Dynamic changes of insulin sensitivity in rats with fetal growth restriction

目的 探讨胎儿生长受限(fetal growth restriction,FGR)大鼠胰岛素敏感性的变化规律.方法 母鼠受孕后第1天始随机分为对照组和低蛋白组,各10只.低蛋白组孕鼠采用低蛋白饮食法建立FGR模型.低蛋白组仔鼠中出生体重低于对照组仔鼠平均出生体重两个标准差者定为FGR鼠.测定对照组和FGR仔鼠(每组雌雄各8只)生后3、7、14、30、60及90 d空腹血浆血糖(fasting plasma glucose,FPG)及空腹血清胰岛索(fasting serum insulin,FINS),计算胰岛素抵抗指数及胰岛素敏感指数.90 d时测定血甘油三酯、低密度脂蛋白胆固醇、高密度脂蛋白胆固醇和糖化血红蛋白,同时行腹腔葡萄糖耐量实验.结果 (1)低蛋白组仔鼠平均出生体重为(4.92±0.36)g,低于对照组的(6.43±0.59)g,差异有统计学意义(t=14.73,P＜0.05).(2)雄性FGR鼠生后60 d时FPG高于对照组[(9.38±1.57)mmol/L与(5.58士1.24)mmol/L],直至90 d[(8.95±1.83)mmol/L与(6.21±1.14)mmol/L],差异有统计学意义(t=-3.291,P＜0.05);雌性FGR鼠90 d时FPG为(9.08±1.65)mmol/L,高于对照组的(6.73土0.67)mmol/L,差异有统计学意义(t=-3.226,P＜0.05);雄性FGR鼠FINS 30 d时开始高于对照组,直至90 d时;雌性FGR鼠60及90 d时FINS 高于对照组,差异均有统计学意义(P＜0.05);雄性及雌性FGR鼠胰岛素抵抗指数及胰岛素敏感指数分别于30 d及60 d始与对照组相比出现改变,直至90 d,差异有统计学意义(P均＜0.05).腹腔葡萄糖耐量实验结果显示,从0 min始各时间点雄性和雌性FGR鼠血糖均高于对照组,差异均有统计学意义(P＜0.05).(3)生后90 d时,雄性FGR鼠糖化血红蛋白为(7.03±0.54)%,高于对照组的(4.37±0.64)%,差异有统计学意义(t=-8.028,P＜0.05).无论雄性或雌性仔鼠,2组血脂水平差异均无统计学意义(P均＞0.05).结论 FGR鼠在生后早期尚能维持正常的FPG和FINS水平,随着日龄增加,胰岛素敏感性从青年期逐渐降低,直至成年期,而且雄性FGR鼠更易发生胰岛素抵抗.Objective To investigate the regular pattern of dynamic changes of insulin sensitivity in fetal growth restriction (FGR) rats. Methods Twenty pregnant female rats were randomly divided into two groups as normal-protein group (NP) and low-protein group (LP), which respectively received normal protein diet (20% protein) and low protein diet (8% protein) during pregnancy. Weights of newborns were measured within 6 hours after birth, and the LP offspring whose birth weights were at least 2 standard deviations below the mean of NP offspring (≤2 standard deviations) were defined as FGR rats. At day 3, 7, 14, 30, 60 and 90 after birth, rats were fasted for 12 hours and then angular vein blood was collected to measure fasting plasma glucose (FPG) and fasting serum insulin (FINS) level. At 90 days of age, intraperitoneal glucose tolerance test (IPGTT)was performed; and blood triglyceride ( TG ), low-density lipoprotein cholesterol ( LDL-C ),high-density lipoprotein cholesterol (HDL-C) and glycosylated hemoglobin Alc (HbAlc) were measured. Insulin sensitivity was evaluated by FINS, insulin resistance index (HOMA-IR), insulin sensitivity index (ISI) and IPGTT. Results (1) Birth weights of LP offspring [(4. 92 ± 0. 36) g]were significantly lower than those of NP ones [(6. 43 ± 0. 59) g] (t = 14. 73, P＜0. 05). The incidence of FGR in LP was 88. 2% ; and for the male and female rats, the FGR rate was 94. 1% and 83. 1%, respectively. (2) FPG levels in the male FGR rats were significantly higher than in the NP from the age of 60 days [(9.38 ± 1.57) mmol/L vs (5. 58 ± 1.24) mmol/L] to 90 days [(8. 95 ±1.83) mmol/L vs (6. 21± 1.14) mmol/L] (t=-3. 291, P＜0. 05), while FPG levels in female FGR rats increased significantly only at 90 days of age [(9. 08±1.65) mmol/L vs (6.73±0. 67) mmol/L](t=-3. 226,P＜0. 05). FINS levels were significantly higher in FGR rats than in the NP from the age of 30 days (male FGR rats) or 60 days (female FGR rats) to 90 days (P＜0. 05, respectively).Similarly, HOMA-IR was significantly higher in FGR rats than in the NP at the age of 30 days (male FGR rats) or 60 days (female FGR rats) to 90 days (P＜0. 05, respectively). ISI in male FGR rats showed a reduction in comparison with the NP from the age of 30 to 90 days, while as to the female FGR rats it was significantly lower than in the NP only at 60 days of age and continued to 90 days (P＜0. 05, respectively). IPGTT showed that after injection of glucose, blood glucose at all four points (from 0 min to 120 min) in both male and female FGR rats were higher than that in the NP (P＜0. 05). (3) No significant difference was observed in TG, LDL-C and HDL-C at 90 days of age between the FGR rats and NP ones, while HbA1c in the male FGR rats was significantly higher than that in the NP [(7. 03±0. 54) % vs (4. 37±0. 64)%,t= -8. 028, P＜0. 05]. Conclusions FGR rats are able to maintain glucose balance and normal insulin levels during their earlier age, while insulin sensitivity decreased from adolescence to adulthood. The change of insulin sensitivity is different between male and female FGR rats, and male FGR rats are more likely to develop insulin resistance.国家自然科学基金青年基金; 教育部博士点基金新教师项目中文核心期刊要目总览(PKU)中国科技核心期刊(ISTIC)04221-2261