Metallothionein as an Adaptive Protein Prevents Diabetes and its Toxicity

Abstract

Metallothioneins (MTs) are a group of intracellular metal-binding and cysteine-enriched proteins and are highly inducible in many tissues in response to various types of stress. Although it mainly acts as a regulator of metal homeostasis such as zinc and copper in tissues, MT also acts as a potent antioxidant and adaptive (or stress) protein to protect cells and tissues from oxidative stress. Diabetes affects many Americans and other populations, and its development and toxic effect on various organs have been attributed to increased oxidative stress. Studies showed that zinc-induced or genetically enhanced pancreatic MT synthesis prevented diabetes induced by chemicals such as streptozotocin and alloxan, and zinc pretreatment also prevented spontaneously developed diabetes. Since diabetic complications are the consequences of organ damage caused by diabetic hyperglycemia and hyperlipidemia through oxidative stress, whether MT in nonpancreatic organs also provides a preventive effect on diabetic toxicity has been recently investigated. We demonstrated that overexpression of cardiac MT significantly prevented diabetes-induced cardiomyopathy. Likewise, overexpression of renal MT also prevented diabetes-induced renal toxicity. In addition, we also found that MT as an adaptive protein is overexpressed in several organs in response to diabetes. Therefore, the biological importance of diabetes-induced MT in diabetic complications and subsequent other pathogenesis was further explored. We found that diabetes-induced hepatic and renal MT synthesis was accompanied by a significant prevention of endotoxin-induced hepatic toxicity and cisplatin-induced renal toxicity. These studies suggest that MT as an adaptive protein can prevent both diabetes development and its complications or subsequent suffered other pathogenic injury.