Overexpression of metallothionein in pancreatic beta-cells reduces streptozotocin-induced DNA damage and diabetes

The release of reactive oxygen species (ROS) has been proposed as a cause o f streptozotocin (STZ)-induced beta -cell damage. This initiates a destruct ive cascade, consisting of DNA damage, excess activation of the DNA repair enzyme poly(ADP-ribose) polymerase, and depletion of cellular NAD(+). Metal lothionein (MT) is an inducible antioxidant protein that has been shown to protect DNA from chemical damage in several cell types. Therefore, we exami ned whether overexpression of MT could protect beta -cell DNA and thereby p revent STZ-induced diabetes. Two lines of transgenic mice were produced wit h up to a 30-fold elevation in beta -cell MT. Cultured islets from control mice and MT transgenic mice were exposed to STZ. MT was found to decrease S TZ-induced islet disruption, DNA breakage, and depletion of NAD(+). To asse ss in vivo protection, transgenic and control mice were injected with STZ. Transgenic mice had significantly reduced hyperglycemia. Ultrastructural ex amination of islets from STZ-treated mice showed that MT prevented degranul ation and cell death. These results demonstrate that MT can reduce diabetes and confirm the DNA damage mechanism of STZ-induced beta -cell death.