Long-term effects of mild intrauterine hyperglycemia on glucose and lipid metabolism in intergenerational rat offspring

目的 观察轻度宫内高血糖暴露对子一代(简称F1)及子二代(简称F2)大鼠远期体重及糖脂代谢的影响.方法 14只Wistar孕鼠给予1％链脲佐菌素25 mg/kg一次性单侧腹腔注射,9只成功建立轻度宫内高血糖模型,对照组7只孕鼠相同时间点腹腔注射等体积的柠檬酸-柠檬酸钠缓冲液.F1大鼠根据是否暴露于宫内高血糖环境及不同性别分为宫内高血糖暴露雌性组(F1-G-♀组)、宫内高血糖暴露雄性组(F1-G-♂组)、宫内正常血糖暴露雌性组(F1-C-♀组)和宫内正常血糖暴露雄性组(F1-C-♂组),每组6只.F1雌鼠与正常雄鼠交配进行传代.F2大鼠分为宫内高血糖暴露传代雌性组(F2-G-♀组)、宫内高血糖暴露传代雄性组(F2-G-♂组)、宫内正常血糖暴露传代雌性组(F2-C-♀组)和宫内正常血糖暴露传代雄性组(F2-C-♂组).记录F2大鼠出生后体重变化,测定各组F1、F2大鼠28周龄时胰腺和内脏脂肪重量,以及空腹血浆葡萄糖、空腹胰岛素、甘油三酯、胆固醇、高密度脂蛋白-胆固醇和低密度脂蛋白-胆固醇水平.同性别不同组间数据比较采用t检验.结果 (1) F2-G-♀组大鼠在6、24和28周龄时体重分别为(177.3±12.3)、(314.5±13.9)和(322.3±16.2)g,明显高于F2-C-♀组[分别为(164.3±6.0)、(290.2±18.3)和(300.2±16.2)g,t值分别为-2.324、-2.584和-2.359,P值均＜0.05].(2) 28周龄时,F1-G-♀组大鼠胰腺重量和胰腺占体重比分别为(0.53±0.05)g和(0.17±0.02)％,均明显低于F1-C-♀组[分别为(0.65±0.04)g和(0.21±0.02)％,t值分别为4.159和2.483,P值均＜0.05].F2-G-♀组和F2-G-♂组大鼠胰腺重量、胰腺占体重比、内脏脂肪重量和脂肪占体重比分别与F2-C-♀组和F2-C-♂组相比,差异均无统计学意义(P值均＞0.05).(3)3周龄时,F2-G-♀组大鼠空腹血浆葡萄糖高于F2-C-♀组[(6.5±0.8)与(4.9±1.2) mmol/L,f=-2.786,P＜ 0.05];F2-G-♂组大鼠空腹血浆葡萄糖高于F2-C-♂组[(6.3±0.8)与(4.7±1.0)mmol/L,t=-2.696,P＜0.05].F2-G-♀组和F2-G-♂组大鼠空腹血浆葡萄糖在28周龄时分别为(6.7±0.6)和(8.4±2.2) mmol/L,分别高于F2-C-♀组和F2-C-♂组[分别为(5.8±0.5)和(6.2±1.0) mmol/L,t值分别为-2.695和-2.337,P值均＜0.05].F1-G-♀组大鼠高密度脂蛋白-胆固醇低于F1-C-♀组[(0.47±0.05)与(0.61±0.10) mmol/L,t=2.433,P＜0.05].(4) F1-G-♀组、F2-G-♀组和F2-G-♂组大鼠与同性别对照组(F1-C-♀组、F2-C-♀组和F2-C-♂组)大鼠相比均表现为胰岛数量较少、体积减小、大小不一,胰岛β细胞数目减少、胞质着色浅、周围囊状腺泡肥大.F1-G-♂组与F1-C-♂组相比表现为胰岛数量增加、大小不一、体积增大,胰岛β细胞增生、胞质丰富、胞核着色深. 结论 轻度宫内高血糖环境暴露F1大鼠表现出生后远期体重增加,胰岛形态结构受损,出现糖代谢异常,内脏脂肪含量增加和脂代谢紊乱,且这一影响可隔代遗传并表现出性别差异.Objective To observe the long-term effects of maternal mild hyperglycemia on the growing development and glucose and lipid metabolism in intergenerational rat offspring.Methods Streptozotocin (25 mg/kg) was administered to 14 pregnant Wistar rats intraperitoneally on the first day of gestation to induce an animal model of mild intrauterine hyperglycemia,which was successful in nine rats.Seven pregnant rats without streptozotocin intervention served as controls.Female first-generation offspring (F1) rats were intercrossed with normal male rats to obtain the second-generation offspring (F2) rats.F1 and F2 rats were divided into 8 groups:female group (group F1-G-♀) or male group (group F1-G-♂) exposed to intrauterine hyperglycemia;female group (group F1-C-♀) or male group (group F1-C-♂) exposed to intrauterine euglycemia;transgenerational female group (group F2-G-♀) or male group (group F2-G ♂)exposed