Matrix Metalloproteinases Contribute to Insulin Insufficiency in Zucker Diabetic Fatty Rats

作者：Yun-Ping Zhou, Azadeh Madjidi, Maria E. Wilson, David A. Nothhelfer, John H. Johnson, John F. Palma, Anthony Schweitzer, Charles Burant, John E. Blume, Jeffrey D. Johnson · 发表于：Diabetes · 年份：2005 · DOI：10.2337/diabetes.54.9.2612 · 被引用次数：38 · 研究领域：Pancreatic function and diabetes、Signaling Pathways in Disease、Diabetes Treatment and Management

To assess the molecular changes associated with pancreatic beta-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 beta-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 beta-cell mass in type 2 diabetes.