Heparan Sulfate Proteoglycans Are Important for Islet Amyloid Formation and Islet Amyloid Polypeptide-induced Apoptosis.
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.
From the Departments of Medical Cell Biology and.
Marie E
ME
Oskarsson
From the Departments of Medical Cell Biology and.
Kailash
K
Singh
Ningxia People's Hospital, Yinchuan 750021, China, and Medical Biochemistry and Microbiology, Uppsala University, Box 571, 75123 Uppsala, Sweden.
Jian
J
Wang
the Cancer and Vascular Biology Research Center, The Bruce Rappaport Faculty of Medicine, Technion, Haifa 31096, Israel.
Israel
I
Vlodavsky
Medical Biochemistry and Microbiology, Uppsala University, Box 571, 75123 Uppsala, Sweden, Jin-ping.Li@imbim.uu.se.
Jin-Ping
JP
Li
From the Departments of Medical Cell Biology and Gunilla.Westermark@mcb.uu.se.
Gunilla T
GT
Westermark
D000682:Amyloid / Q000096:biosynthesis*; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001483:Base Sequence; D016466:CHO Cells; D002478:Cells, Cultured; D006224:Cricetinae; D003412:Cricetulus; D017931:DNA Primers; D005966:Glucuronidase / Q000378:metabolism; D019812:Heparan Sulfate Proteoglycans / Q000502:physiology*; D006801:Humans; D058228:Islet Amyloid Polypeptide / Q000502:physiology*; D007515:Islets of Langerhans / Q000201:enzymology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D060888:Real-Time Polymerase Chain Reaction; D000099175:Heparanase
D000682:Amyloid; D017931:DNA Primers; D005966:Glucuronidase; D019812:Heparan Sulfate Proteoglycans; D058228:Islet Amyloid Polypeptide; D000099175:Heparanase
amyloid; cell death; heparan sulfate; pancreatic islet; proteoglycan