链脲佐菌素诱导大鼠父代糖尿病引起老年子代胰岛素抵抗

STZ-induced paternal diabetes in rats contributes to insulin resistance in the aged offspring

目的:探讨父代糖尿病对老年子代胰岛素敏感性的影响。方法:雄性SD大鼠每组10只,腹腔注射链脲佐菌素建立糖尿病模型;成模后,挑选符合要求的模型鼠5只与正常雌鼠交配;子鼠断奶后随机挑选10只雄性;监测子鼠体质量、随机血糖和空腹血糖;子鼠老龄期实施高胰岛素正常血糖钳夹实验;检测胰岛素信号通路关键因子蛋白激酶B(protein kinase B,PKB,Akt)和胰岛素受体底物1(insulin receptor substrate 1,Irs1)的磷酸化;肝脏油红染色;检测肝脏甘油三酯(triglyceride,TG)含量。结果:父代糖尿病组(DM组)血糖(22.60±1.32)mmol/L较对照组(CT组)(5.88±0.13)mmol/L明显升高(P=0.000);糖尿病子代组(DM-O组)80周体质量(652.0±10.7)g较对照组(CT-O组)(598.0±11.9)g明显升高(P=0.003);钳夹实验表明DM-O组葡萄糖输注率(6.23±0.30)mg/(kg·min)较CT-O组(8.65±0.43)mg/(kg·min)明显降低(P=0.005 2);Western blot结果显示DM-O组胰岛素信号通路关键因子Akt的磷酸化程度(0.023 4±0.004 4)较CT-O组(0.059 8±0.011 0)明显降低(P=0.016),DM-O组Irs1的磷酸化程度(0.255 0±0.030 6)较CT-O组(0.452 0±0.057 0)明显降低(P=0.016);DM-O组肝脏脂质沉积较CT-O组明显增加;DM-O组肝脏TG含量(86.2±10.2)mol/g较CT-O组(61.1±4.71)mol/g明显增加(P=0.046)。结论:父代糖尿病可引起子代体质量增加、老年期胰岛素敏感性降低,胰岛素信号通路激活受限,这一现象可能是由于父代糖尿病引起子代肝脏脂质沉积增加所致。

Objectives：To investigate the influence of paternal diabetes on insulin sensitivity of the aged offspring. Methods：Male SD rats were intraperitoneally injected with streptozotocin（STZ） and then mated with healthy female SD rats. Body weight,fed and fasting blood glucose were determined in the offspring. Hyperinsulinemic-euglycemic clamp was performed to assess insulin sensitivity in the aged offspring. Western blot was implemented to evaluate the following proteins ：p-Akt,Akt,p-Irs and Irs in liver tissues. Oil red O staining and liver triglyceride（TG） analysis were employed to evaluate the liver tissues lipidosis. Results：Blood glucose levels in STZ-treated male rats（DM）（22.6 ± 1.32） mmol/L were significantly higher than that in control group（CT）（5.88±0.13） mmol/L（P=0.000）. Body weight analysis showed that the body weight of 80-week-age offspring of paternal diabetic rats（DM-O）（652.0±10.7） g was significantly higher than that in the offspring of control group（CT-O）（598.0±11.9）g（P=0.003）. Hyperinsulinemic-euglycemic clamp test showed that the glucose infusion rate was significantly lowered in aged DM-O（6.23± 0.30） mg/（kg·min） than in the CT-O（8.65±0.43） mg/（kg·min）（P=0.005 2）. Western blot showed that p-Akt/Akt level in the aged DM-O（0.023 4±0.004 4） was significantly lowered than that in the CT-O（0.059 8 ± 0.011 0）（P=0.016）,and p-Irs1/Irs1 level in the aging DM-O（0.255±0.031） was significantly lower than that in the CT-O（0.452±0.057）（P=0.016）. Oil red O staining revealed that liver tissues lipidosis was more serious in the aged DM-O than in the CT-O. Liver TG content was significantly increased in the aged DM-O（86.2±10.2） mol/g,but was significantly lower than in the CT-O（61.10±4.71）mol/g（P=0.045 7）. Conclusion：Paternal diabetes mellitus induces insulin resistance in the aged offspring,possibly caused by liver tissues lipidosis.