Metallothionein in streptozotocin-induced diabetes

Streptozotocin (STZ), diabetogenic agent is selectively toxic to pancreatic beta cells and may cause their lysis through the formation of nitric oxide (NO), released either from STZ or from chemo-attracted macrophages. However, the involvement of NO in mediating STZ-induced diabetes needs further clarification and this subject is one of the main objectives of this investigation. Metallothionein (MT) is a cysteine-rich polypeptide with a number of postulated functions including detoxification of metals and protection against oxygen free radicals including NO-induced toxicity. However, the protective mechanism of MT against NO-induced toxicity in STZ-induced diabetes is not well understood. The study of this protective mechanism is a main objective of this investigation. Experiments were undertaken in vivo as well as in vitro. The protective role of MT and glutathione (GSH) on blood glucose level, NO synthase activity and DNA damage was investigated in STZ induced diabetic rats. Plasma glucose levels were increased in STZ-injected rats as compared to the control, but were lower in rats pretreated with either zinc (Zn) a MT inducer or N-acetylcysteine (NAC) a GSH inducer. MT levels in Zn treated rats and GSH levels in NAC treated rats were substantially increased both in pancreas and liver. Enhanced NO synthase activity and DNA damage were also observed in the pancreas of STZ-treated rats, but not in the liver. Pretreatment with Zn and NAC reduced NO synthase activity and DNA damage to near control levels in STZ-injected rats. These results suggest that increased levels of MT or GSH partially prevented the development of diabetes after STZ-injection and this may be due to the formation of nitrosothiols with MT or GSH.