IUGR幼鼠IR机制及营养干预作用
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摘要
目的：
探讨IUGR幼鼠胰腺组织增殖和凋亡,肝脏mTOR/S6K通路及肝糖异生关键酶的变化与幼鼠IR发生的关系及营养干预的影响。
方法：
1.采用孕鼠妊娠期全程低蛋白饮食的方法建立IUGR幼鼠模型。通过控制每只母鼠喂哺幼鼠的个数,达到早期营养干预的目的。通过对3周龄和7周龄幼鼠进行腹腔葡萄糖耐量试验评价胰岛素敏感性。
2.应用Real-time PCR方法测定IUGR幼鼠出生时,1周龄,3周龄和7周龄胰腺组织中增殖指标PDX-1和凋亡指标caspase-3,bax和bcl-2mRNA表达。
3.应用Western Blot方法测定IUGR幼鼠出生时,3周龄和7周龄肝脏组织中mTOR/S6K,IRS-1以及p-IRS-1的蛋白表达。
4.应用Real-time PCR方法测定IUGR幼鼠出生时,1周龄,3周龄和7周龄肝脏组织中PGC-1α和糖异生关键酶PEPCK和G-6-Pase mRNA表达。
5.数据采用SPSS10.0软件进行统计学分析。
结果：
1.妊娠期全程低蛋白饮食母鼠(LPM)在妊娠第8天,第15天和分娩前体重均明显低于对照组(CM),P<0.01。并且LPM体重呈现先降低后升高的态势,而CM体重在整个妊娠期均呈增高趋势。
2.宫内发育迟缓(IUGR)幼鼠出生时体重,鼻臀长和尾长都低于对照组(C),P<0.001。1周龄时,宫内发育迟缓未加强营养(IUGR-UN)幼鼠体重,鼻臀长和尾长均低于C,P<0.001。而宫内发育迟缓加强营养(IUGR-N)幼鼠体重已经达到对照组水平,P值为0.279;但是鼻臀长和尾长还落后于C,P值均为0.000。IUGR-N在体重,鼻臀长和尾长均高于IUGR-UN,P<0.01。3周龄时,IUGR-UN体重和鼻臀长明显低于C,P均值为0.000,但是尾长与C的差异没有统计学意义,P值为0.173。IUGR-N体重,鼻臀长和尾长不但超过了IUGR-UN,而且超过了C,P值均为0.000。7周龄时,IUGR-UN体重,鼻臀长和尾长都达到与C相同的水平,P>0.05;IUGR-N体重超过了C和IUGR-UN,P<0.05。但是鼻臀长和尾长在3组间是没有差异的,P>0.05。
3.3周龄时,3组幼鼠的空腹血.糖(FPG)和腹腔糖耐量120分钟血糖(G120)水平没有差异,P>0.05。IUGR-N空腹胰岛素(PINS)120分钟胰岛素(I120)水平均明显高于C和IUGR-N,P<0.01。但是C和IUGR-UN胰岛素水平没有差异,P>0.05。7周龄时,IUGR-N FPG高于C,P值为0.022。IUGR-UN和IUGR-N G120均高于C组,P<0.05。但是这2组之间G120水平的差异没有统计学意义,P>0.05。IUGR-UN和IUGR-N PINS和I120均明显高于C,P<0.001。同时,IUGR-N FINS和I120水平亦明显高于IUGR-UN,P<0.001。
4.3周龄时,IUGR-N HOMA-IR明显高于C组和IUGR-UN组,P值分别为0.000和0.000,IUGR-NU组和C组幼鼠的HOMA-IR差异没有统计学意义,P值为0.708。IUGR-N HOMA-IS明显低于C和IUGR-UN,P值分别为0.033和0.028,但C和IUGR-UN间差异没有统计学意义,P值为0.9111。IUGR-UN HOMA-β与C和IUGR-N的差异均存在统计学意义,P值分别为0.022和0.004。C组和IUGR-N组的差异没有统计学意义,P值为0.192。7周龄时,IUGR-UN和IUGR-N两组的HOMA-IR均明显高于C,P值均为0.000,这两组间的差异亦存在统计学意义,P值为0.006。IUGR-UN和IUGR-N两组幼鼠的HOMA-IS均明显低于C组,P值均为0.000,这两组间的差异也存在统计学意义,P值为0.016。IUGR-UN和IUGR-N两组HOMA-β均明显低于C组,P值均为0.000,这两组间的差异无统计学意义,P值为0.717。
5.出生时,IUGR PDX-1mRNA表达低于C,P<0.05。1周龄时,3组幼鼠PDX-1mRNA表达差异无统计学意义,P>0.05。3周龄时,IUGR-N PDX-1mRNA表达高于C组和IUGR-UN,P<0.05。C和IUGR-UN间的差异没有统计学意义,P>0.05。7周龄时IUGR2组PDX-1mRNA表达明显高于C,P<0.05。IUGR-UN2组间的差异没有统计学意义,P<0.05。
