Abstract: Objective: To investigate the effects of metformin and sitagliptin on the function of islet β cells in insulin resistance pre-diabetic KKay mice. Methods: Thirty 6-week-old KKAy mice were randomly divided into two groups: normal diet fed group (NC group, n=10) and high-fat diet fed group (n=20). At 8 weeks, KKAy mice were randomly divided into two groups: metformin intervention group (met group, n=10) and sitagliptin intervention group (SP group, n=10), which were treated by gavage for 8 weeks. Glucose tolerance was measured by oral glucose tolerance test (OGTT), serum insulin level and plasma lipid level were measured by tail blood sampling, and HOMA-β and HOMA-IR were calculated. The mice were killed after blood collection, and the pancreas of KKAy mice was taken. The β cell volume of each group was compared by immunofluorescence staining of insulin and glucagon, respectively. The proliferation and apoptosis of β cell were analyzed by Ki67/INS. The expressions of pancreatic transcription factors PDX-1 and MafA were detected by Western blot. Results: ① The OGTT results indicated that blood glucose of KKAy mice at fast, 30, 60 and 120 min after oral administration of glucose in the Met and SP groups were decreased significantly compared with the NC group, and the area under the blood glucose time curve (AUC) was significantly reduced (P＜0.01, P＜0.01). There was no significant difference between the Met group and the SP group in blood glucose level at 30 and 60 min after oral administration of glucose. Compared with the SP group, the blood glucose of Met group at 120 min was decreased significantly (P＜0.05). There was no significant difference in AUC between the two groups. ② The results of the insulin tolerance test (ITT) indicated that, compared with NC, the fasting blood glucose and the blood glucose at 30, 60 and 90 min after insulin injection in KKAy mice in the Met and SP groups were decreased significantly, and the area under the ITT blood glucose curve (AUC) was increased significantly (P＜0.01), while there was no significant difference between the Met and SP groups. ③ In the NC group, the brightness of the areas of the islet β cells was low and the edges were scattered. After treated with metformin, the areas and brightness of the β cells were increased. After treatment with sitagliptin, the area and brightness of the β cells were increased significantly. In the NC group, the α cells were disordered in the islet distribution and the brightness was large. After the administration of metformin, the α cell area and the brightness were decreased, and distributed to the edge of the islet to a certain extent. After the administration of sitagliptin, there was a significant decrease in the area of the α cells, with a significant decrease in the brightness and distribution at the edge of the islet. ④ Compared with the NC group, the expression levels of pancreatic MafA in the Met group and SP group were increased significantly, which were 1.63 times and 1.58 times, respectively (P＜0.01, P＜0.01). There was no significant difference in the expression of pancreatic PDX-1 between the groups. Conclusion: In pre-diabetes mellitus KKAy mice with insulin resistance, metformin can maintain the function and morphology of pancreatic islets, and sitagliptin may promote the proliferation of islet βcells, improve the expression level of insulin transcription factor MafA, and prevent the occurrence and development of diabetes.

Key words: Metformin, sitagliptin, KKAy mice, insulin resistance, islet β cell, MafA, PDX-1