Gestational diabetes and offspring aging and metabolism

妊娠期糖尿病与后代衰老和代谢

• 批准号: 10577849
• 负责人: CATHERINE KIM
• 金额: $ 19.46万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-01 至 2024-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10577849
• 关键词: 19 year old; Acceleration; Adolescent; Adult; Affect; Age; Aging; Biological Markers; Blood specimen; Cell Aging; Cell division; Child; Childhood; Chromosomes; Chronology; Collaborations; Cytosine; DNA; DNA Methylation; DNA Structure; Data; Diabetes Mellitus; Diabetes prevention; Diagnosis; Disparate; Epigenetic Process; Event; Exposure to; Familiarity; Generations; Genetic Transcription; Gestational Diabetes; Glucose; Glucose Intolerance; Goals; Guanine; Hormones; Insulin Resistance; Intervention; Knowledge; Laboratories; Length; Life; Life course epidemiology; Link; Longevity; Measures; Metabolic syndrome; Metabolism; Metformin; Methylation; Molecular; Mothers; Obesity; Pathway interactions; Pattern; Phenotype; Positioning Attribute; Prediabetes syndrome; Public Health; Reporting; Research Personnel; Resources; Risk Factors; Sampling; Siblings; Site; Somatic Cell; Telomere Shortening; Time; Tribes; United States; Uterus; Work; Youth; biobank; cohort; diabetes risk; dietary supplements; epigenome-wide association studies; experience; glucose metabolism; high risk; imprint; in utero; inorganic phosphate; insulin secretion; intrauterine environment; methylation pattern; mortality; offspring; peripheral blood; prenatal exposure; racial diversity; sample collection; sex; stress reduction; telomere; transmission process

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.

这个R21应用程序“妊娠期糖尿病与后代衰老和代谢”的目标是检查 妊娠期糖尿病（GDM）是否与不良的后代代谢有关， 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， 患有葡萄糖耐受不良的青少年有很高的并发症风险。因此，重要的是要了解如何 生命早期发生的事件会改变他们的葡萄糖代谢。在子宫内暴露于GDM是一种 建立了后代胰岛素抵抗（IR）的危险因素。这种现象最早记录在皮马 Dabelea博士是该应用程序的共同研究者：兄弟姐妹患糖尿病的风险显著较高 在母亲患糖尿病后出生的人比在母亲确诊前出生的人更容易患糖尿病。的机制 这种情况发生的原因尚不完全清楚，但对公共卫生有重要的影响。 糖尿病的代际传播。我们认为母性失调可能影响 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值来自于 在特定的CpG位点的甲基化水平，和“老”的表观遗传年龄估计预测死亡率。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， 糖尿病然而，没有EAA和葡萄糖代谢在青年的研究。母性失调也 据报道，与较短的端粒长度和后代的代谢综合征有关， 端粒长度的缩短以及后代是否经历了这些衰老机制的衰老， 没有被检查。因此，我们建议检查分子衰老和葡萄糖代谢的措施 在一个不同种族的队列中，EPOCH（R 01 DK 068001）进行了检查和采血 约10年（范围6-12年）和约17年（范围12-19年）的样本。使用现有EWAS数据 （R 01 DK 100340），我们将计算EPOCH后代的EAA。使用现有的血液样本，我们将测量 使用UCSF Blackburn实验室测量端粒长度。我们将研究母体GDM是否与 与EAA和端粒缩短的后代（目的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（目的2）。我们的初步数据支持这样的假设， 妊娠期糖尿病可预测后代EAA，而EAA又与更大的后代IR和代偿性胰岛素相关 分泌物我们的团队处于有利地位，以实现研究目标，由于我们熟悉的队列和 肥胖与糖尿病生命过程流行病学中心（Lifecourse Epidemiology of Adiposity & Diabetes Center）我们有一个既定的记录 合作。这项拟议的工作是必要的，以确定是否靶向衰老生物标志物，即使在 儿童期糖尿病可能是青年糖尿病预防的重点。该建议适用于新兴的研究， 衰老机制对青春的新陈代谢有很大影响，因而是高影响。

项目成果

Antimüllerian hormone and leukocyte aging markers in the Coronary Artery Risk Development in Young Adults study.

• DOI: 10.1016/j.fertnstert.2022.03.021
• 发表时间: 2022-07
• 期刊: FERTILITY AND STERILITY
• 影响因子: 6.7
• 作者: Kim, Catherine;Puterman, Eli;Hou, Lifang;Slaughter, James C.;Terry, James G.;Wellons, Melissa F.
• 通讯作者: Wellons, Melissa F.

Gestational diabetes mellitus, epigenetic age and offspring metabolism.

• DOI: 10.1111/dme.14925
• 发表时间: 2022-11
• 期刊: DIABETIC MEDICINE
• 影响因子: 3.5
• 作者: Kim, Catherine;Harrall, Kylie K.;Glueck, Deborah H.;Needham, Belinda L.;Dabelea, Dana
• 通讯作者: Dabelea, Dana

Antimüllerian hormone and F2-isoprostanes in the Coronary Artery Risk Development in Young Adults (CARDIA) Study.

• DOI: 10.1016/j.fertnstert.2020.04.028
• 发表时间: 2020-09
• 期刊: FERTILITY AND STERILITY
• 影响因子: 6.7
• 作者: Kim, Catherine;Slaughter, James C.;Terry, James G.;Jacobs, David R., Jr.;Parikh, Nisha;Appiah, Duke;Leader, Benjamin;Moravek, Molly B.;Wellons, Melissa F.
• 通讯作者: Wellons, Melissa F.