Perinatal and intergenerational influences on adult diabetes

该项目的目的是确定出生前后限制营养供应对成人发病糖尿病的生长和发展的影响。出生时身材矮小及其相关的新生儿追赶生长可以独立预测成人糖尿病。胎盘限制是出生前营养和生长减少的主要原因，并与这种疾病的规划有关。我们的新发现表明，胎盘受损会增加食欲，但也会损害牛奶质量和供应，这限制了最初的过度喂养和追赶生长，但在断奶时，可能会独立导致糖尿病。我们将确定这是否是营养不良的直接结果，以及是否因营养恢复后的过度喂养而变得更糟。我们假设胎盘损伤永久性地降低了个体的代谢能力，出生后营养的可用性程度决定了胰岛素作用和体脂增加的后果。将进行产后营养（通过交叉培养）和脂肪氧化操作，这对于理解追赶生长和增加食物摄入量在疾病发病中的作用至关重要。我们发现，在哺乳正常的母鼠身上交叉饲养幼鼠可以促进哺乳期间的生长。拟议的研究将确定对糖尿病发展的交叉促进作用，并确定营养或其他操作可能对母乳喂养的小婴儿的健康产生有益影响的发育阶段。我们建议确定成年女性在胎儿时期受到胎盘限制是否会产生患糖尿病的后代，并确定这种影响是否由孕前编程和或胎儿环境改变引起。确定出生后而不是出生前的关键时期，将更有可能制定切实可行的公共卫生干预措施，以改善成人健康。

The aim of this project is to determine the effects of restriction of nutrient supply before and after birth on growth and the development of adult onset diabetes. Being born small and its associated neonatal catch-up growth independently predict adult diabetes. Placental restriction is a major cause of reduced nutrition and growth before birth and is implicated in this programming of disease. Our novel findings suggest that placental compromise increases appetite but also impairs milk quality and supply which limits overfeeding and catch-up growth initially, but on weaning, may independently lead to diabetes. We will determine if this is a direct result of poor nutrition and made worse by overfeeding in response to restored nutrition. We hypothesize that placental compromise permanently reduces an individual's metabolic capacity and that the extent of availability of nutrition after birth determines the consequences for insulin action and increased body fat. Manipulations of postnatal nutrition (by cross-fostering) and fat oxidation will be performed, which are pivotal to understanding the roles of catch-up growth and increased food intake in disease onset. We have found that cross-fostering small rat pups at birth onto mothers with normal lactation improves growth during lactation. The proposed studies will establish the cross-fostering effect on the development of diabetes and identify a developmental stage during which nutritional or other manipulations may have beneficial consequences for the health of the breastfeeding small infant. We propose to determine whether adult females, exposed to placental restriction as a fetus, produce offspring that develop diabetes, and establish whether this effect is caused by programming before conception and-or an altered fetal environment. Identification of critical periods after birth, rather than before, would offer a greater likelihood that practical public health interventions can be developed to improve adult health.