Mechanisms by which GDM Leads to Diabetes in Offspring

描述：(申请人提供) 在人类中，糖尿病妊娠会导致显著的血糖异常 胎儿的动态平衡和胰岛素分泌导致胎儿异常 成长。研究表明，这会带来长期的后果 糖尿病母亲的后代。我们已经开发了一种妊娠模型 糖尿病(GDM)大鼠是否存在代谢改变 宫内环境与晚期糖尿病的发生有直接关系 生活。妊娠19d大鼠子宫胎盘功能不全 怀孕了。后代在出生时发育迟缓，但他们会追上5-5岁。 7周大。在8周大的时候，它们被饲养给正常的雄性。在.期间 怀孕后，这些动物会出现高血糖、高胰岛素血症和 高脂血症伴糖耐量和胰岛素受损 抵抗。后代(F2‘S)出生时体重较大，并在整个过程中保持较重 生活。F2的S在很小的时候就有胰岛素抵抗，血糖稳态是 逐渐受损。F2大鼠成年后会患上糖尿病。虽然 F2动物表现出明显的胰岛素抵抗，即β细胞不能 弥补胰岛素作用缺陷是符合的基本因素 随着糖尿病的发作。这种Beta-cell无法补偿可能是由于 胰岛素分泌缺乏代偿性增加， 细胞死亡，β细胞增殖率的降低，或两者的组合 在这些事件中。缺乏贝塔细胞补偿背后的机制(S) 而F2动物β细胞质量的最终减少是这一点的焦点 求婚。我们假设高血糖引起的线粒体DNA损伤是通过 活性氧物种(ROS)的产生导致进一步升级 线粒体的遗传损伤，特别是突变。一个自我-- 线粒体功能进行性恶化的强化循环导致 导致贝塔细胞功能相应下降。最后，一个门槛是 线粒体功能障碍和ROS的产生与β细胞死亡 发生。当β细胞异常达到临界水平时，糖尿病就会发生 胰岛素分泌与β细胞丢失相结合。我们将测试 假设妊娠期糖尿病确实会导致线粒体功能障碍，氧化 应激，以及后代β细胞中mtDNA的缺失，以及 这些效应协同作用导致Beta细胞的发育 失败和II型糖尿病。为了将线粒体的损伤与 高血糖对II型糖尿病患者β细胞表型的影响 转移受损的F2代线粒体在体外诱导β细胞衰竭 从未受影响的动物体内转化为β细胞。非F2级动物。

DESCRIPTION: (provided by applicant) In the human, diabetic pregnancy induces marked abnormalities in glucose homeostasis and insulin secretion in the fetus that results in aberrant fetal growth. Studies have suggested that there are long-term consequences for the offspring of diabetic mothers. We have developed a model of gestational diabetes (GDM) in the rat to determine whether an altered metabolic intrauterine milieu is directly linked to the development of diabetes later in life. Uteroplacental insufficiency is induced in the pregnant rat on day 19 of gestation. Offspring are growth retarded at birth, however they catch-up by 5- 7 weeks of age. At 8 weeks of age they are bred to normal males. During pregnancy these animals develop hyperglycemia, hyperinsulinemia, and hyperlipidemia accompanied by impaired glucose tolerance and insulin resistance. Offspring, (F2's) are heavier at birth and remain heavy throughout life. F2's are insulin resistant very early in life and glucose homeostasis is progressively impaired. F2 rats go on to develop diabetes as adults. Although F2 animals display marked insulin resistance, the failure of the Beta-cell to compensate for defects in insulin action is the essential factor coincident with onset of diabetes. This failure of the Beta-cell to compensate may be due to a lack of compensatory increase in insulin secretion, an increased rate of cell death, a reduction in the rate of Beta-cell proliferation, or a combination of these events. The mechanism(s) underlying this lack of Beta-cell compensation and eventual decrease in Beta-cell mass in F2 animals are the focus of this proposal. We hypothesize that mitochondrial DNA damage from hyperglycemia via the production of reactive oxygen species (ROS) results in further escalation of genetic damage in the mitochondria, specifically in mutations. A self- reinforcing cycle of progressive deterioration in mitochondrial function leads to a corresponding decline in Beta-cell function. Finally, a threshold in mitochondrial dysfunction and ROS production is reached and Beta-cell death occurs. The onset of diabetes ensues when a critical level of abnormal Beta-cell insulin secretion combined with Beta-cell loss is reached. We will test the hypothesis that GDM does in fact cause mitochondrial dysfunction, oxidative stress, and deletions in mtDNA in the Beta-cell of the offspring, and whether these effects act synergistically to lead to the development of the Beta-cell failure and type II diabetes. To link the damage to the mitochondria caused by hyperglycemia to the Beta-cell phenotype observed in type II diabetes we will induce Beta-cell failure in vitro by transferring damaged mitochondria from F2 animals into Beta-cells from unaffected. non-F2 animals.