Safety And Efficacy Of Oral Metformin In Rats With GDM

Objective:The emergence of more and more randomized clinical trials has raised questions about whether metformin can be used as an oral treatment for GDM.Therefore,this study investigated the safety and efficacy of oral metformin in rats with GDM.Method:Forty-five female SD rats and 16 male SD rats were selected.After one week of adaptive feeding,they were divided into NP group and experimental group.The NP group was fed with regular diet,and the experimental group was fed with high-fat diet for 4 weeks.Body weight and fasting blood glucose(FBG)of the rats were monitored during feeding,and FBG > 7.8mmol/L was excluded before pregnancy.After 4 weeks,the rats were combined in a 2:1 ratio of male to female,and the sperm found on the vaginal smear the next morning was recorded as day 0 of gestation(D0).The rats in the experimental group were intraperitoneally injected with 40mg/kg STZ and FBG≥ 16.7mmol/L after 72h(D6).After successful modeling,the experimental group was divided into GDM group,,GDM+Ins group and GDM+Met group.The experiment was divided into 4 groups with 7 rats in each group.Treatment was given after successful modeling,GDM group: normal saline 1ml/d by gastric lavage,GDM+Ins group: insulin 2 IU/d by hypodermic medication,GDM+Met group:metformin 400mg/kg/d by by gastric lavage.The body weight and FBG of all pregnant rats were measured at intervals of one day.Samples were collected on D19 to detect the body weight and FBG of the rats.Fasting serum lisulin(FINS)was determined by enzyme linked immunosorbent assay(ELISA).After caesarean section,the placenta and fetal rats were weighed,the diameter of placenta and the crown-rump length of fetal were measured and recorded.The placenta was placental histomorphology;The expression of glucose transporter Glucose 1,3 and 4 in placenta was detected by western blot and immunohistochemical staining.Results:1.The results showed that there were significant differences in body weight,FBG and FINS among the four groups after pregnancy.In GDM group,body weight decreased,FBG increased and FINS increased.After oral metformin treatment,GDM rats showed delayed weight gain and decreased FBG,but had no effect on FINS.2.The results of related parameters of placenta and progeny showed that the weight and diameter of placenta and progeny weight of the four groups had significant differences(P<0.001,P<0.001,P<0.001),and the diameters of the progeny were not different(P=0.025).After treatment with metformin,placental weight increased in GDM group,and the difference was statistically significant,but placental diameter and progeny weight were not affected.3.Placental tissue results showed that the placental stratification of GDM rats was disordered,the number of glycogen cells invaded the labyrinthine zone,the maternal blood space in labyrinthine zone increased,and the vascular hyperplasia.After treatment with metformin,placental stratification disorder was improved,glycogen cells in the junction area were reduced,and glycogen cell invasion in the labyrinthine zone was rare.4.Western blotting showed that GLUT1,3 and 4 expression were significantly different among the four groups(P<0.001,P=0.04,P=0.024).The expression of GLUT1 and GLUT3 and GLUT4 was increased in the placenta of GDM group,and the expression of GLUT1 and GLUT3 and GLUT4 was decreased after metformin treatment of GDM rats.5.Immunohistochemical results showed that GLUT1,3 and 4 were all expressed in the placenta of rats.GLUT1 is mainly expressed in the labyrinthian region,but less in the junction region.The expression of GLUT3 and GLUT4 is concentrated in the labyrinthic region,but almost not in the junction region.Morphological analysis showed that GLUT1,3 and 4 expression were significantly different among the four groups(P=0.002,P=0.017,P=0.038).The expression of GLUT1 and GLUT3 and GLUT4 was increased in the placenta of GDM group,and the expression of GLUT1 and GLUT3 and GLUT4 was decreased after metformin treatment of GDM rats.Conclusion:Metformin is safe and effective in GDM rats.Metformin can delay weight gain and decrease FBG in pregnant rats,but has no effect on FINS.Increasing placenta weight had no effect on progeny body weight;After metformin treatment of GDM rats,the expression level of GLUT1 protein in placenta decreased,while the expression level of GLUT3 and GLUT4 protein increased.However,the specific regulatory mechanism and the molecules involved are still unclear,so we should carry out in-depth research in the latter step,and combine basic experiments with clinical practice to transform the research results.