The self-assembly of amyloid proteins into β-sheet rich assemblies is associated with human amyloidoses including Alzheimer's disease, Parkinson's disease, and type 2 diabetes. An attractive therapeutic strategy therefore is to develop small molecules that would inhibit protein self-assembly. Natural polyphenols are potential inhibitors of β-sheet formation. How these compounds affect the kinetics of self-assembly studied by thioflavin T (ThT) fluorescence is not understood primarily because their presence interferes with ThT fluorescence. Here, we show that by plotting peak intensities from nuclear magnetic resonance (NMR) against incubation time, kinetic profiles in the presence of the polyphenol can be obtained from which kinetic parameters of self-assembly can be easily determined. In applying this technique to the selfassembly of the islet amyloid polypeptide in the presence of curcumin, a biphenolic compound found in turmeric, we show that the kinetic profile is atypical in that it shows a prenucleation period during which there is no observable decrease in NMR peak intensities. KEYWORDS: amyloid, ThT fluorescence, curcumin, NMR A total of 27 proteins have been identified to form the extracellular β-sheet containing amyloid fibrils associated with human amyloidoses. 1 These include the amyloid-β protein (Aβ) in Alzheimer's disease, α-synuclein in Parkinson's disease, and the islet amyloid polypeptide (IAPP) in type 2 diabetes (T2D). In spite of the large differences in the primary structure of the precursor proteins, the mature fibrils possess common characteristics including unbranched, 10 nm wide morphology as determined by electron microscopy, the ability to bind Congo red and exhibit green birefringence, and X-ray diffraction patterns consistent with cross-β-sheet. 1 Mechanistic studies of fibril formation in hydro have shown that Aβ, α-synuclein, and IAPP undergo a random coil to β-sheet conformational transition. 2 IAPP is a 37-residue polypeptide ( Figure 1A) that is cosecreted with insulin by β-cells of the islets of Langerhans in the pancreas. Molecular biological, biophysical, and genetic evidence support a central role for IAPP in β-cell death and dysfunction associated with T2D. 3,4 The progressive formation of islet amyloid leads to a decrease in β-cell mass. 5 The toxicity of fibrillar IAPP was first demonstrated in the early 1990s, 6 but more recent studies suggest that oligomeric assemblies could be the proximate cytotoxic species in T2D. 3,7 A number of mechanisms behind the toxicity of IAPP oligomers have been proposed, 8 but recent biophysical studies have focused on the ability of IAPP to disrupt model membranes, as reviewed recently. 3 A missense mutation involving the substitution of serine at position 20 with glycine ( Figure 1A) has been linked to an early onset, more severe form of T2D. 9 The mutant polypeptide aggregates faster 10,11 and is more toxic than wildtype IAPP. 10 Together, these findings suggest that molecules that significantly delay or completely inhibit IAP...