Proteoglycans synthesized and secreted by pancreatic islet β-cells bind amylin

Abstract

Pancreatic islet amyloid deposits in type 2 diabetes are associated with decreased islet β-cell function. They contain both amylin (islet amyloid polypeptide), the β-cell-derived unique fibrillogenic component, and heparan sulfate proteoglycans (HSPGs). We hypothesized that β-cell HSPGs contribute to islet amyloidogenesis. [ 35 S ]Sulfate-labeled proteoglycans from islet-derived β-TC3 cell cultures eluted from diethylaminoethyl Sephacel at 0.35 M NaCl. Chromatography on Sepharose CL-4B and SDS–PAGE analysis revealed distinct populations of proteoglycans. Medium HSPGs eluted at K av∼0.18 and 0.50 with glycosaminoglycan chains of ∼28 and 19 kDa, respectively. A third population containing chondroitin/dermatan sulfate eluted at K av∼0.70 with glycosaminoglycan chains of ∼10 kDa. A single size class of heparan and chondroitin/dermatan sulfate proteoglycans in the cell layer eluted at K av∼0.40 with glycosaminoglycan chains of ∼19 kDa. Medium and cell layer proteoglycans bound exclusively to fibrillogenic amylin, as determined by gel mobility shift assays, indicating a possible role for β-cell-derived proteoglycans in islet amyloid formation.