6.出生时,IUGR caspase-3mRNA表达高于C,P<0.05。1周龄时,3组幼鼠caspase-3mRNA表达的差异没有统计学意义,P>0.05。3周龄时,IUGR2组caspase-3mRNA表达均高于C,P<0.05。此2组间的差异没有统计学意义,P>0.05。7周龄时,IUGR2组caspase-3mRNA表达仍均高于C,P<0.05；IUGR-N caspase-3mRNA的表达明显高于IUGR-UN,P<0.05。
7.出生时,IUGR bcl-2mRNA表达低于C,P<0.01。1周龄时,3组幼鼠bcl-2mRNA表达的差异没有统计学意义,P>0.05。3周龄时,IUGR2组bcl-2mRNA表达均低于C,P<0.05。此2组间的差异没有统计学意义。7周龄时IUGR2组bcl-2mRNA表达均低于C,P<0.05;此2组间的差异没有统计学意义。
8.出生时,IUGR bax mRNA表达高于C,P<0.05。但是IUGR2组间bax mRNA表达的差异没有统计学意义。1周龄时,IUGR2组幼鼠bax mRNA表达均高于C组,P<0.05。IUGR-Nbax mRNA表达高于IUGR-UN,P值为0.000。3周龄时,IUGR2组bax mRNA表达均高于C,P值均为0.000。此2组间的差异没有统计学意义。7周龄时IUGR2组bax mRNA的表达均高于C组,P值分别为0.001和0.000；此2组间的差异没有统计学意义。
9.出生时,IUGRmTOR, S6K, IRS-1和p-IRS-1ser636蛋白表达低于C,,P值分别为0.000,0.003,0.023和0.007。3周龄时,IUGR-UN和IUGR-N2组幼鼠mTOR和p-IRS-lser636的蛋白表达超过C组,P为0.000和0.000及0.019和0.012,虽然mTOR蛋白表达在IUGR2组间没有差异,P值为0.120；但是,p-IRS-1ser636蛋白表达在2组间有差异,P值为0.032。同时,S6K和IRS-1蛋白表达水平在3组间没有差异。7周龄时,IUGR mTOR,S6K和p-IRS-1ser636蛋白表达均超过C,P<0.05。但是IRS-1的蛋白表达在3组间没有差异。
10.出生时,IUGR PGC-1α mRNA, G-6-Pase mRNA和PEPCK mRNA基因表达均高于C,P<0.05。1周龄时,3周龄时和7周龄时,IUGR PGC-la mRNA, G-6-Pase mRNA和PEPCK mRNA基因表达均高于C组,P<0.01。同时,IUGR-N PGC-la mRNA, G-6-Pase mRNA和PEPCK mRNA基因表达均高于IUGR-UN, P<0.01。
结论：
1.应用孕鼠妊娠期全程低蛋白饮食的方法,可以成功建立IUGR幼鼠的模型。
2.对于IUGR幼鼠,哺乳期营养的加强只是加快了追赶生长的速度,加速了肥胖的出现,对于性成熟期前的最终身高没有影响。而且哺乳期营养的加强会造成性成熟期前IR的出现和血糖的异常。而正常喂养方式可以延缓IR和血糖异常的发生,但在性成熟期前,仍会造成糖代谢的异常。这或许是IUGR婴儿成年后2型糖尿病发病率增高的一个原因。因此对于具有IUGR病史的婴儿,应该尽早监测糖代谢的情况；阻止哺乳期婴儿快速体重增加或许可以预防儿童时期体重的增加。
3.孕母妊娠期营养不良会使IUGR幼鼠出生时胰腺组织凋亡增加,增殖降低。营养干预影响IUGR幼鼠胰腺的凋亡和增殖。在生命早期,bax首先触发凋亡过程,哺乳期给予适当的营养干预,抑制凋亡基因的表达,增加胰腺增殖,是改善IUGR儿童今后糖代谢的关键。
4.宫内不良的营养环境造成肝脏糖异生关键酶的表达增加,而这种增加持续至出生后,支持节俭表型假说,同时是IUGR幼鼠成年时期发生2型糖尿病的基础。
5.营养是一柄双刃剑,通过激活mTOR/S6K途径,一方面促进机体的生长发育,另一方面造成IR,合理平衡营养,或许是改善IUGR婴儿成年预后的关键。对于mTOR/S6K途径的干预或许可以成为治疗IR的新靶点。
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. Conclusions
1We 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.
