生命早期饥饿和成年饱食糖代谢稳态失衡的同位素示踪研究

In our previous study, we found that the rapid increase in the prevalence of diabetes in middle-aged and elderly people in China was associated with the combination of exposure to starvation during early life and overnutrition in adulthood (two hit hypothesis). Now there are still 200 million people in poverty and 8 million children with malnutrition in China and with the continuing economic development, they will have more food or even overnutrition. Therefore, their risk for diabetes should not be ignored. It has significant meaning to prevent diabetes that exploring the mechanism of glucose metabolism dysregulation after Two Hits (malnutrition followed by overnutrition). So far to our knowledge, no study has systematically explored the pathophysiological changes of intestinal glucose absorption, hepatic glucose production, peripheral tissue glucose uptake and the appearance and disappearance of glucose in the blood under the condition of malnutrition followed by overnutrition, all of which are closely related with glucose metabolism homeostasis..This study aims to demonstrate the mechanism of dysregulation of glucose metabolism homeostasis after starvation in early life followed by hyperphagia in adulthood. The SD rats will be divided into normal diet group, normal diet in early life+high fat diet in adulthood group, starvation in early life+normal diet in adulthood group and starvation in early life+high fat diet in adulthood group. We will detect the intestinal glucose absorption, hepatic glucose production, peripheral tissue glucose uptake in each group using isotope tracer technique and measure the expression of muscle insulin signaling molecules including insulin receptor, insulin receptor substrate-1 and glucose transporter 4. This project could provide scientific proof for preventing diabetes in people experiencing starvation in early life followed by hyperphagia in adulthood.

课题组前期研究发现生命早期经历饥饿继而成年经历饱食营养过剩（二次打击假说）与中国糖尿病高发的现状有关。目前中国尚有2亿贫困人口和8百万营养不良儿童，随着经济发展会经历营养改善甚至过剩，其面临的糖尿病风险不容忽视。探究二次打击下糖代谢紊乱发生机制对控制糖尿病发生具有重要意义。然而迄今未见系统地研究二次打击下与糖代谢紊乱密切相关的葡萄糖肠道吸收率、 肝脏输出率、组织的摄取率、葡萄糖出现率和消失率的病理生理改变。.本项目拟建立正常饮食组、早期正常饮食+成年高脂组、早期饥饿+成年正常饮食组和早期饥饿+成年高脂组SD大鼠模型，主要采用稳定性同位素示踪技术，完整地阐述生命早期饥饿和/或成年饱食血糖稳态（肠道葡萄糖吸收率、肝糖输出和组织葡萄糖摄取异常）以及肌肉胰岛素通路分子表达（GLUT4等）的改变，探讨其糖代谢稳态失衡的可能机制，为经历二次打击的人群预防糖尿病的发病提供科学依据。

生命早期营养失衡与成年期代谢性疾病密切相关，临床研究发现早期经历饥荒、成年后由于快速的经济发展而过度营养的人群更容易患代谢性疾病。本项目通过建立早期饥饿-过度营养大鼠模型，采用同位素示踪标记化合物，系统跟踪经历生命早期饥饿营养不良和/或成年饱食营养过剩大鼠模型中肝脏葡萄糖生成率和外周组织葡萄糖摄取率的代谢变化。同时检测大鼠的血葡萄糖浓度、胰岛素、腹腔葡萄糖耐量试验、体脂率、胰岛素信号分子和脂代谢关键蛋白表达。从而从功能到机制深入探讨生命早期营养不良和成年营养过剩血糖的稳态失衡情况。研究发现：（1）饥饿高脂组大鼠体重增长速率与体重匹配高脂组相同，饥饿普食组大鼠体重增长速率与体重匹配普食组相同。实验组与对照组血糖无明显统计学差异。饥饿高脂组的血清胰岛素水平、HOMA-IR指数和IPGTT曲线下面积明显升高。（2）饥饿高脂组肝脏脂滴面积增大，脂滴数目增多。饥饿高脂组脂肪细胞直径增大。（3）饥饿高脂组的股四头肌、腓肠肌和睾脂、肾脂、肠脂和皮脂葡萄糖摄取率明显降低，肝糖异生率明显升高；饥饿普食组的睾脂、肾脂、肠脂和皮脂的葡萄糖摄取率升高；但肝糖生成、利用FFA的脂肪合成无显著差异。（4）肝脏中脂质从头合成的关键酶FAS在饥饿高脂组中的表达显著升高。脂肪生成的重要转录调节因子SREBP1c在饥饿高脂组的表达也明显升高。肠脂的GLUT4表达低于其他组别。因此，早期饥饿-过度营养“两次打击”的作用下，实验组大鼠的肌肉和脂肪组织葡萄糖摄取能力下降，肝糖异生升高，大鼠出现了胰岛素抵抗，并进一步导致了肝脏和脂肪组织脂质沉积的加重。藉此为生命早期营养失衡所致糖脂代谢异常相关疾病的治疗提供理论依据和实验基础。