Biomarker of Pancreatic B-cell Loss Predicting Progression to Type 2 Diabetes After Gestational Diabetes

摘要/项目摘要 在这个项目中，我们前瞻性地研究了非甲基化胰岛素基因的关联性和预测能力。 (INS)产后6-12周的DNA及其几年后发病前的变化 在两组既往有妊娠期糖尿病(GDM)的妇女中，2型糖尿病(T2D)的发病率。 我们将利用来自两个大型前瞻性研究的现有资源，这些研究涉及1410名被诊断为妊娠期糖尿病的女性： 美国资助的妊娠期糖尿病后妇女、婴儿喂养和2型糖尿病(SWIFT)研究 由美国国立卫生研究院和由欧洲科学基金会资助的天津大米观测研究(TGDM-O)在中国进行 糖尿病研究(EFSD)。SWIFT研究对990名女性进行了持续的前瞻性纵向队列研究 (75%的少数族裔；亚裔、西班牙裔、黑人)被诊断为妊娠期糖尿病(2008-2011)，他们接受了三次研究 G产后6-9周口服葡萄糖耐量试验(OGTT)(基线)，产后第1年和第2年随访 基线，以及通过Kaiser Permanente电子健康对糖尿病进行长达12年的额外测试(10/2020) 记录系统。TGDM-O研究是一项为期4年的前瞻性纵向研究，对象为420名患有 在产后6-12周或~1年期间接受5项研究2小时75克OGTT的妊娠期糖尿病患者(基线)至最多4- 基线后7年(2020年)。所有研究参与者都有空腹血糖，连续2小时OGTT期间的2小时血糖， 除了其他实验室(例如，糖化血红蛋白、胰岛素、血脂)、临床(例如，肥胖)和行为(例如，饮食， 运动、哺乳)基线测量和后续研究访问。从存储的空腹血清样本中 从多个OGTT收集，我们将在基线、年份测量未甲基化的INS DNA和甲基化的DNA 在目标1中，我们将在产后6-9周和纵向识别未甲基化的INS DNA水平 基线后的变化及其与妊娠期糖尿病妊娠12年后T2D事件的关系 斯威夫特。在目标2中，我们将通过评估TGDM-O队列来确定目标1.A-D在TGDM-O队列中的普遍性 使用荟萃分析技术估计和计算集合关联度的异质性。在……里面 探索性目标3，我们将确定基线时未甲基化的INS DNA水平及其时间变化 与IR和β细胞分泌功能的基线测量及其在AIMS 1-2中的变化有关。如果 如果成功，我们的研究将提供评估β细胞死亡的新方法，并帮助将这一检测转移到 抑制β细胞凋亡的早期预防和潜在治疗的临床实践。

ABSTRACT/PROJECT SUMMARY In this project, we prospectively examine the associations and predictive ability of unmethylated insulin gene (INS) DNA from 6-12 weeks postpartum and their subsequent changes several years later preceding the onset of type 2 diabetes (T2D) among two cohorts of women with prior gestational diabetes mellitus (GDM). We will leverage the extant resources from two large prospective studies of 1410 women diagnosed with GDM: the Study of Women, Infant Feeding, and Type 2 Diabetes After Gestational Diabetes (SWIFT) in the U.S. funded by NIH, and the Tianjin GDM Observational study (TGDM-O) in China funded by the European Foundation for the Study of Diabetes (EFSD). The SWIFT study is an ongoing, prospective, longitudinal cohort of 990 women (75% minority; Asian, Hispanic, Black) diagnosed with GDM (2008-2011) who underwent three research 2-h 75 g oral glucose tolerance tests (OGTT) from 6-9 weeks postpartum (baseline), follow up Year 1 and Year 2 post- baseline, and additional testing for diabetes up to 12 years (10/2020) via the Kaiser Permanente electronic health records system. The TGDM-O study is a 4-year, prospective, longitudinal study of 420 Chinese women with GDM who underwent 5 research 2-hr 75 g OGTTs from 6-12 weeks or ~1 year postpartum (baseline) to up to 4- 7 years after baseline (2020). All study participants have fasting glucose, 2-h glucose during serial 2-h OGTTs, in addition to other laboratory (e.g., HbA1c, insulin, lipids), clinical (e.g., adiposity) and behavioral (e.g., diet, exercise, lactation) measures at baseline and follow-up research visits. From the stored fasting serum samples collected from multiple OGTTs, we will measure unmethylated INS DNA and methylated DNA at baseline, Year 1 and Year 2. In Aim 1, we will identify unmethylated INS DNA levels at 6-9 weeks postpartum and longitudinal changes after baseline, and their associations with incident T2D up to ~12 years after GDM pregnancy in the SWIFT. In Aim 2, we will determine the generalizability of Aim 1.a-d in the TGDM-O cohort by assessing heterogeneity in effect estimates and computing pooled associations using a meta-analysis technique. In exploratory Aim 3, we will identify whether unmethylated INS DNA levels at baseline and their temporal changes are associated with baseline measures of IR and β-cell secretory function and their changes in Aims 1-2. If successful, our study will provide novel methodology to assess β-cell death and help transfer this assay into clinical practice for early prevention and potential treatment for inhibiting β-cell apoptosis.