链脲佐菌素诱导孕鼠高血糖子鼠高出生体质量模型的建立及孕鼠高血糖对子鼠远期生长代谢的影响

目的链脲佐菌素（STZ）诱导孕鼠，建立宫内高血糖、高出生体质量子鼠模型，并观察宫内高血糖环境对子鼠远期生长代谢的影响。方法Wistar孕鼠21只，其中14只一次性腹腔注射STZ25mg／kg，诱导发生宫内高血糖环境，孕鼠血糖10—20mmol／L为模型组（9只j；恤糖〉20mmol／L的5只为重度高血糖模型组（高糖组）。对照组孕鼠（7只）以同样方法注射等体积的柠檬酸一柠檬酸钠缓冲液。记录各组孕鼠体质量和血糖情况，并行灌胃糖耐量试验（LGTT）后检测各时间点血糖水平，观察各组子鼠生长发育的相关指标。结果（1）建模5d后，模型组及高糖组孕鼠血糖水平[分别为（16．8±5．4）及（20．5±5．6）mmol／L]已显著高于对照组的（7．0±1．4）mmol／L，分别比较，差异均有统计学意义（P〈0．01）；且模型组及高糖组孕鼠孕期平均血糖水平[分别为（16．6±3．4）及（23．8±1．5）mmol／L]也显著高于对照组的（5．8±1．1）mmol／L，分别比较，差异有统计学意义（P〈0．01）。（2）建模第4天和第10天，模型组孕鼠LGTT各时间点血糖水平均显著高于对照组，两组比较，差异有统计学意义（P〈0．01）。（3）模型组雌、雄性子鼠平均出生体质量分别为（6．9±0．4）、（7．4±0．6）g，较对照组（6．4±0．3）、（6．6±0．4）g和高糖组（6．3±0．4）、（6．5±0．4）g显著增加，分别比较，差异均有统计学意义（P〈0．05）；高糖组子鼠出生时血糖为（6．5±1．2）mmol／L，对照组和模型组均为（4．1±0．8）mmol／L，分别比较，差异均有统计学意义（P〈0．05）。（4）出生后12周，模型组雌性子鼠体质量为（263±28）g，与对照组（251±22）g比较，差异无统计学意义（P〉0．05）；出生后第16周，模型组雌性子鼠体质量为（292±27）g，并一直呈显著增高趋势，直至出生后第26周为（317±30）g，与对照组雌性子鼠分别比较[分别为（264±20）g、（318±43）g]，差异有统计学意义（P〈0．05）。模型组雄性子鼠出生时及出生后第4周体质量显著高于对照组，两组比较，差异有统计学意义（P〈0．05）；模型组雄性子鼠体质量虽然一直呈增高趋势，但与对照组比较，差异均无统计学意义（P〉0．05）。（5）模型组雌性子鼠生长期第20周和24周时开始，LGTF30和60rain血糖水平显著高于对照组，分别比较，差异均有统计学意义（P〈0．05）；在生长期第28周时，模型组雌性子鼠血糖虽有升高趋势，但与对照组比较，差异已无统计学意义（P〉0．05）。模型组雄性子鼠从生长期第16周开始，其LGTT30min血糖水平即显著高于对照组，两组比较，差异有统计学意义（P〈0．05）；而第24周和28周，两组LGTT30min和60min血糖水平比较，差异均无统计学意义（P〉0．05）。（6）模型组雄性子鼠血压在生长期第12周时显著高于对照组，两组比较，差异有统计学意义（P〈0．05）；第20周时，模型组雄性子鼠血压水平有不同程度的升高，并保持至生长期第26周，但与对照组比较，差异无统计学意义（P〉0．05）。结论给Wistar孕鼠空腹一次性腹腔注射STZ25mg／kg的方法可成功诱导出一定数量的宫内高血糖性高出生体质量子鼠模型，并且可观察到其成年期出现体质量增加、糖代谢紊乱和雄性子鼠血压升高的情况，为人类临床妊娠期糖尿病孕产巨大儿的成年期代谢特点、发生机制和制定防治策略的研究提供动物模型基础。

Objective To establish and assess the high-birth-weight offspring model of the diabetic rat induced by stueptozotocin,and the long-term metabolic impact of maternal hyperglycemia of those offsprings.Methods Streptozotocin (STZ,25 mg/kg) was given to Wistar rats (G group,n =14) once intraperitoneally to induce maternal hyperglycemia model (blood glucose between 10-20 mmol/L),and there still had a number of rats defined as severe hyperglycemia model group (SG group,n =5).The Control group (C group,n =7) were given the same volume citrate buffer solution.The body weight and blood glucose were recorded,and the lavaging glucose tolerance test (LGTT) was performed by a glucose meter in the gestation.The offsprings were corresponding allocated into 2 groups,and the birth weight were recorded.All the offsprings were observated body weight,blood glucose blood pressure (male rats only),and so on.Results (1) The blood glucose of G group (16.8 ±5.4 mmol/L) and SG group (20.5 ±5.6 mmol/L) were increased significantly as compared with C group (7.0 ± 1.4 mmol/L) 5 days after the model was established (P ＜ 0.01) ; and the average blood glucose of G group (16.6 ± 3.4 mmol/L) and SG group (23.8 ± 1.5 mmol/L) increased too as comparede with C group (5.8 ± 1.1 mmol/L),the difference was significance according to statistics (P ＜ 0.01).