Overexpression of Metallothionein in Pancreatic β-Cells Reduces Streptozotocin-Induced DNA Damage and Diabetes
Overexpression of Metallothionein in Pancreatic β-Cells Reduces Streptozotocin-Induced DNA Damage and Diabetes Hainan Chen 1 , Edward C. Carlson 2 , Lori Pellet 3 , Jon T. Moritz 3 and Paul N. Epstein 1 1 Department of Pediatrics, University of Louisville, Louisville, Kentucky 2 Department of Anatom...
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Published in | Diabetes (New York, N.Y.) Vol. 50; no. 9; pp. 2040 - 2046 |
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Main Authors | , , , , |
Format | Journal Article |
Language | English |
Published |
Alexandria, VA
American Diabetes Association
01.09.2001
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Subjects | |
Online Access | Get full text |
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Summary: | Overexpression of Metallothionein in Pancreatic β-Cells Reduces Streptozotocin-Induced DNA Damage and Diabetes
Hainan Chen 1 ,
Edward C. Carlson 2 ,
Lori Pellet 3 ,
Jon T. Moritz 3 and
Paul N. Epstein 1
1 Department of Pediatrics, University of Louisville, Louisville, Kentucky
2 Department of Anatomy and Cell Biology, University of North Dakota, Grand Forks, North Dakota
3 Department of Pharmacology, Physiology and Therapeutics, University of North Dakota, Grand Forks, North Dakota
Abstract
The release of reactive oxygen species (ROS) has been proposed as a cause of streptozotocin (STZ)-induced β-cell damage. This
initiates a destructive cascade, consisting of DNA damage, excess activation of the DNA repair enzyme poly(ADP-ribose) polymerase,
and depletion of cellular NAD + . Metallothionein (MT) is an inducible antioxidant protein that has been shown to protect DNA from chemical damage in several
cell types. Therefore, we examined whether overexpression of MT could protect β-cell DNA and thereby prevent STZ-induced diabetes.
Two lines of transgenic mice were produced with up to a 30-fold elevation in β-cell MT. Cultured islets from control mice
and MT transgenic mice were exposed to STZ. MT was found to decrease STZ-induced islet disruption, DNA breakage, and depletion
of NAD + . To assess in vivo protection, transgenic and control mice were injected with STZ. Transgenic mice had significantly reduced
hyperglycemia. Ultrastructural examination of islets from STZ-treated mice showed that MT prevented degranulation and cell
death. These results demonstrate that MT can reduce diabetes and confirm the DNA damage mechanism of STZ-induced β-cell death.
Footnotes
Address correspondence and reprint requests to Paul N. Epstein, Department of Pediatrics, University of Louisville, Louisville,
KY 40202. E-mail: paul.epstein{at}louisville.edu .
Received for publication 26 September 2000 and accepted in revised form 15 June 2001.
BSA, bovine serum albumin; FBS, fetal bovine serum; HBSS, Hanks’ balanced salt solution; KRBB, Krebs-Ringer bicarbonate buffer;
MT, metallothionein; ROS, reactive oxygen species; STZ, streptozotocin. |
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ISSN: | 0012-1797 1939-327X |
DOI: | 10.2337/diabetes.50.9.2040 |