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

胰腺 B 细胞损失的生物标志物可预测妊娠期糖尿病后进展为 2 型糖尿病

• 批准号: 10583645
• 负责人: Erica Pauline Gunderson
• 金额: $ 68.01万
• 依托单位: LSU PENNINGTON BIOMEDICAL RESEARCH CTR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2027-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10583645
• 关键词: Adult; Affect; Amino Acids; Anthropometry; Apoptosis; Asian; Autopsy; Behavioral; Beta Cell; Biological Assay; Biological Markers; Black race; Blood specimen; C-Peptide; Cell Death; Cell physiology; Cells; China; Chinese; Clinical; Collection; DNA; DNA Methylation; Data; Defect; Diabetes Mellitus; Diagnosis; Diet; Disease; Early treatment; European; Exercise; Fasting; Foundations; Functional disorder; Funding; Future; Genes; Gestational Diabetes; Glucose; Glycosylated hemoglobin A; Goals; Heterogeneity; Hispanic; Human; Hyperglycemia; Impairment; Infant; Insulin; Insulin Resistance; Insulin-Dependent Diabetes Mellitus; Laboratories; Lactation; Link; Lipids; Longitudinal cohort; Measures; Mediating; Meta-Analysis; Methodology; Methylation; Minority; Monitor; Newly Diagnosed; Non-Insulin-Dependent Diabetes Mellitus; OGTT; Obesity; Observational Study; Participant; Pathogenesis; Patients; Peptide Initiation Factors; Populations at Risk; Postpartum Period; Pregnancy; Pregnant Women; Prevention; Proinsulin; Prospective Studies; Prospective cohort; Reporting; Research; Research Design; Resources; Risk Factors; Sampling; Secretory Cell; Serum; Source; Structure of beta Cell of islet; Techniques; Testing; Therapeutic Intervention; Time; United States National Institutes of Health; Visit; Woman; aggressive therapy; biobank; cell type; clinical practice; cohort; cost effective; diabetes risk; digital; electronic health record system; fasting glucose; feeding; follow-up; improved; in vivo evaluation; indexing; insulin secretion; insulin sensitivity; intergenerational; longitudinal, prospective study; novel; novel marker; observational cohort study; prevent; prospective; response; risk stratification

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.

摘要/项目总结 在本项目中，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及其在发病前几年的后续变化 2型糖尿病（T2 D）在两个队列的妇女与既往妊娠糖尿病（GDM）。 我们将利用现有的资源，从两个大型的前瞻性研究的1410名妇女诊断为GDM： 美国资助的妇女、婴儿喂养和2型糖尿病后的研究（SWIFT） 由NIH资助的天津GDM观察性研究（TGDM-O），由欧洲基金会资助， 糖尿病研究（EFSD）SWIFT研究是一项正在进行的前瞻性纵向队列研究，共有990名女性参与 (75%少数民族;亚裔、西班牙裔、黑人）诊断为GDM（2008-2011年），接受了3项研究2-h 75 产后6-9周（基线）的口服葡萄糖耐量试验（OGTT），产后第1年和第2年随访 基线，并通过Kaiser Permanente电子健康进行长达12年（10/2020）的糖尿病额外检测 记录系统。TGDM-O研究是一项为期4年的前瞻性纵向研究，纳入了420名中国女性， 从产后6-12周或产后约1年（基线）至产后4 - 12周或产后约1年（基线）接受5次研究性2小时75 g OGTT的GDM患者， 基线后7年（2020年）。所有的研究参与者都有空腹血糖，在连续的2小时OGTT期间的2小时血糖， 除了其它实验室（例如，HbA 1c、胰岛素、脂质）、临床（例如，肥胖）和行为（例如，饮食， 运动、哺乳）在基线和随访研究访视时测量。从储存的空腹血清样本中 从多个OGTT中收集，我们将测量基线时的未甲基化INS DNA和甲基化DNA， 1年和2年。在目标1中，我们将确定产后6-9周和纵向的非甲基化INS DNA水平。 基线后的变化及其与GDM妊娠后约12年内T2 D事件的相关性， SWIFT。在目标2中，我们将通过评估目标1.a-d在TGDM-O队列中的普遍性， 效果估计的异质性和使用荟萃分析技术计算汇总关联。在 探索性目的3，我们将确定基线时未甲基化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目的1-2中的变化相关。如果 成功，我们的研究将提供新的方法来评估β细胞死亡，并帮助将这种测定转移到 用于早期预防和抑制β细胞凋亡的潜在治疗的临床实践。