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EXTRACELLULAR MATRIX, CELL INTERACTIONS
1Division of Metabolism, Endocrinology, and Nutrition, Veterans Affairs Puget Sound Health Care System and University of Washington, Seattle, Washington; 2Department of Pathology and Molecular Medicine, Department of Biochemistry, and 3Department of Chemistry, Ontario; Queen's University, Kingston, Ontario, Canada; and 4Hope Heart Program, Benaroya Research Institute at Virginia Mason and Department of Pathology, University of Washington, Seattle, Washington
Submitted 22 May 2007 ; accepted in final form 3 September 2007
Deposition of islet amyloid polypeptide (IAPP) as amyloid in the pancreatic islet occurs in 
90% of individuals with Type 2 diabetes and is associated with decreased islet β-cell mass and function. Human IAPP (hIAPP), but not rodent IAPP, is amyloidogenic and toxic to islet β-cells. In addition to IAPP, islet amyloid deposits contain other components, including heparan sulfate proteoglycans (HSPGs). The small molecule 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. To determine whether WAS-406 inhibits localized amyloid formation in the islet, we incubated hIAPP transgenic mouse islets for up to 7 days in 16.7 mM glucose (conditions that result in amyloid deposition) plus increasing concentrations of the inhibitor. WAS-406 at doses of 0, 10, 100, and 1,000 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 β-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, including heparan sulfate, synthesis was inhibited in both hIAPP transgenic and nontransgenic islets (the latter is a control that does not develop amyloid), while O-linked protein glycosylation was also decreased, and WAS-406 treatment tended to decrease islet viability in nontransgenic islets. Azaserine, an inhibitor of the rate-limiting step 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 both 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.
islet amyloid polypeptide; heparan sulfate; proteoglycan; β-cell mass; β-cell dysfunction
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