探讨IUGR幼鼠胰腺组织增殖和凋亡,肝脏mTOR/S6K通路及肝糖异生关键酶的变化与幼鼠IR发生的关系及营养干预的影响。
方法：
1.采用孕鼠妊娠期全程低蛋白饮食的方法建立IUGR幼鼠模型。通过控制每只母鼠喂哺幼鼠的个数,达到早期营养干预的目的。通过对3周龄和7周龄幼鼠进行腹腔葡萄糖耐量试验评价胰岛素敏感性。
2.应用Real-time PCR方法测定IUGR幼鼠出生时,1周龄,3周龄和7周龄胰腺组织中增殖指标PDX-1和凋亡指标caspase-3,bax和bcl-2mRNA表达。
3.应用Western Blot方法测定IUGR幼鼠出生时,3周龄和7周龄肝脏组织中mTOR/S6K,IRS-1以及p-IRS-1的蛋白表达。
4.应用Real-time PCR方法测定IUGR幼鼠出生时,1周龄,3周龄和7周龄肝脏组织中PGC-1α和糖异生关键酶PEPCK和G-6-Pase mRNA表达。
5.数据采用SPSS10.0软件进行统计学分析。
结果：
1.妊娠期全程低蛋白饮食母鼠(LPM)在妊娠第8天,第15天和分娩前体重均明显低于对照组(CM),P<0.01。并且LPM体重呈现先降低后升高的态势,而CM体重在整个妊娠期均呈增高趋势。
2.宫内发育迟缓(IUGR)幼鼠出生时体重,鼻臀长和尾长都低于对照组(C),P<0.001。1周龄时,宫内发育迟缓未加强营养(IUGR-UN)幼鼠体重,鼻臀长和尾长均低于C,P<0.001。而宫内发育迟缓加强营养(IUGR-N)幼鼠体重已经达到对照组水平,P值为0.279;但是鼻臀长和尾长还落后于C,P值均为0.000。IUGR-N在体重,鼻臀长和尾长均高于IUGR-UN,P<0.01。3周龄时,IUGR-UN体重和鼻臀长明显低于C,P均值为0.000,但是尾长与C的差异没有统计学意义,P值为0.173。IUGR-N体重,鼻臀长和尾长不但超过了IUGR-UN,而且超过了C,P值均为0.000。7周龄时,IUGR-UN体重,鼻臀长和尾长都达到与C相同的水平,P>0.05;IUGR-N体重超过了C和IUGR-UN,P<0.05。但是鼻臀长和尾长在3组间是没有差异的,P>0.05。
3.3周龄时,3组幼鼠的空腹血.糖(FPG)和腹腔糖耐量120分钟血糖(G120)水平没有差异,P>0.05。IUGR-N空腹胰岛素(PINS)120分钟胰岛素(I120)水平均明显高于C和IUGR-N,P<0.01。但是C和IUGR-UN胰岛素水平没有差异,P>0.05。7周龄时,IUGR-N FPG高于C,P值为0.022。IUGR-UN和IUGR-N G120均高于C组,P<0.05。但是这2组之间G120水平的差异没有统计学意义,P>0.05。IUGR-UN和IUGR-N PINS和I120均明显高于C,P<0.001。同时,IUGR-N FINS和I120水平亦明显高于IUGR-UN,P<0.001。
4.3周龄时,IUGR-N HOMA-IR明显高于C组和IUGR-UN组,P值分别为0.000和0.000,IUGR-NU组和C组幼鼠的HOMA-IR差异没有统计学意义,P值为0.708。IUGR-N HOMA-IS明显低于C和IUGR-UN,P值分别为0.033和0.028,但C和IUGR-UN间差异没有统计学意义,P值为0.9111。IUGR-UN HOMA-β与C和IUGR-N的差异均存在统计学意义,P值分别为0.022和0.004。C组和IUGR-N组的差异没有统计学意义,P值为0.192。7周龄时,IUGR-UN和IUGR-N两组的HOMA-IR均明显高于C,P值均为0.000,这两组间的差异亦存在统计学意义,P值为0.006。IUGR-UN和IUGR-N两组幼鼠的HOMA-IS均明显低于C组,P值均为0.000,这两组间的差异也存在统计学意义,P值为0.016。IUGR-UN和IUGR-N两组HOMA-β均明显低于C组,P值均为0.000,这两组间的差异无统计学意义,P值为0.717。
5.出生时,IUGR PDX-1mRNA表达低于C,P<0.05。1周龄时,3组幼鼠PDX-1mRNA表达差异无统计学意义,P>0.05。3周龄时,IUGR-N PDX-1mRNA表达高于C组和IUGR-UN,P<0.05。C和IUGR-UN间的差异没有统计学意义,P>0.05。7周龄时IUGR2组PDX-1mRNA表达明显高于C,P<0.05。IUGR-UN2组间的差异没有统计学意义,P<0.05。
