The Study Of The Interventional Effect On Insulin Resistance During The Catch-up Growth Period In FGR Mice

ObjectiveThe "program process change" of the fetal growth restriction will leads to metabolic and reproductive endocrine disease in the adulthood, and the "catch-up growth" after the birth will enlarge the effect-of the "programmed" damage. Insulin resistance is the pathological and physiological basis of the "program process change" of the FGR. Our study is to explore the interventional effect of the insulin resistance by metformin during the catch-up growth period in the FGR mice, providing a theoretical basis and practical guidance for the future early clinical intervention of the FGR.Methods1、Using low protein diet during pregnancy to establish the FGR mice model. Then establish the catch-up growth FGR mice model and the metformin intervention model by fed the high-fat diet、metformin after weaning. Six mice of each group were taken to be observed the vaginal opening time and estrus cycle changes from 6 weeks old to 12 weeks old. The weight、the height、the poundera index (PI), the fasting blood glucose (FBG)、the fasting insulin (Fins)、the triglycerides (TG)、 the free fatty acid (FFA)、 the adiponectin (ADP)、 the follicle stimulating hormone (FSH)、the anti-mullerian hormone (AMH) of each group mice were measured at 12 weeks old, and the homeostasis model assessment-insulin resistance (HOM-IR) index and the insulin sensitivity index (ISI) were then be calculated.2、Using SPSS17.0 statistical software to processe the statistics, data are presented as meanS. E. M. Experiments among multiple groups were analyzed by ony-way ANOVA followed by LSD multiple comparison test, or test by Dunnett T3 if variance is not equal. a=0.05.Results1、Establish FGR animal model in mice by low protein diet during pregnancy had a high success rate, the average birth weight of the low protein diet group mice was significantly lower than the average birth weight of normal diet group mice (P<0.01).2、The FGR group mice grew faster than the normal group mice, the average weight of the two groups had no significant difference at 4 weeks old (P>0.05) and the average weight of the FGR group mice is heavier than the normal group mice at 8 weeks old(P<0.05).3. The comparisons of the weight、the length the poundera index of each group mice at 12 weeks old:The weight、the PI index of the FGR+SF+NS group were obviously higher than the NC+SF+NS group (P<0.05), and the length was less than the NC+SF+NS group (P<0.05).After weaning, the HF factor expanded the difference between the two groups. In the catch-up growth period, MF factor could reduce the weight of the FGR mice, so as to reduce the PI index. The results of the multiple factors analysis of variance showed that:high-fat diet (HF) factor, metformin (MF) factor had an effect on the weight (all P<0.01);HF factor interacted with MF factor, FGR factor interacted with MF factor (P<0.01);HF factor interacted with FGR factor, HF、MF、FGR interacted between each other (P<0.05). HF factor, FGR factor had an effect on the length (all P<0.01);HF factor interacted with FGR factor (P<0.01). HF、MF、FGR had an effect on the PI index(all P<0.01);HF factors interacted with MF factor, FGR factor interacted with MF factor and HF factor interacted with FGR factor (P<0.01);HF、MF、FGR interacted between each other(P<0.05)..4、The comparisons of the fasting glucose (FBG)、the fasting insulin (FINS)、the homeostasis model assessment for insulin resistance index (HOMA-IR)、the insulin sensitive index (ISI) of each group mice at 12 weeks old:The FBG. the FINS、the HOMA-IR index of the FGR+SF+NS group were obviously higher than the NC+SF+NS group (P<0.05), and the ISI was less than the NC+SF+NS group (P<0.05). After weaning, the HF factor expanded the difference between the two groups. In the catch-up growth period, MF factor could reduce the FINS the FGR mice, so as to reduce the HOMA-IR index, improve the ISI index. The results of the multiple factors analysis of variance showed that:The HF、MF、FGR factor had effect on the fasting glucose、the fasting insulin the homeostasis model assessment for insulin resistance index、the insulin sensitive index (all P<0.01).5、The comparisons of the triglycerides (TG)、 the free fatty acids (FFA) the adiponectin (ADP) index of each group mice at 12 weeks old:The TG、the FFA of the FGR+SF+NS group were obviously higher than the NC+SF+NS group (P<0.05), and the ADP was less than the NC+SF+NS group (P<0.05). After weaning, the HF factor expanded the difference between the two groups.In the catch-up growth period, MF factor could reduce the TG、the FFA of the FGR mice, increase the ADP, so as to reduce the body fat level in the catch-up growth period of the FGR mice. The results of the multiple factors analysis of variance showed that:HF、FGR、MF factor had an effect on the triglycerides、the free fatty acids and the adiponectin index(all P<0.01).6、The comparisons of the follicle stimulating hormone、the anti-mullerian hormone of each group mice at 12 weeks old:The FSH of the FGR+SF+NS group was obviously higher than the NC+SF+NS group(P<0.05), and the AMH was less than the NC+SF+NS group(P<0.05). After weaning, the HF factor expanded the difference between the two groups. In the catch-up growth period, MF factor could reduce the FSH of the FGR mice, increase the AMH, so as to improve the ovarian reserve function. The results of the multiple factors analysis of variance showed that:FGR factor has effect on the follicle stimulating hormone-, the anti-mullerian hormone (all P<0.01).7、The comparisons of the vaginal opening time、 the start time of the estrus cycle、 the number of the estrus cycle of each group mice at 12 weeks old:The the vaginal opening time、 the start time of the estrus cycle of the FGR+SF+NS group were obviously later than the NC+SF+NS group (P<0.05), and the the number of the estrus cycle was less than the NC+SF+NS group (P<0.05). After weaning, the HF factor delayed the start time of the estrus cycle, reduced the number of the estrus cycle.In the catch-up growth period,MF factor could improve the start time of the estrus cycle of the FGR mice, so as to increase the number of the estrus cycle. The results of the multiple factors analysis of variance showed that:the HF、FGR factor had an effect on the vaginal opening time (all P<0.01), the MF factor has effect on the vaginal opening time (all P<0.05);The HF、MF、FGR factor have an effect on the estrus cycle start time、 the estrus cycle number(all P<0.01).Conclusion1、Through the low protein diet during pregnancy could successfully establish the FGR mice model, and nutritionally adequate after the birth could lead to the phenomenon of the catch-up growth.2、The phenomenon of the insulin resistance could occur in the adulthood of the FGR mice, characterized by obesity, higher fasting blood glucose, lower insulin senstitive index, increased serum lipid, delayed puberty, ovarian function decrease and thin hair ovulation. The high-fat diet after weaning could increase the phenomenon of the insulin resistance, expand the effect of the "programmed" damage.3、Metformin as a sensitization agent could strengthen the peripheral tissue intake of the glucose, improve the operational capacity of the glucose, improve the body’s sensitivity to the insulin, reduce insulin resistance, thus reduce the glucolipid metabolism and reproductive endocrine disorders in the maturation period of the catch-up growth FGR mice, so as to provide a theoretical basis and practical guidance for the future early clinical intervention of the FGR.