Physiological and molecular metabolic consequences of fetal hyperglycernia

胎儿高血糖的生理和分子代谢后果

• 批准号: 10403005
• 负责人: Yann Gibert
• 金额: $ 24.42万
• 依托单位: UNIVERSITY OF MISSISSIPPI MED CTR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10403005
• 关键词: Adult; Atherosclerosis; Biological; Body mass index; Cardiovascular Diseases; Deposition; Development; Diabetes Mellitus; Diet; Disease; Embryo; Embryonic Development; Exposure to; Fatty acid glycerol esters; Fetal Death; Fetal Development; Fetal Macrosomia; Fetus; Glucose; Glycolysis; Goals; Health; Human; Hyperglycemia; Hyperlipidemia; Individual; Insulin Resistance; Life; Link; Lipids; Metabolic; Metabolic Diseases; Metabolic syndrome; Modeling; Molecular; Mothers; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Ovulation; Physiological; Research; Risk; System; Testing; Therapeutic Intervention; Yolk Sac; Zebrafish; fetal; fetal hyperglycemia; non-alcoholic fatty liver disease; oxidation; prevent

Fetal hyperglycemia occurs when the developing fetus is exposed to high levels of glucose. For example in humans, this is the case when the mother has diabetes. Fetal hyperglycemia is linked to health complications for the fetus, including preeclamsia, fetal macrosomia and even fetal death. In addition, fetal hyperglycemia also increases the risk for the individual to develop a variety of diseases later in life. Adults exposed to fetal hyperglycemia are more susceptible to obesity, insulin resistance, type 2 diabetes, cardiovascular diseases and several metabolic syndromes. To date, the physiological and molecular mechanisms that underlie the link between fetal hyperglycemia and the adult sequelae are poorly understood. The central goal of this project is to examine the physiological and molecular basis of metabolic diseases in adults exposed to high levels of glucose only during embryogenesis. To accomplish this goal, we have recently developed a zebrafish model of fetal hyperglycemia. Zebrafish offers several advantages to complete this project. From a biological point of view, zebrafish embryos have the unique feature of being a “closed system” i.e for the first 5 days of development, the embryo solely relies on the yolk sac reserved deposited by the mother during ovulation and no energy exchange happens with the exterior world prior the end of embryogenesis. Therefore, in zebrafish we can directly expose the embryos to known concentration of glucose. Thus, specific aim 1 will test the hypothesis that fetal hyperglycemia leads to an increase in BMI, fat mass and insulin resistance in adults fed normal diet. Specific aim 2 will test the hypothesis that embryonic hyperglycemia increases glycolysis while decreasing 􀈕-oxidation in embryos and in adults. Specific aim 3 will test the hypothesis that fetal hyperglycemia causes hyperlipidemia and non-alcoholic fatty liver disease in adults. Specific aim 4 will test the hypothesis that embryonic hyperglycemia increases the levels of circulating lipids and causes atherosclerosis later in life. Successful completion of this proposal will lead to a better understanding of the physiological and molecular consequences of fetal hyperglycemia and will help in defining strategic therapeutic interventions to prevent the development of metabolic diseases in adults exposed to glucose during embryogenesis.

例如，当发育中的胎儿暴露于高水平的葡萄糖时，就会发生胎儿高血糖。 在人类中，当母亲患有糖尿病时就会出现这种情况。 胎儿的并发症，包括先兆子痫、巨大胎儿甚至胎儿死亡。 胎儿高血糖还会增加个体在以后的生活中患各种疾病的风险。 暴露于胎儿高血糖的成年人更容易患肥胖、胰岛素抵抗、2 型糖尿病、 心血管疾病和几种代谢综合征迄今为止，在生理和分子方面。 胎儿高血糖与成人后遗症之间联系的机制尚不清楚 该项目的中心目标是检查其生理和分子基础。 成人的代谢疾病只有在胚胎发生期间暴露于高水平的葡萄糖才能实现。 为了实现这一目标，我们最近开发了斑马鱼胎儿高血糖模型，为斑马鱼提供了几种方法。 从生物学角度来看，斑马鱼胚胎具有独特的优势。 作为“封闭系统”的特征，即在发育的前 5 天，胚胎仅依赖于 卵黄囊在排卵期间由母亲保留，与卵子不发生能量交换 因此，在斑马鱼中，我们可以直接暴露胚胎。 因此，具体目标 1 将检验胎儿高血糖浓度的假设。 导致正常饮食的成年人体重指数、脂肪量和胰岛素抵抗增加。 具体目标 2 将。 检验胚胎高血糖增加糖酵解同时减少氧化的假设 具体目标 3 将检验胎儿高血糖导致的假设。 成人高脂血症和非酒精性脂肪肝疾病的具体目标 4 将检验以下假设： 胚胎高血糖会增加循环脂质水平，并导致以后的动脉粥样硬化。 该提案的成功完成将有助于更好地了解生理和 胎儿高血糖的分子后果，将有助于确定战略治疗 预防暴露于葡萄糖的成年人发生代谢疾病的干预措施 胚胎发生。