(2) According to the LGTT result,which operationed on generation day 4 and day 10,the blood glucose of every time point of G group were increased significantly as compared with C group (P ＜ 0.01).(3) The male and female birth weight of G group was remarkably higher than the C group and the SG group (P ＜ 0.05),and the blood glucose of SG /G/C group was (6.5 ±1.2) mmol/L,(4.1 ± 0.8) mmol/L,(4.1 ± 0.8) mmol/L respectively,according to the statistics results,the difference between SG group and G/C group respectively both remarkable (P ＜ 0.05).(4) The body weight,Lee's index,fat weight,and the fat weight of mass ratio in C group mother rats after lactation presented dressed compared with the SG group (P ＜ 0.05),and so as to the G group compared with the SG group (P ＜ 0.05).(5) In the female offsprings of G group,the birth weight was remarkably increased compared with the C group (P ＜ 0.05) ; the body weight of the female offsprings presented an increased trend compared with the C group since the 12 weeks,but had no statistical significance; there were significant differences of body weight between G group and C group since 15 weeks (P ＜ 0.05),and the trend kept up until 26 weeks; in the male offsprings of G group,the body weight on birth day and 4 weeks had a marked rise compared with the C group (P ＜ 0.05) ; and from then on,the body weight of the male offsprings presented an increased trend compared with the C group,but had no statistical significance until 26 weeks (P＞0.05).(6) In G group,the blood glucose on 30 min and 60 min of LGTT in female offsprings were increased than the C group since 20 weeks (P ＜ 0.05) ; the blood glucose of LGTT (30 min) still had a marked rise until 24 weeks (P ＜ 0.05) ; in G group,the blood glucose on 30 min of LGTT in male offsprings was remarkably incrcascd than the C group since 16 weeks (P ＜0.05) ; the blood glucose of LGTT (30 min) still had a marked rise until 24 weeks (P ＜ 0.05).(7) The blood pressure of male offsprings in G group had a marked rise on 12 weeks compared with the C group (P ＜ 0.05) ; from then on the blood pressure of G group kept up a rise trend until 26 weeks,but had no statistical significance (P ＞0.05).Conclusion The diabetic high-birth-weight rat model could be duplicated with STZ (25 mg/kg) once intrapertoneally on the first day of gestation,which were observed some evidently metabolic changes in weight,glucose tolerance and blood pressure.These results could represent an forward step in the clinical study of human gestational diabetes mellitus and their macrosomia babies,which may suffer some metabolic disease in their later life.