6.出生时,IUGR caspase-3mRNA表达高于C,P<0.05。1周龄时,3组幼鼠caspase-3mRNA表达的差异没有统计学意义,P>0.05。3周龄时,IUGR2组caspase-3mRNA表达均高于C,P<0.05。此2组间的差异没有统计学意义,P>0.05。7周龄时,IUGR2组caspase-3mRNA表达仍均高于C,P<0.05；IUGR-N caspase-3mRNA的表达明显高于IUGR-UN,P<0.05。
7.出生时,IUGR bcl-2mRNA表达低于C,P<0.01。1周龄时,3组幼鼠bcl-2mRNA表达的差异没有统计学意义,P>0.05。3周龄时,IUGR2组bcl-2mRNA表达均低于C,P<0.05。此2组间的差异没有统计学意义。7周龄时IUGR2组bcl-2mRNA表达均低于C,P<0.05;此2组间的差异没有统计学意义。
8.出生时,IUGR bax mRNA表达高于C,P<0.05。但是IUGR2组间bax mRNA表达的差异没有统计学意义。1周龄时,IUGR2组幼鼠bax mRNA表达均高于C组,P<0.05。IUGR-Nbax mRNA表达高于IUGR-UN,P值为0.000。3周龄时,IUGR2组bax mRNA表达均高于C,P值均为0.000。此2组间的差异没有统计学意义。7周龄时IUGR2组bax mRNA的表达均高于C组,P值分别为0.001和0.000；此2组间的差异没有统计学意义。
9.出生时,IUGRmTOR, S6K, IRS-1和p-IRS-1ser636蛋白表达低于C,,P值分别为0.000,0.003,0.023和0.007。3周龄时,IUGR-UN和IUGR-N2组幼鼠mTOR和p-IRS-lser636的蛋白表达超过C组,P为0.000和0.000及0.019和0.012,虽然mTOR蛋白表达在IUGR2组间没有差异,P值为0.120；但是,p-IRS-1ser636蛋白表达在2组间有差异,P值为0.032。同时,S6K和IRS-1蛋白表达水平在3组间没有差异。7周龄时,IUGR mTOR,S6K和p-IRS-1ser636蛋白表达均超过C,P<0.05。但是IRS-1的蛋白表达在3组间没有差异。
10.出生时,IUGR PGC-1α mRNA, G-6-Pase mRNA和PEPCK mRNA基因表达均高于C,P<0.05。1周龄时,3周龄时和7周龄时,IUGR PGC-la mRNA, G-6-Pase mRNA和PEPCK mRNA基因表达均高于C组,P<0.01。同时,IUGR-N PGC-la mRNA, G-6-Pase mRNA和PEPCK mRNA基因表达均高于IUGR-UN, P<0.01。
结论：
1.应用孕鼠妊娠期全程低蛋白饮食的方法,可以成功建立IUGR幼鼠的模型。
2.对于IUGR幼鼠,哺乳期营养的加强只是加快了追赶生长的速度,加速了肥胖的出现,对于性成熟期前的最终身高没有影响。而且哺乳期营养的加强会造成性成熟期前IR的出现和血糖的异常。而正常喂养方式可以延缓IR和血糖异常的发生,但在性成熟期前,仍会造成糖代谢的异常。这或许是IUGR婴儿成年后2型糖尿病发病率增高的一个原因。因此对于具有IUGR病史的婴儿,应该尽早监测糖代谢的情况；阻止哺乳期婴儿快速体重增加或许可以预防儿童时期体重的增加。
3.孕母妊娠期营养不良会使IUGR幼鼠出生时胰腺组织凋亡增加,增殖降低。营养干预影响IUGR幼鼠胰腺的凋亡和增殖。在生命早期,bax首先触发凋亡过程,哺乳期给予适当的营养干预,抑制凋亡基因的表达,增加胰腺增殖,是改善IUGR儿童今后糖代谢的关键。
4.宫内不良的营养环境造成肝脏糖异生关键酶的表达增加,而这种增加持续至出生后,支持节俭表型假说,同时是IUGR幼鼠成年时期发生2型糖尿病的基础。
5.营养是一柄双刃剑,通过激活mTOR/S6K途径,一方面促进机体的生长发育,另一方面造成IR,合理平衡营养,或许是改善IUGR婴儿成年预后的关键。对于mTOR/S6K途径的干预或许可以成为治疗IR的新靶点。
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. Conclusions
1We 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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