that the strong binding of hIAPP to GO nanosheets was driven by hydrogen bonding and aromatic stacking and that the strong peptide-GO binding efficiently inhibited hIAPP self-association and aggregation on the nanosheet surface. Secondary structural changes of hIAPP upon GO binding derived from DMD simulations were consistent with circular dichroism (CD) spectroscopy measurements. Transmission electron microscopy (TEM) images confirmed the reduction of hIAPP aggregation in the presence of GO. Furthermore, we carried out a cell toxicity assay and found that these nanosheets protected insulin-secreting NIT-1 pancreatic β-cells against hIAPP-induced toxicity. Our multidisciplinary study suggests that GO nanosheets have the potential to be utilized as an anti-aggregation nanomedicine itself in addition to a biosensor or delivery vehicle for the mitigation of T2D progression.
authors.affiliation: Department of Physics and Astronomy, Clemson University, Clemson, SC 29634, USA. fding@clemson.edu.
authors.forename: Praveen
authors.initials: P
authors.lastname: Nedumpully-Govindan
authors.forename: Esteban N
authors.initials: EN
authors.lastname: Gurzov
authors.forename: Pengyu
authors.initials: P
authors.lastname: Chen
authors.forename: Emily H
authors.initials: EH
authors.lastname: Pilkington
authors.forename: William J
authors.initials: WJ
authors.lastname: Stanley
authors.forename: Sara A
authors.initials: SA
authors.lastname: Litwak
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Davis
authors.forename: Pu Chun
authors.initials: PC
authors.lastname: Ke
authors.forename: Feng
authors.initials: F
authors.lastname: Ding
mesh_terms: D002460:Cell Line; D006108:Graphite / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007328:Insulin / Q000096:biosynthesis*; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism; D058228:Islet Amyloid Polypeptide / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D056004:Molecular Dynamics Simulation; D010087:Oxides / Q000737:chemistry / Q000494:pharmacology*; D066329:Protein Aggregates / Q000187:drug effects*
chemical_list: D007328:Insulin; D058228:Islet Amyloid Polypeptide; D010087:Oxides; D066329:Protein Aggregates; D006108:Graphite