| Objective:To study the relationships between insulin resistance of juvenile rats with intrauterine growth retardation and changes of pancreatic apoptosis and proliferation, mTOR/S6K pathway in the liver and key enzymes of gluconeogenesis and effect of nutritional intervention.Methods:1To establish the juvenile rats with intrauterine growth retardation model through low protein diet of whole pregnant process. To limit the number of juvenile rats in order to give early nutritional intervention. To evaluate insulin sensitivity of juvenile rats with intrauterine growth at3weeks and7weeks through intraperitoneal glucose tolerance test.2To measure PDX-1, caspase-3, bax and bcl-2mRNA expression of pancreatic tissue of IUGR juvenile rats by real time PCR at birthday,1week,3weeks and7weeks.3To measure mTOR/S6K, IRS-1and p-IRS-1protein expression of liver of IUGR juvenile rats by Western Blot at birth,3weeks and7weeks.4To measure PGC-1α, and PEPCK and G-6-Pase, which are the key enzymes of gluconeogeneis, mRNA expression of liver of IUGR juvenile rats by real time PCR at bithday,1week,3weeks and7weeks.5To statistical analyze the data with SPSS software10.0.Results:1The weights of mother rats with low protein diet of whole pregnant process(LPM) were lower than those of control mother(CM) at the8days,15days and before delivery during pregnance(p<0.01). The weights of LPM became lighter firstly and then heavier, hower the weights of CM became heavier and heavier during whole pregnance.2The birthweight, nose-hip length and tail length of intrauterine growth retardation (IUGR) juvenile rats were lower than those of control group (C)(p<0.001). At1week, the weight, nose-hip length and tail length of intrauterine growth retardation of un-nutrition (IUGR-UN) juvenile rats were lower than those of C (p<0.01). However, the weight of intrauterine growth retardation of nutrition (IUGR-N) juvenile rats was as same as that of C (the value of P was0.219). At the same time, nose-hip length and tail length of IUGR-N were lower than those of C(the values of P were0.000, respectively). The weight, nose-hip length and tail length of IUGR-N were higher than those of IUGR-UN(p<0.01). At3weeks, the weight and nose-hip length of IUGR-UN were lower than those of C(the values of P were0.000, respectively). The tail length of IUGR-UN was as same as that of C(the value of P was0.173). The weight, nose-hip length and tail length of IUGR-N were higher than those of both IUGR-UN and C(the value of P were0.000, respectively). At7weeks, the weight, nose-hip length and tail length of IUGR-UN were as same as those of C (P>0.05) and the weight of IUGR-N was heavier than that of C and IUGR-UN (P<0.05, respectively). However, there were no differences of nose-hip length and tail length between C, IUGR-UN and IUGR-N (P>0.05).3There were on differences of the levels of fast plasma glucose(FPG) and intraperitoneal glucose tolerance test120minute glucose(G120) between three groups at3weeks(P>0.05). At the same time, the concentrations of fast insulin(FINS) and intraperitoneal glucose tolerance test120minute insulin(I120) of IUGR-N were significantly higher than those of C and IUGR-UN(.P<0.01). However, there was no difference between C and IUGR-UN. At7weeks, the concentration of FPG in IUGR-N was higher than that of C, the value of P was0.022. The levels of G120in IUGR-UN and IUGR-N were all higher than that of C(P<0.05). There was no difference of G120between IUGR-UN and UGR-N. The levels of FINS and1120in IUGR-UN and IUGR-N were higher significantly than those of C. The concentrations of FINS and1120in IUGR-N were all higher than those of IUGR-UN.4At3threes, HOMA-IR of IUGR-N was significantly higher than that of C and IUGR-UN, the value of P were0.000and0.000, respectively. There was no difference between IUGR-UN and C, the value of P was0.708. HOMA-IS of IUGR-N was lower than that of C and IUGR-UN, the values of P were0.033and0.028, respectively. Hower there was no difference between C and IUGR-UN. There were differences of HOMA-β between IUGR-UN and C and between IUGR-UN and IUGR-N, the value of P were0.022and0.004, respectively. There was no difference between C and IUGR-N. At7weeks, HOMA-IR of IUGR-UN and IUGR-N were all higher than that of C, the value of P were all0.000. At same time, there was difference between IUGR-UN and IUGR-N, the value of P was0.006. HOMA-IS and HOMA-β of IUGR-UN and IUGR-N were all lower than those of C. The levels of HOMA-IS in IUGR-N was lower than that of IUGR-UN.5The level of PDX-1mRNA expression in IUGR pancreatic tissue was lower than that of C at birthday. There were no differences in PDX-1mRNA expression between three groups at1week. The level