OBJECTIVE: To provide selectable microRNA for intervening diabetes mellitus diseases, NOD mice's expression of microRNA in pancreas tissues and blood under the exendin-4 intervention of was observed and the difference of microRNA target gene was screened. MATERIALS AND METHODS: Forty clean NOD mice were randomly divided into four groups (in each group, n = 10): One is blank control group D which is intervened with normal saline, and the other three groups were divided into low-dose group A, middle-dose group B, and high-dose group C according to the different exendin- 4 dosage 2, 4, and 8 mu g/kg.d. After the 8-week intervention, these four groups were killed, and the pancreatic tissue and blood were left to prepare specimens for morphology and molecular biology analysis. The specimen with differential expression microRNA in pancreas tissue and blood should be screened out after detected with the locked nucleic acid array system (LNATM) microRNA expression profile chip. The primers should be designed, and the ABI7500 real-time fluorescent quantitative PCR should be applied to amplify, analyze, and verify according to the screen results of the microRNA chip in order to screen out the significant differentially expressed microRNA. RESULTS: Histological detection showed that the pancreas of the mice in control group D was fibrosis gradually and the islet frame was relatively disordered and significantly atrophied. Groups A, B, and C have no islet hypertrophy or atrophy and the degree of fibrosis of the pancreas has reduced. According to the gene chip detection, there are four significantly differently expressed microRNAs in pancreas tissue and blood among the group A, B, and C, among which miR-19a, miR-19b, and miR-22 were down-regulated expressed while the miRNA-1 was upregulated expressed. Bioinformatics analysis showed that the target genes of 4 differentially regulated microRNA genes were related to cell proliferation, apoptosis, glucose metabolism, and angiogenesis. The expression of microRNA in pancreatic tissue and blood of NOD rats was highly consistent. CONCLUSIONS: MicroRNA expression file of pancreatic tissue and blood can be changed during the intervention of the NOD rat model with exendin-4. MicroRNA that indicates the differential expression may take part in the recovering process of the NOD pancreatic trauma. At the same time, the administration of exendin- 4 can protect NOD mice, reduce its pancreatic tissue fibrosis, and regulate molecular markers of pancreatic cells in size and pancreatic mast cells. This may be one of the main mechanisms of pancreatic injury in diabetes prevention.