n-3脂肪酸对孕期糖尿病母鼠及其子代糖代谢和Insulin/IGF1信号通路的影响及机理研究

Prevalence of type 2 diabetes and gestational diabetes mellitus (GDM) increases rapidly in China during the last few years. Higher intake of long chain n-3 polyunsaturated fatty acids (LC n-3 PUFA) C20:5n-3 and C22:6n-3 is associated with lower risk of insulin resistance and type 2 diabetes in Asian populations. However, the effects of LC n-3 PUFA on diabetic patients and their offspring are still unclear. The aim of the present project is to examine the effects of LC n-3 PUFA supplementation during pregnancy and lactation on the glucose metabolism for the diabetic rats and their offspring and related mechanisms. The present project will establish two diabetic rat models: type 2 diabetes and GDM. In each model, diabetic rats will be divided into three groups: controlled diabetic rats, diabetic rats supplemented with LC n-3 PUFA, and diabetic rats with LC n-3 PUFA deficiency. This project will explore the effects of LC n-3 PUFA on glucose metabolism and insulin sensitivity in diabetic rats and their offspring, and examine the influence of LC n-3 PUFA on enzyme activity, mRNA and protein expression of key genes in the Insulin/IGF1 signaling pathway. In addition, the effects of LC n-3 PUFA supplementation on the methylation of key genes in the Insulin/IGF1 signaling pathway will be explored. Influences of LC n-3 PUFA on the telomere length on different ages of the offspring will be examined. Furthermore, metabonomics technique will be used to determine the in vivo metabolites of LC n-3 PUFA in type 2 diabetes and GDM rats and their offsprings to explore the relationship between the metabolites of LC n-3 PUFA and relevant parameters. Based on the above results to ascertain the effect of LC n-3 PUFA on diabetic pregnant rats and their offspring and its mechanism. The present project will facilitate a better nutritional treatment for the pregnant women with type 2 diabetes or GDM in China.

我国2型糖尿病和妊娠期糖尿病的发病率均呈逐年上升趋势。长链n-3多不饱和脂肪酸（n-3 PUFA）C20:5n-3和C22:6n-3的摄入能显著降低亚洲人群胰岛素抵抗和2型糖尿病发病风险。然而，n-3 PUFA对妊娠期糖尿病及其子代的影响仍不清楚。本项目旨在通过对糖尿病Wistar母鼠孕期及哺乳期进行n-3 PUFA干预，研究其对母鼠及子代糖代谢的调节作用及机理。将糖尿病和妊娠期糖尿病母鼠分为糖尿病组、n-3 PUFA干预组及n-3 PUFA缺乏组，探索糖尿病母鼠孕期及哺乳期摄入n-3 PUFA对母鼠及子代糖代谢和胰岛素敏感性的调节作用；对Insulin/IGF1信号通路关键酶活性、关键基因mRNA表达和蛋白表达的影响；对该通路中相关基因甲基化的影响；对子代成长过程中端粒缩短的改善作用以及n-3 PUFA在体内的代谢产物与相关参数的关系来探明n-3 PUFA对糖尿病母鼠及子代的影响及机理。

妊娠期糖尿病 (gestational diabetes mellitus, GDM) 严重威胁母婴健康，并增加子代各种患病风险。n-3脂肪酸对GDM孕妇的子代的影响尚不清楚。.目的：（一）研究GDM母鼠的子代成长过程及n-3脂肪酸对GDM子代的干预效果；（二）研究GDM能对子代脑组织的影响，以及n-3脂肪酸干预对GDM子代脑组织的作用及机制；（三）基于代谢组学分析，研究GDM母鼠的子代血液代谢组学变化，揭示子代年老时的身体状态和相关的疾病风险。 方法：利用Wistar雌鼠构建GDM模型。正常子代断奶后自由摄入标准饲料（7%豆油）至11月龄。GDM子代断奶后分三组，分别摄入标准饲料（7%豆油）、n-3脂肪酸干预组（3%豆油+4%鱼油）及n-3脂肪酸缺乏的GDM子代组（7%红花油）。.结果：（一）GDM子代呈现体重降低和终生生长受限，11月龄表现出明显糖尿病风险。n-3脂肪酸通过改善GDM子代肝脏和胰腺氧化应激和炎症状态，降低了其糖尿病的风险。n-3脂肪酸也延缓了GDM子代肝脏和胰腺端粒的缩短。（二）GDM子代11月龄海马体和大脑皮层表现出氧化应激。n-3脂肪酸通过提高海马体SOD和CAT活性、降低脑皮层中MDA水平、提高GSH水平和SOD、CAT活性改善了其氧化应激。其次，GDM子代11月龄脑组织呈现炎症状态。n-3脂肪酸通过降低海马体中IL-1β和IL-6的水平、提高IL-10的水平、降低脑皮层炎症状态。此外，GDM子代断奶时海马和大脑皮层体端粒长度变短。（三）GDM子代11月龄时血液代谢物发生变化。这些改变的代谢物及其代谢通路提示GDM子代远期成年后机体氧化应激增强、炎症状态、易衰老、糖尿病风险、心血管疾病等代谢疾病风险、肝功能降低、认知功能下降、肠道菌群代谢异常、生育功能降低等风险增加。n-3脂肪酸干预后调节了血清中21个代谢物。 .结论：（一）GDM子代鼠到远期成年后表现出明显糖尿病风险，n-3脂肪酸干预可降低其风险；（二）GDM能对子代脑组织造成长期影响，增加了子代年老后患脑及神经系统疾病的风险。（三） n-3脂肪酸对GDM子代血清代谢具有调节作用。