Heparan Sulfate Proteoglycans Are Important for Islet Amyloid Formation and Islet Amyloid Polypeptide-induced Apoptosis

Marie E Oskarsson,Kailash Singh,Jian Wang,Israel Vlodavsky,Jin-Ping Li,Gunilla T Westermark

doi:10.1074/jbc.m114.631697

Abstract

Deposition of β cell toxic islet amyloid is a cardinal finding in type 2 diabetes. In addition to the main amyloid component islet amyloid polypeptide (IAPP), heparan sulfate proteoglycan is constantly present in the amyloid deposit. Heparan sulfate (HS) side chains bind to IAPP, inducing conformational changes of the IAPP structure and an acceleration of fibril formation. We generated a double-transgenic mouse strain (hpa-hIAPP) that overexpresses human heparanase and human IAPP but is deficient of endogenous mouse IAPP. Culture of hpa-hIAPP islets in 20 mm glucose resulted in less amyloid formation compared with the amyloid load developed in cultured islets isolated from littermates expressing human IAPP only. A similar reduction of amyloid was achieved when human islets were cultured in the presence of heparin fragments. Furthermore, we used CHO cells and the mutant CHO pgsD-677 cell line (deficient in HS synthesis) to explore the effect of cellular HS on IAPP-induced cytotoxicity. Seeding of IAPP aggregation on CHO cells resulted in caspase-3 activation and apoptosis that could be prevented by inhibition of caspase-8. No IAPP-induced apoptosis was seen in HS-deficient CHO pgsD-677 cells. These results suggest that β cell death caused by extracellular IAPP requires membrane-bound HS. The interaction between HS and IAPP or the subsequent effects represent a possible therapeutic target whose blockage can lead to a prolonged survival of β cells.

Highlights

Islet amyloid causes ␤ cell death in T2D
The codeposition of heparan sulfate proteoglycan with islet amyloid in patients with type 2 diabetes, A␤-amyloid in Alzheimer disease, and amyloid in all other amyloid-related diseases suggests that this ubiquitously expressed macromolecule plays an active role in amyloidogenesis [35, 36]
We show, for the first time, that overexpression of the Heparan sulfate (HS)-degrading enzyme heparanase in pancreatic islets reduces islet amyloid formation

Summary

Introduction

Islet amyloid causes ␤ cell death in T2D. Results: Overexpression of heparanase reduced islet amyloid formation in cultured islets, and cells lacking surface associated HS were protected against IAPP-mediated toxicity. Significance: Inhibition of the HS and hIAPP interaction poses a potential intervention target to prevent ␤ cell death in diabetes. Culture of hpa-hIAPP islets in 20 mM glucose resulted in less amyloid formation compared with the amyloid load developed in cultured islets isolated from littermates expressing human IAPP only. Seeding of IAPP aggregation on CHO cells resulted in caspase-3 activation and apoptosis that could be prevented by inhibition of caspase-8. No IAPP-induced apoptosis was seen in HS-deficient CHO pgsD-677 cells. These results suggest that ␤ cell death caused by extracellular IAPP requires membrane-bound HS. The interaction between HS and IAPP or the subsequent effects represent a possible therapeutic target whose blockage can lead to a prolonged survival of ␤ cells

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