to intrauterine hyperglycemia;and transgenerational female group (group F2-C-♀) or male group (group F2-C-♂) exposed to intrauterine euglycemia.Body weight of the offspring was recorded.At the age of 28 weeks,the weight of pancreas and visceral fat,fasting plasma glucose (FPG),fasting insulin,total triglyceride,total cholesterol,high-density lipoprotein-cholesterol,low-density lipoprotein-cholesterol were measured in all groups.Two sample t test was used for statistical analysis.Results (1) At 4,24 and 28 weeks old,the body weight of group F2-G-♀ [(177.3± 12.3),(314.5± 13.9) and (322.3± 16.2) g] was remarkably increased compared with group F2-C-♀ [(164.3±6.0),(290.2± 18.3) and (300.2± 16.2) g,t=-2.324,-2.584and-2.359,all P ＜ 0.05].(2) At 28 weeks,the pancreas weight and the ratio of pancreas weight to body weight of group F1-G-♀ [(0.53 ±0.05) g and (0.17±0.02)％] were decreased significantly compared with group F1-C-♀ [(0.65±0.04) g and (0.21±0.02)％,t=4.159 and 2.483,both P ＜ 0.05].The pancreas weight,ratio of pancreas weight to body weight,visceral fat weight and fat weight of mass ratio in groups F2-G-♂ and F2-G-♀ were not remarkably different from groups F2-C-♂ and F2-C-♀,respectively (all P ＞ 0.05).(3)The level of FPG at three weeks of age in F2-G-♀ group was higher than in F2-C-♀ group [(6.5±0.8) vs (4.9±1.2) mmol/L,t=-2.786,P ＜ 0.05],and it was also higher in F2-G-♂ group than in F2-C-♂ group [(6.3±0.8) vs (4.7± 1.0) mmol/L,t=-2.696,P ＜ 0.05].At 28 weeks,the FPG level was (6.7±0.6) and (8.4±2.2) mmol/L in F2-G-♀ and F2-G-♂ groups,being higher than in F2-C-♀ and F2-C-♂ groups,respectively [(5.8±0.5) and (6.2± 1.0) mmol/L,t=-2.695 and-2.337,both P ＜ 0.05].Compared with F1-C-♀ group [(0.61 ±0.10) mmol/L],the high-density lipoprotein-cholesterol level was lower in F1-G-♀ group [(0.47±0.05) mmol/L,t=2.433,P ＜ 0.05].(4) In groups F1-G-♀,F2-G-♀ and F2-G-♂,the structure of the islet cells was obviously atrophic and disordered,and β-cells were slightly decreased and distributed unevenly,but group F1-G-♂ had significantly increased β-cells with hypertrophic islet size compared with control group.Conclusions F 1 rat offsprings exposed to mild intrauterine hyperglycemia experience excessive weight gain after birth,impaired structure of the islet,metabolic abnormality,increased visceral fat weight and glucose and lipid metabolism disorder,which show intergenerational inheritance and gender differences.国家自然科学基金中国科技核心期刊(ISTIC)中国科学引文数据库(CSCD)6455-4611