AIMTo investigate the inhibitory effect of Liuwei Dihuang Pill (LDP) on gastric tumorigenesis induced by N-methyl-N-nitrosourea (MNU) in diabetic mice.METHODSFour-week-old mice were divided into four groups: A, 12 db/m mice treated with MNU and saline, as the non-diabetic control; B, 12 db/db mice treated with MNU and saline, as the diabetic control; C, 12 db/db mice treated with MNU and metformin, as the positive control; and D, 12 db/db mice treated with MNU and LDP. MNU was administrated for 20 wk to induce gastric carcinogenesis. LDP was administrated for 10 wk for improvement of insulin resistance. Body weight and food intake were measured every week. Blood samples were collected for assays of fasting blood glucose, insulin, insulin-like growth factor (IGF)-1, adiponectin and leptin. Stomach tissues were collected for histopathological analysis, immunohistochemical staining of Ki67, quantitative reverse transcription-polymerase chain reaction and western blotting.RESULTSThe incidence of MNU-induced gastric dysplasia was significantly elevated in diabetic (db/db) mice relative to the control (db/m) mice. The incidence of gastric dysplasia was significantly reduced by LDP with suppression of cell proliferation, as demonstrated by a decrease in Ki67 staining. Hyperglycemia, hyperinsulinemia and serum IGF-1 were inhibited by LDP. Expression of IGF-1 and insulin receptor mRNAs was decreased, phosphorylation of IGF-1 receptor and AKT protein was reduced in the stomach tissues by LDP. In addition, adiponectin was increased and leptin was decreased in the serum by LDP.CONCLUSIONLDP decreased risk of gastric dysplasia in type 2 diabetic mice by down-regulation of IGF and insulin activity and correction of adipokines disorders.

Type 2 diabetes can elevate risk of gastric cancer and metformin, an anti-diabetic agent, has an inhibitory effect against gastric cancer cell in vitro. However, the effect of metformin on type 2 diabetes-related gastric tumorigenesis in vivo is still not clear. In the present study, we aim to detect whether metformin can inhibit increased risk of gastric cancer in diabetic db/db mice and which the potential anti-cancer mechanisms of metformin are. 4-week-old mice were divided into 3 groups (2 db/db mice groups and one wild type mice group). All diabetic and non-diabetic mice were treated with N-Methyl-N-Nitrosourea (MNU) for 20 weeks to induce gastric tumorigenesis. At week 21, one db/db mice group were treated with metformin (5 mg/ml) for 10 weeks and the other 2 groups were treated with saline. Blood samples were collected for testing insulin and insulin-like growth factor (IGF)-1. Stomach tissues were collected for histopathological evaluation and mRNAs analysis. Metformin significantly decreased incidence of MNU-induced gastric dysplasia and cancer in diabetic db/db mice. Furthermore, metformin reduced serum insulin as well as IGF-1, and also suppressed expression of insulin receptor, IGF-1, IGF-1 receptor and several pro-inflammatory cytokines mRNAs in stomach of db/db mice, but did not significantly influence IGF-2 and IGF-2 receptor expressions. The results show that metformin can prevent the risk of gastric cancer in type 2 diabetes and the protective mechanisms may involve in an inhibitory effect of metformin on insulin as well as IGF-1 signals and cancer related pro-inflammatory cytokines.