Objective:To study the effect of rat proinsulin gene therapy by intramuscular injection on blood glucose and insulin secretion in streptozotocin-induced diabetic rats. Methods:Recombinant eukaryotic cell expression plasmid of rat proinsulin gene pCMV/proinsulin was transferred into streptozotocin-induced diabetic rats by intramuscular injection. The treatment group(Group A) was injected with pCMV/proinsulin naked plasmid DNA 100 μg,whereas the corresponding control group(Group B) was treated with similar amount of pCMV DNA. Normal group and DM group were also observed at the same time. Blood glucose levels and plasma insulin levels were determined by hypersensitive radioimmunoassay. RT-PCR was used to determine the alteration of proinsulin mRNA expression in skeletal muscles and pancreas. Sections of skeletal muscles and pancreas in each group were also observed. Results:①The blood glucose level in Group A was decreased about 4 mmol/L and maintained for 1~2 weeks. The serum insulin level increased significantly after pCMV/proinsulin gene therapy. The blood glucose in Group A was significantly lower than Group B and DM Group(P < 0.05),while serum insulin was higher than that of two groups(P < 0.05). ②Proinsulin mRNA expression could be detected in skeletal muscle cells of Group A,but no detected in that of Group B and DM Group. It was also showed that proinsulin mRNA expression was higher in pancreas of Group A than Group B and DM Group. ③Immunohistochemistry studies showed that insulin staining was positive in the sections of skeletal muscles of Group A,whereas the same results were not obtained in Group B and DM Group. And insulin staining was more intensive in pancreas of Group A than that of Group B. Conclusion:Direct injection of naked plasmids encoding rat proinsulin gene intramuscularly led to the reduction of blood glucose level,suggesting that proinsulin gene therapy offers a potential approach to diabetes.