Matrix Metalloproteinases Contribute to Insulin Insufficiency in Zucker Diabetic Fatty Rats

Matrix Metalloproteinases Contribute to Insulin Insufficiency in Zucker Diabetic Fatty Rats Yun-Ping Zhou 1 , Azadeh Madjidi 1 , Maria E. Wilson 1 , David A. Nothhelfer 1 , John H. Johnson 2 , John F. Palma 1 , Anthony Schweitzer 1 , Charles Burant 2 , John E. Blume 1 and Jeffrey D. Johnson 1 1 Metabolex, Hayward, California 2 Pfizer Global Research and Development, Ann Arbor, Michigan Address correspondence and reprint requests to Dr. Jeffrey D. Johnson, Metabolex, 3876 Bay Center Place, Hayward, CA 94583. E-mail: jjohnson{at}metabolex.com Abstract To assess the molecular changes associated with pancreatic β-cell dysfunction occurring during the onset of type 2 diabetes, we profiled pancreatic islet mRNAs from diabetic male and high-fat–fed female Zucker diabetic fatty (ZDF) rats and their nondiabetic lean counterparts on custom islet-specific oligonucleotide arrays. The most prominent changes in both the male and female models of type 2 diabetes were increases in the mRNAs encoding proteases and extracellular matrix components that are associated with tissue remodeling and fibrosis. The mRNAs for metalloproteinase (MMP)-2, -12, and -14 were sharply increased with the onset of islet dysfunction and diabetes. Zymography of islet extracts revealed a concurrent, >10-fold increase in MMP-2 protease activity in islets from 9-week-old male ZDF rats. Treatment of female ZDF rats receiving a diabetogenic diet with PD166793, a broad-spectrum MMP inhibitor, substantially prevented diabetes. The effect of this compound was due in part to marked β-cell expansion. These studies indicate that MMPs contribute to islet fibrosis and insulin insufficiency in ZDF rats. Class-targeted protease inhibitors should be explored for their potential therapeutic utility in preservation of β-cell mass in type 2 diabetes. ECM, extracellular matrix IPGTT, intraperitoneal glucose tolerance test MMP, metalloproteinase Footnotes Y.-P.Z. is currently affiliated with Metabolic Disorders, Merck Research Laboratories, Rahway, New Jersey. J.F.P. and J.E.B. are currently affiliated with Affymetrix, Santa Clara, California. C.B. is currently affiliated with the Department of Medicine, University of Michigan, Ann Arbor, Michigan. C.B. has been on advisory boards for Takeda and has received consulting fees from Takeda, Concurrent, and Sankyo. Accepted June 20, 2005. Received October 21, 2004. DIABETES