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Islet amyloid is a pathologic feature of type 2 diabetes (T2D) that is associated with β-cell loss and dysfunction. These amyloid deposits form via aggregation of the β-cell secretory product islet amyloid polypeptide (IAPP) and contain other molecules including the heparan sulfate proteoglycan perlecan. Perlecan has been shown to bind amyloidogenic human IAPP (hIAPP) via its heparan sulfate glycosaminoglycan (HS GAG) chains and to enhance hIAPP aggregation  in vitro . We postulated that reducing the HS GAG content of perlecan would also decrease islet amyloid deposition  in vivo . hIAPP transgenic mice were crossed with  Hspg2 Δ3/Δ3   mice harboring a perlecan mutation that prevents HS GAG attachment (hIAPP; Hspg2 Δ3/Δ3 ) , and male offspring from this cross were fed a high fat diet for 12 months to induce islet amyloid deposition. At the end of the study body weight, islet amyloid area, β-cell area, glucose tolerance and insulin secretion were analyzed. hIAPP; Hspg2 Δ3/Δ3   mice exhibited significantly less islet amyloid deposition and greater β-cell area compared to hIAPP mice expressing wild type perlecan. hIAPP; Hspg2 Δ3/Δ3   mice also gained significantly less weight than other genotypes. When adjusted for differences in body weight using multiple linear regression modeling, we found no differences in islet amyloid deposition or β-cell area between hIAPP transgenic and hIAPP; Hspg2 Δ3/Δ3   mice. We conclude that loss of perlecan exon 3 reduces islet amyloid deposition  in vivo  through indirect effects on body weight and possibly also through direct effects on hIAPP aggregation. Both of these mechanisms may promote maintenance of glucose homeostasis in the setting of T2D.

protein engineering, design and selection

Loss of perlecan heparan sulfate glycosaminoglycans lowers body weight and decreases islet amyloid deposition in human islet amyloid polypeptide transgenic mice