Matrix metalloproteinases contribute to insulin insufficiency in Zucker diabetic fatty rats.
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.
Zhou
Yun-Ping
YP
Metabolex, 3876 Bay Center Place, Hayward, CA 94583, USA.
Madjidi
Azadeh
A
Wilson
Maria E
ME
Nothhelfer
David A
DA
Johnson
John H
JH
Palma
John F
JF
Schweitzer
Anthony
A
Burant
Charles
C
Blume
John E
JE
Johnson
Jeffrey D
JD
D000818:Animals; D004041:Dietary Fats / Q000378:metabolism*; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006877:Hydroxamic Acids / Q000494:pharmacology; D007328:Insulin / Q000502:physiology*; D007515:Islets of Langerhans / Q000187:drug effects / Q000502:physiology*; D008297:Male; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D009842:Oligopeptides / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011924:Rats, Zucker; D013997:Time Factors; D015854:Up-Regulation
C370242:(R)-2-(4'-bromo-biphenyl-4-sulfonyl-amino)-3-methyl-butyric acid; D004041:Dietary Fats; D006877:Hydroxamic Acids; D007328:Insulin; D061965:Matrix Metalloproteinase Inhibitors; D009842:Oligopeptides; D012333:RNA, Messenger; D020782:Matrix Metalloproteinases