Gestational diabetes and offspring aging and metabolism

R21 应用程序“妊娠糖尿病与后代衰老和新陈代谢”的目标是检查 妊娠期糖尿病（GDM）是否通过加速代谢与后代不良代谢有关 分子老化。在美国，五分之一的青少年患有糖尿病前期。尽管他们年纪轻轻， 患有葡萄糖不耐症的青少年出现并发症的风险很高。因此，了解如何 生命早期发生的事件可以改变他们的葡萄糖代谢。在子宫内暴露于 GDM 是一种 确定了后代胰岛素抵抗（IR）的危险因素。这种现象最早记录在皮马文献中 该应用程序的联合研究员 Dabelea 博士提出的部落：兄弟姐妹患糖尿病的风险明显更高 母亲患糖尿病后出生的人比母亲诊断前出生的人多。机制 这种情况发生的原因尚不完全清楚，但对公共卫生具有重要影响 糖尿病的代际传播。我们提出母亲血糖异常可能影响的一种方式 后代葡萄糖代谢是通过改变后代分子衰老途径，特别是表观遗传途径 年龄和端粒长度。由“表观遗传时钟”产生的表观遗传年龄的估计源自 特定 CpG 位点的甲基化水平和“较旧”的表观遗传年龄估计可预测死亡率。在成年人中， 表观遗传年龄加速（EAA）预测更大的胰岛素抵抗（IR）、更低的胰岛素分泌和 糖尿病。然而，目前还没有关于青少年EAA和葡萄糖代谢的研究。产妇也有血糖异常 据报道，它与后代的端粒长度较短和代谢综合征有关，但影响 端粒长度缩短以及后代是否通过这些衰老机制经历衰老的研究 没有经过检查。因此，我们建议检查分子衰老和葡萄糖代谢的测量 在一个种族多元化的队列中，EPOCH（R01DK068001）进行了检查并采集了血液 〜10年（范围6-12年）和〜17年（范围12-19年）的样本。使用现有的 EWAS 数据 (R01DK100340)，我们将计算 EPOCH 后代中的 EAA。使用现有的血液样本，我们将测量 使用加州大学旧金山分校布莱克本实验室的端粒长度。我们将检查母亲 GDM 是否与 后代的 EAA 和端粒缩短（目标 1），以及是否加速表观遗传衰老和端粒 缩短与葡萄糖代谢有关（目标 2）。我们的初步数据支持以下假设： GDM 预测后代 EAA，而 EAA 又与更大的后代 IR 和代偿性胰岛素相关 分泌。由于我们熟悉队列和研究对象，我们的团队有能力实现研究目标 肥胖和糖尿病生命历程流行病学中心的资源。我们拥有良好的业绩记录 的合作。拟议的工作对于确定是否针对衰老生物标志物是必要的，即使在 儿童期可能是青少年糖尿病预防的重点。该提案应用了新兴的研究 衰老机制取决于新陈代谢对年轻的影响，因此影响很大。

The goal of this R21 application, “Gestational diabetes and offspring aging and metabolism,” is to examine whether gestational diabetes mellitus (GDM) is linked to adverse offspring metabolism through accelerated molecular aging. In the United States, one in five adolescents has pre-diabetes. Despite their young age, adolescents with glucose intolerance have a high risk of complications. Thus, it is important to understand how events that happen early in life can alter their glucose metabolism. Exposure to GDM while in-utero is an established risk factor for offspring insulin resistance (IR). This phenomenon was first documented in the Pima tribe by Dr. Dabelea, a co-investigator on this application: risk of diabetes was significantly higher in siblings born after the mother developed diabetes than in those born before the mother’s diagnosis. The mechanisms through which this happens are incompletely understood, but have important public health implications for the transmission of diabetes across generations. We propose that one way that maternal dysglycemia might affect offspring glucose metabolism is via alteration of offspring molecular aging pathways, particularly epigenetic age and telomere length. Estimates of epigenetic age, generated from “epigenetic clocks,” are derived from methylation levels at specific CpG sites, and “older” epigenetic age estimates predict mortality. In adults, epigenetic age acceleration (EAA) predicts greater insulin resistance (IR), lower insulin secretion, and diabetes. However, there are no studies of EAA and glucose metabolism in youth. Maternal dysglycemia also has been reported to be linked to shorter telomere length and metabolic syndrome in offspring, but the impact of shortening of telomere length and whether offspring experience aging across these aging mechanisms has not been examined. Therefore, we propose to examine molecular aging and measures of glucose metabolism in a racially diverse cohort, EPOCH, (R01DK068001) which conducted examinations and collected blood samples at ~10 years (range 6-12 years) and ~17 years (range 12-19 years). Using existing EWAS data (R01DK100340), we will calculate EAA in EPOCH offspring. Using existing blood samples, we will measure telomere length using the UCSF Blackburn laboratory. We will examine whether maternal GDM is associated with EAA and telomere shortening in offspring (Aim 1), and whether accelerated epigenetic aging and telomere shortening are associated with glucose metabolism (Aim 2). Our preliminary data support the hypotheses that GDM predicts offspring EAA, which in turn is associated with greater offspring IR and compensatory insulin secretion. Our team is well-positioned to achieve the study aims, due to our familiarity with the cohorts and the resources of the Lifecourse Epidemiology of Adiposity & Diabetes Center. We have an established track record of collaboration. The proposed work is necessary to determine whether targeting aging biomarkers, even in childhood, could be a focus of diabetes prevention in youth. The proposal applies the burgeoning study of aging mechanisms upon metabolism to youth, and thus is high impact.