In-utero metabolic programming of the offspring

后代的子宫内代谢编程

• 批准号: 8066260
• 负责人: Sherin U Devaskar
• 金额: $ 14.05万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8066260
• 关键词: 2,4-thiazolidinedione; Adult; Age; Agonist; Animal Model; Animals; Attenuated; Awareness; Barker Hypothesis; Childhood; Consumption; Defect; Developed Countries; Development; Diabetes Mellitus; Disease; Endocytosis; Epidemic; Epidemiology; Epigenetic Process; Euglycemic Clamping; Event; Exercise; Exocytosis; Fasting; Female; Future; GLUT 4 protein; GLUT4 gene; Genetic Transcription; Gestational Diabetes; Glucose; Glucose Clamp; Glucose Intolerance; Growth; Incidence; Insulin; Insulin Resistance; Insulin Signaling Pathway; Intake; Intervention; Investigation; Islet Cell; Life; Link; Mediating; Metabolic; Modality; Modeling; Modification; Molecular; Molecular Target; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Nutritional; Organ; Pancreas; Phase; Phenotype; Population; Pregnancy; Process; Protein Isoforms; Protein Kinase C; Protein-Serine-Threonine Kinases; Proto-Oncogene Proteins c-akt; Publishing; Rattus; Regulation; Research Personnel; Role; Skeletal Muscle; Staging; Symptoms; Testing; Therapeutic; Thiazolidinediones; Time; adenylate kinase; basal insulin; base; citrate carrier; disease phenotype; fetal; glucose transport; in utero; in vivo; insight; insulin sensitivity; intervention effect; islet; male; novel; offspring; postnatal; preempt; prevent; programs; response; sex

Intra-Uterine Growth Restriction (IUGR) with postnatal nutritional modifications leads to sex- and age- specific metabolic aberrations setting the stage for development of type 2 diabetes mellitus (T2DM). T2DM has reached epidemic proportions creating a world-wide crisis. In determining the mechanistic link between intra-uterine and postnatal metabolic events and the ultimate adult phenotype, we have observed molecular changes that alter the skeletal muscle rate limiting step of glucose transport. These consist of intra-uterine aberrations in the epigenetic regulation and vesicular translocation of the insulin responsive glucose transporter isoform (GLUT4). Based on these preliminary observations, we hypothesize that 1) intra-uterine events prematurely alter the transcriptional and post-translational processing of skeletal muscle GLUT4 and set the stage for development of insulin resistance and T2DM in the adult, 2) these events set the stage for development of gestational diabetes that epigenetically influences trans-generational propagation of insulin resistance, and 3) these events also provide the basis for introducing certain interventional strategies prior to the onset of symptoms thereby preventing the onset of T2DM. These hypotheses will be tested in a rat model of IUGR with three specific aims: 1) To investigate the effect of IUGR with postnatal calorie modifications on male and female SkM a) transcriptional machinery involved in GLUT4 expression, and b) function assessed by quantifying glucose utilization in-vivo under basal and hyperinsulinemic-euglycemic clamp conditions. 2) To determine a) the effect of fasting in the IUGR male and female offspring, and b) the presence of gestational diabetes in the IUGR female offspring, and assess the impact on SkM GLUT4 expression, translocation and function. 3) To examine the effect of interventions consisting of a) 5'-AMP kinase activation via exercise, and b) PPARY agonists (thiazolidinediones) in the IUGR male offspring targeted at increasing SkM GLUT4 expression, translocation and function. The results of our proposed investigations will provide necessary insights into mechanisms that connect intra-uterine metabolic aberrations to T2DM. In addition, the studies will validate interventions targeted at some of the molecular events thereby preventing the disease. These insights will prove to be crucial in directing the development of future therapeutic modalities aimed at preventing the onset of T2DM. These efforts will contribute towards controlling the world-wide crisis of T2DM particularly in a subset of the population exposed to nutrient restriction in-utero as is common in most developing and to some extent in developed countries.

带有产后营养修饰的 - 局内生长限制（IUGR）导致性别和年龄 特定的代谢畸变为2型糖尿病（T2DM）的发展奠定了基础。 T2DM 已经达到了造成全球危机的流行比例。在确定机械联系 - 局内和产后代谢事件以及最终的成人表型，我们观察到分子 改变葡萄糖转运的骨骼肌速率限制步骤的变化。这些由内部内部组成 胰岛素反应性葡萄糖的表观遗传调节和囊泡易位的畸变 转运蛋白同工型（GLUT4）。基于这些初步观察，我们假设1） 事件过早改变骨骼肌glut4和 在成人中为胰岛素抵抗和T2DM的发展设定阶段，2）这些事件为 妊娠糖尿病的发展，从表观上影响胰岛素的跨代繁殖 抵抗和3）这些事件还为引入某些介入策略的基础提供了基础 症状的发作，从而阻止了T2DM的发作。这些假设将在大鼠中进行测试 IUGR的模型具有三个具体目标：1）研究IUGR使用产后卡路里的效果 对男性和女性SKM的修改a）参与GLUT4表达的转录机械，b） 通过在基础和高胰岛素血糖中量化葡萄糖利用率来评估的功能 夹具条件。 2）确定a）在IUGR男性和女性后代中禁食的影响，b） IUGR女性后代存在妊娠糖尿病，并评估对Skm Glut4的影响 表达，易位和功能。 3）检查由A）5'-AMP组成的干预措施的效果 通过运动激活激酶，b）在IUGR雄性后代 针对增加SKM GLUT4表达，易位和功能。 我们提议的调查结果将提供对连接机制的必要见解 Uterine内代谢畸变对T2DM。此外，研究将验证针对针对的干预措施 一些分子事件，从而防止了疾病。这些见解将被证明至关重要 指导旨在防止T2DM发作的未来治疗方式的发展。这些 努力将有助于控制T2DM的全球危机，特别是在 在大多数发育中，在某种程度上常见的人群中受到营养限制的人口 发达国家。