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 |
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| Rok vydání: | 2005 |
| Předmět: |
Male
medicine.medical_specialty Proteases Time Factors endocrine system diseases Endocrinology Diabetes and Metabolism medicine.medical_treatment Type 2 diabetes Matrix Metalloproteinase Inhibitors Biology Matrix metalloproteinase Hydroxamic Acids Islets of Langerhans Fibrosis Diabetes mellitus Internal medicine Internal Medicine medicine Animals Insulin RNA Messenger Pancreatic hormone geography geography.geographical_feature_category Gene Expression Profiling medicine.disease Islet Dietary Fats Matrix Metalloproteinases Rats Rats Zucker Up-Regulation Endocrinology Gene Expression Regulation Female Oligopeptides |
| 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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