【背景】女性生命早期营养不良是其成年后2型糖尿病（T2DM）发病的重要危险因素，但对其后代T2DM发病的关联性及其机理尚不清楚。【目的】研究我国女性出生体重（BW）与T2DM的代际关联模式，评估其关联强度，并探索相关机理。【方法】通过女性家庭大样本队列随访，评估BW与成年后空腹血糖、餐后血糖、糖化血红蛋白（HbA1c）、胰岛素水平以及T2DM发病风险的关联性；借助结构方程等统计模型，研究母亲代BW对女儿代和外孙女代BW及T2DM风险的影响；检测母亲代生命早期暴露于60年代饥荒的三代女性家庭的父源和母源印记基因及非印记基因的外周血甲基化水平，评估三代女性DNA甲基化的关联性，以及DNA甲基化与T2DM发病之间的关联。【预期结果】揭示BW与T2DM关联的代际传递模式以及DNA甲基化在T2DM跨代传递中的作用。【研究意义】揭示我国T2DM持续上升的原因，为新的干预措施提供依据。

【Background】Malnutrition in early life has been an important risk factor for subsequent type 2 diabetes. Its effect on the risk of type 2 diabetes in offspring and possible mechanisms, however, remain unclear.【Objectives】To establish an trans-generational association model of birth weight with the risk of type 2 diabetes in Chinese females, and seek the possible epigenetic mechanisms underlying the associations.【Methods】Following-up surveys for an established family cohort which includes 10,324 females in communities of Shanghai, China, will be conducted to collect information on incident type 2 diabetes and blood samples to measure the levels of glycosylated homoglobin A1c (HbA1c), fasting insulin, and fasting and 2-hour postprandial blood glucose. Based on the female family cohort, we will select all 381 three-generation families with the first generation (F1) exposured to the Chinese famine to further assay methylation of loci implicated in the transcriptional regulation of 6 candidate genes for metabolic disease.The loci studied will include three imprinted loci of guanine nucleotide binding protein (GNASAS), insulin-like growth factor 2 (IGF-2), and insulin-like growth factor 2 receptor (IGF2R) and three non-imprinted loci of interleukin 10 (IL10), fat mass and obesity associated (FTO) and leptin (LEP). Cox model will be applied to evaluate the associations of birth weight with risk of type 2 diabetes in different birth cohorts. Path analysis and mediation analysis will be used to evaluate the impact of birth weight and type 2 diabetes of F1 generation on F2 and F3 generations.【Expected Results】In the view of phenotype and epigenetics, we will evaluate the trans-generational impact of birth weight on the risk of type 2 diabetes in Chinese females.【Significance】Our results will help to better understand the biological mechanisms underlying the increasing trend of T2DM in China, and aid to develop an effective intervention approach to curb the upward trend in the country.