of PDX-1mRNA expression in IUGR-N was higher than that of C and IUGR-UN (P<0.05) at three weeks. There was no difference in PDX-1mRNA expression between C and IUGR-UN. The levels of caspase-3mRNA expression in IUGR were higher than that of C (P<0.05) at7weeks. There was no significant difference between IUGR-UN and IUGR-N.6The level of caspase-3mRNA expression in IUGR pancreatic tissue was higher than that of C at birthday. There were no differences in PDX-1mRNA expression between three groups at1week. The levels of PDX-1mRNA expression in IUGR-N and IUGR-UN were higher than that of C (P<0.05) at three weeks. There was no difference in caspase-3mRNA expression between IUGR-N and IUGR-UN. The level of caspase-3mRNA expression in IUGR were higher than that of C(P <0.05) at7weeks. The level of caspase-3mRNA expression in IUGR-N was higher than that of IUGR-UN(P<0.05).7The levels of bcl-2mRNA expression in IUGR pancreatic tissue was lower than that of C at birthday. There were no differences in bcl-2mRNA expression between three groups at1week. The levels of bcl-2mRNA expression in IUGR-N and IUGR-UN were lower than that of C (P<0.05) at three weeks. There was no difference in bcl-2mRNA expression between IUGR-N and IUGR-UN. The level of bcl-2mRNA expression in IUGR were lower than that of C(P<0.05) at7weeks. There was no significant difference between IUGR-UN and IUGR-N.8The levels of bax mRNA expression in IUGR pancreatic tissue was higher than that of C at birthday. The levels of bax mRNA expression in IUGR pancreatic tissue were higher than that of C at1week. The levels of bax mRNA expression in IUGR-N and IUGR-UN were higher than that of C (the value of P was0.000) at three weeks. There was no difference in bax mRNA expression between IUGR-N and IUGR-UN. The level of bax mRNA expression in IUGR were higher than that of C(P<0.05) at7weeks. There was no significant difference between IUGR-UN and IUGR-N.9The levels of mTOR, S6K, IRS-1and p-IRS-1ser636protein expressions in IUGR were lower than those of C at birthday. There were no differences in S6K and IRS-1protein expressions between C and IUGR at3weeks. The levels of mTOR and p-IRS-1ser636protein expressions in IUGR were higher than those of C at3weeks. The levels of mTOR, S6K and p-IRS-1ser636protein expressions in IUGR-UN and IUGR-N were higher than those of C at7weeks, but there was no difference in IRS-1protein expressions among these three groups.10The levels of PGC-1a mRNA, G-6-Pase mRNA and PEPCK mRNA expressions in IUGR were higher than those of C at birthday. The levels of PGC-1α mRNA, G-6-Pase mRNA and PEPCK mRNA expressions in IUGR were still higher than those of C at1week,3weeks and7weeks. The levels of PGC-la mRNA, G-6-Pase mRNA and PEPCK mRNA expressions in IUGR-N were higher than those of IUGR-UN at1week,3weeks and7weeks, too. Conclusions1We can establish intrauterine growth retardation juvenile rats model successfully through low protein diet during whole pregnant process.2For intrauterine growth juvenile rats, nutritional enhancement only accelerates speed of the catch-up growth and obesity appearance during the lactation. Nutritional enhancement will not influence the terminal height before sex maturity. However, nutritional enhancement during the lactation will lead to insulin resistance and abnormal blood glucose before sex maturity. Usual diet will postpone the insulin resistance and abnormal blood glucose, but at last, it will lead to abnormal glucose metabolism. Maybe it is the reason that leads to higher incidence of type2diabetes for IUGR infants. So the glucose metabolism condition should be monitored earlier.3The low protein diet during pregnance will lead to both apoptosis increase and proliferation decrease of pancreatic tissue for IUGR juvenile rat at birth. In the early life, bax triggers the apoptosis process firstly. It is the key point to improve glucose metabolism for children with IUGR in the future through suppressing apoptosis gene expression and increasing proliferation gene expression.4The malnutrition condition in intrauterine leads to key enzyme of gluconeogenesis expression increasing, which will last until after birth. This manifestation supports the thrift hypothesis, which is the basis that IUGR juvenile rats suffer from type2diabetes during adult period.5Nutrition has effect on IUGR juvenile rats by mTOR/S6K pathway with two sides. One side, it can promote growth and development, on the other side, it leads to insulin resistance. So, nutrition balance may be a key point to improve prognosis for IUGR infants. The mTOR/S6K pathway will be a new target for treatment of insulin resistance. |
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