Matrix Metalloproteinases Contribute to Insulin Insufficiency in Zucker Diabetic Fatty Rats

Autor: Maria E. Wilson, John E. Blume, John F. Palma, Yun Ping Zhou, Jeffrey D. Johnson, David A. Nothhelfer, Anthony C. Schweitzer, Azadeh Madjidi, John H. Johnson, Charles F. Burant
Rok vydání: 2005
Předmět:
Zdroj: Diabetes. 54:2612-2619
ISSN: 1939-327X
0012-1797
DOI: 10.2337/diabetes.54.9.2612
Popis: 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.
Databáze: OpenAIRE
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