Fuel-mediated functional teratogenesis' in offspring of diabetic mothers: Role of the neonatal period

新生儿关键时期的营养种类和数量对以后超重和糖尿病的风险有着深远的影响。糖尿病母亲（ODM）的后代是一个重要的高危人群，在儿童时期就已经显示出超重和糖耐量受损（IGT）的患病率增加。直到最近，这完全归因于产前，父母和社会经济因素，但这些都不足以完全解释ODM的风险增加。我们获得的第一批数据表明，新生儿早期摄入（出生后第1周）糖尿病母亲的母乳可能是一个新的，迄今未知的风险因素，持久的编程不良超重处置的ODM。然而，在这些初步成果的背景下，仍有一些重要问题有待回答。首先，新生儿早期摄入“糖尿病”母乳的影响程度，特别是与母亲怀孕期间母乳喂养的影响相比，尚不清楚。其次，目前尚不清楚新生儿体重快速增加是否偶尔会介导新生儿母乳喂养的影响。第三，我们不知道早期新生儿摄入“糖尿病”母乳是否也会影响更高年龄后代的长期结局。第四，早期“糖尿病”母乳中可能导致这些影响的致病因素完全未知。为了获得这些问题的答案，我们提出了一个两部分的研究，将持续两年，需要由两个博士奖学金和技术助理的支持。在A部分，我们将创建并分析前瞻性“考尔斯多夫队列研究（KCS）”的完整数据库，以确定可能的类型特异性（妊娠期糖尿病与妊娠期1型糖尿病）和/或新生儿摄入“糖尿病”ODM中的初乳、新生儿体重增加和随后的超重和/或IGT风险，并将其与妊娠第1、2和/或3个月期间母体高血糖程度的影响进行比较，并考虑到大量产前、父母和社会经济混杂因素。此外，在B部分，我们将通过进行一项临床研究，即ODM中的“糖尿病初乳研究（DCS）”，关注潜在的致病因素（妊娠期糖尿病与1型糖尿病）和非糖尿病妇女的后代进行比较，以发现早期“糖尿病”的可能变化。母乳及其与新生儿体重增加的可能剂量-反应关系，这是一个重要的风险因素，也是持久的脂肪形成和糖尿病形成结局的介导因素。总之，拟议的研究预计将为了解早期“糖尿病”母乳的变化是否以及如何成为ODM中后来超重和/或IGT和糖尿病的风险因素提供重要贡献。最终，预期的数据应该有助于确定新的策略，主要是预防超重和糖尿病在这个永久增加的风险人群。

The kind and amount of nutrition during the critical neonatal period has a profound impact on later risk of overweight and diabetes. Offspring of diabetic mothers (ODM) are an important at-risk population showing increased prevalences of overweight and impaired glucose tolerance (IGT) already in childhood. Until recently, this was exclusively attributed to prenatal, parental and socioeconomic factors but these are not sufficient to completely explain the increased risk in ODM. We have obtained first data indicating that early neonatal ingestion (1st week of life) of breast milk from diabetic mothers might be a new, as yet unknown risk factor for lasting malprogramming of overweight disposition in ODM. Against the background of these first results, however, a number of important questions remain to be answered. First, the magnitude of the effect of early neonatal ingestion of `diabetic¿ breast milk, especially as compared to the impact of maternal glycemia during pregnancy, is unknown. Second, it is unclear whether rapid neonatal weight gain might occasionally mediate the effects of neonatal breast feeding. Third, we do not know whether early neonatal ingestion of `diabetic¿ breast milk might also affect long-term outcome at higher offspring age. Fourth, pathogenetic factors in early `diabetic¿ breast milk possibly responsible for these effects are completely unknown. To gain answers to these questions, we propose a two-part study which will endure two years and needs to be supported by two doctoral fellowships and a technical assistant. In part A, we will create and analyze a completed database of the prospective `Kaulsdorf Cohort Study (KCS)¿ to identify a possible type-specific (gestational diabetes vs. type 1 diabetes during pregnancy) and/or dose-response relationship between neonatal ingestion of `diabetic¿ colostrum, neonatal weight gain, and subsequent risk of overweight and/or IGT in ODM, and compare it to the impact of the degree of maternal hyperglycemia during the 1st, 2nd and/or 3rd trimester of pregnancy, and this under consideration of a large range of prenatal, parental and socioeconomic confounders. In part B, we will, moreover, focus on potential pathogenetic factors by conducting a clinical investigation, the `Diabetic Colostrum Study (DCS)¿ in ODM (gestational diabetes vs. type 1 diabetes) and offspring of non-diabetic women to compare the composition and discover possible alterations of early `diabetic¿ breast milk as well as its possible dose-response relationship to neonatal weight gain, an important risk factor and mediator for lasting adipogenic and diabetogenic outcome. In summary, the proposed study is expected to provide an important contribution to the knowledge on whether and how alterations in early `diabetic¿ breast milk may represent a risk factor for later overweight and/or IGT and diabetes in ODM. Ultimately, the anticipated data should help to identify new strategies to primarily prevent overweight and diabetes in this permanently increasing at-risk population.