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Originally published In Press as doi:10.1074/jbc.M006170200 on September 5, 2000

J. Biol. Chem., Vol. 275, Issue 47, 36621-36625, November 24, 2000
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Degradation of Amylin by Insulin-degrading Enzyme*

Robert G. BennettDagger §, William C. Duckworth||, and Frederick G. Hamel**

From the Dagger  Medical Research Service, Omaha Veterans Affairs Medical Center and Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska 68105, the  Section of Endocrinology, Carl T. Hayden Veterans Affairs Medical Center, Phoenix, Arizona 85012, the || Department of Molecular and Cellular Biology, Arizona State University, Tempe, Arizona 85287, and the ** Medical Research Service, Omaha Veterans Affairs Medical Center and Departments of Internal Medicine and Pharmacology, University of Nebraska Medical Center, Omaha, Nebraska 68105

A pathological feature of Type 2 diabetes is deposits in the pancreatic islets primarily composed of amylin (islet amyloid polypeptide). Although much attention has been paid to the expression and secretion of amylin, little is known about the enzymes involved in amylin turnover. Recent reports suggest that insulin-degrading enzyme (IDE) may have specificity for amyloidogenic proteins, and therefore we sought to determine whether amylin is an IDE substrate. Amylin-degrading activity co-purified with IDE from rat muscle through several chromatographic steps. Metalloproteinase inhibitors inactivated amylin-degrading activity with a pattern consistent with the enzymatic properties of IDE, whereas inhibitors of acid and serine proteases, calpains, and the proteasome were ineffective. Amylin degradation was inhibited by insulin in a dose-dependent manner, whereas insulin degradation was inhibited by amylin. Other substrates of IDE such as atrial natriuretic peptide and glucagon also competitively inhibited amylin degradation. Radiolabeled amylin and insulin were both covalently cross-linked to a protein of 110 kDa, and the binding was competitively inhibited by either unlabeled insulin or amylin. Finally, a monoclonal anti-IDE antibody immunoprecipitated both insulin- and amylin-degrading activities. The data strongly suggest that IDE is an amylin-degrading enzyme and plays an important role in the clearance of amylin and the prevention of islet amyloid formation.

* This work was funded in part by the Department of Veterans Affairs Research Service and in part by the Bly Memorial Research Fund, University of Nebraska Medical Center.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ To whom correspondence should be addressed: Medical Research Service (151), Veterans Affairs Medical Ctr., 4101 Woolworth Ave., Omaha, NE 68105. Tel.: 402-346-8800 ext. 3105; Fax: 402-449-0604; E-mail: rgbennet@unmc.edu.

Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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