Deposition of islet amyloid polypeptide (IAPP) as amyloid occurs in the pancreatic islets of ~90% of individuals with type 2 diabetes and is associated with decreased islet -cell mass and function. Human IAPP (hIAPP), but not rodent IAPP, is amyloidogenic and toxic to islet cells. Islet amyloid also contains other components, including heparan sulfate proteoglycans (HSPGs). The inhibitor 2-acetamido-1,3,6-tri-O-acetyl-2,4-dideoxy--D-xylo-hexopyranose (WAS-406) inhibits HSPG synthesis in hepatocytes and blocks systemic amyloid A deposition in vivo. We incubated hIAPP transgenic mouse islets for up to seven days in 16.7 mM glucose (conditions that result in amyloid deposition), plus increasing concentrations of WAS-406. WAS-406, at 0, 10, 100 and 1000 µM resulted in a dose-dependent decrease in amyloid deposition (% islet area occupied by amyloid: 0.66±0.14, 0.10±0.06, 0.09±0.07 and 0.004±0.003%, p<0.001) and an increase in -cell area in hIAPP transgenic islets (55.0±2.6 vs. 60.6±2.2 % islet area for 0 vs. 100 µM inhibitor, p=0.05). Glycosaminoglycan synthesis and O-linked protein glycosylation were decreased in both hIAPP transgenic and non-transgenic islets (the latter a non-amyloidogenic control), and WAS-406 treatment tended to decrease islet viability in non-transgenic islets. Azaserine, an inhibitor of the hexosamine biosynthesis pathway, replicated the effects of WAS-406, resulting in reduction of O-linked protein glycosylation and glycosaminoglycan synthesis and inhibition of islet amyloid formation. In summary, interventions that decrease glycosaminoglycan synthesis and O-linked protein glycosylation are effective in reducing islet amyloid formation, but their utility as pharmacological agents may be limited due to adverse effects on the islet.