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

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 perl...

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Published in:	Protein engineering, design and selection design and selection, 2019-12, Vol.32 (2), p.95-102
Main Authors:	Templin, Andrew T, Mellati, Mahnaz, Soininen, Raija, Hogan, Meghan F, Esser, Nathalie, Castillo, J Josh, Zraika, Sakeneh, Kahn, Steven E, Hull, Rebecca L
Format:	Article
Language:	eng
Subjects:	Animals Body Weight Cell Count Endocrinologie, métabolisme & nutrition Endocrinology, metabolism & nutrition heparan sulfate proteoglycan Heparan Sulfate Proteoglycans - deficiency Human health sciences Humans Insulin-Secreting Cells - cytology Insulin-Secreting Cells - metabolism Insulin-Secreting Cells/cytology/metabolism islet amyloid Islet Amyloid Polypeptide - genetics Islet Amyloid Polypeptide - metabolism Islet Amyloid Polypeptide/genetics/metabolism Mice Mice, Transgenic Original perlecan Sciences de la santé humaine type 2 diabetes
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Summary:	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 Hspg2Δ3/Δ3 mice harboring a perlecan mutation that prevents HS GAG attachment (hIAPP;Hspg2Δ3/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;Hspg2Δ3/Δ3 mice exhibited significantly less islet amyloid deposition and greater β-cell area compared to hIAPP mice expressing wild type perlecan. hIAPP;Hspg2Δ3/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;Hspg2Δ3/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.
ISSN:	1741-0126 1741-0134 1741-0134