Pregravid biomarkers of GDM risk, fetal growth and progression to diabetes

描述(申请人提供)：妊娠期糖尿病(GDM)对母亲和她的后代都有短期和长期的后果。患有妊娠期糖尿病的妇女更有可能生下大的妊娠期(LGA)婴儿，其中高达50%的人会患上2型糖尿病。然而，多达一半患有妊娠期糖尿病的女性没有已知的风险因素，这表明肯定有其他因素参与其中。与各种代谢途径(胰岛素抵抗、炎症和氧化应激)相关的生物标记物可能有助于识别有GDM风险的女性，这些女性可以作为预防的靶点，也可能加深我们对GDM的病理生理学及其后果的理解。妊娠固有的代谢和荷尔蒙变化使得在怀孕前评估这些代谢生物标志物以确定相关性的时间序列是重要的。在三个主要目标中，我们建议评估：1)胰岛素抵抗(脂联素、高分子脂联素、胎球蛋白-A和低密度脂蛋白-C颗粒大小)、2)炎症(CRP)和3)氧化应激(GGT)的生物标记物是否与GDM的风险增加有关。我们将在次级目标中探索：4)孕前脂联素及其异构体水平是否与LGA婴儿的风险相关，这种关联是否由GDM介导；5)在GDM妇女中，胰岛素抵抗、炎症和氧化应激的孕前水平及其长期变化与T2 DM和胰岛素抵抗的程度相关。我们建议在1984-1996年间参加北加州凯撒永久健康体检(KPNC)多相体检(MHC)的4084名妇女中进行嵌套式病例对照研究，她们的血清样本被储存，并有过一次怀孕。我们将研究235名妊娠期糖尿病妇女和470名血糖正常的对照组妇女，在MHC检查的年份、MHC检查的年龄和怀孕年龄方面进行匹配。到目前为止，还没有研究检查孕前代谢风险和妊娠期糖尿病风险的生物标记物。这项研究将通过确定在健康年轻女性中测量的孕前生物标记物是否与妊娠期糖尿病的风险有关来填补科学知识的空白。妊娠期糖尿病是一种发生在生命早期的代谢改变。这项研究可能对预防妊娠期糖尿病及其进展为T2 DM及其后代的健康后遗症具有翻译价值。 与公共卫生相关：妊娠期糖尿病在美国的发病率正在增加，但其根本原因仍有许多未知之处。这项研究将首次确定在健康年轻女性中测量的孕前生物标记物是否与妊娠期糖尿病、胎儿过度生长(LGA)和进展为2型糖尿病的风险有关。识别妊娠期糖尿病的孕前代谢生物标志物及其不良健康后果可能有助于深入了解导致妊娠期糖尿病发生及其后果的潜在原因。这些信息可用于为妊娠期糖尿病和糖尿病预防战略提供信息。

DESCRIPTION (provided by applicant): Gestational diabetes mellitus (GDM) has short and long-term consequences for both the mother and her offspring. Women with GDM are more likely to deliver a large for gestational (LGA) infant and up to 50% of them will develop type 2 diabetes. However, up to half of women with GDM have no known risk factors, suggesting that other factors must be involved. Biomarkers associated with various metabolic pathways (insulin resistance, inflammation and oxidative stress) might be useful for identifying women at risk of GDM who could be targeted for prevention and may also further our understanding of the pathophysiology of GDM and its consequences. The metabolic and hormonal changes intrinsic to pregnancy make it important to assess these metabolic biomarkers before pregnancy to determine the temporal sequence of the associations. In three primary aims we propose to evaluate whether biomarkers of: 1) insulin resistance (adiponectin, HMW adiponectin, Fetuin-A and LDL-C particle size), 2) inflammation (CRP), and 3) oxidative stress (GGT) assessed before pregnancy, are associated with increased risk GDM. We will explore in the secondary aims whether: 4) pregravid levels of adiponectin and its isoforms are associated with the risk of having a LGA infant and whether this association is mediated by GDM; 5) among the women with GDM, pre-gravid levels of biomarkers of insulin resistance, inflammation, and oxidative stress and their long-term changes are associated with T2DM and degree of insulin resistance. We propose a nested case-control study within a multi-ethnic cohort of 4,084 women who took part in the Kaiser Permanente Northern California (KPNC) multiphasic health checkup (MHC) exam between 1984-1996, had serum samples stored, and had a subsequent pregnancy. We will study 235 women with GDM and 470 normoglycemic control women matched on year of MHC exam, age at MHC exam and age at pregnancy. No studies to date have examined biomarkers of metabolic risk before pregnancy and risk of GDM. This study will fill a gap in scientific knowledge by determining if pregravid biomarkers, measured among healthy young women, are associated with the risk of GDM, a metabolic alteration occurring early in life. This research could have translational value in the prevention of GDM its progression to T2DM, and health sequelae in their offspring. PUBLIC HEALTH RELEVANCE: The incidence of GDM is increasing in the United States, however much remains unknown about its underlying cause. This study will determine for the first time if the proposed pregravid biomarkers measured among healthy young women are associated with the risk of GDM, excessive fetal growth (LGA) and progression to type 2 diabetes. Identification of pregravid metabolic biomarkers of GDM and its adverse health consequences may give insights to the underlying causes leading to the development of GDM and its consequences. This information can be used to inform strategies for GDM and diabetes prevention.