Developmental Infant Effects of Exposure to High Doses of Oral Insulin in Human Milk

项目摘要/叙述(原始应用程序) 这项建议利用尖端的机械方法来研究临床上有意义的但困难的 研究母乳中的胰岛素(HM)对婴儿发育的影响。这个研究问题是 尤其与不断增长和研究不足的婴儿人口有关，这些婴儿从患有HM的母亲那里获得HM 肥胖和/或胰岛素抵抗(IR)--他们生产的牛奶中胰岛素浓度明显较高。 动物模型显示，通过母乳给婴儿口服胰岛素对正常 后代的发育和成熟。这项建议记录了这些对人类婴儿和 调查在母亲IR(和婴儿持续暴露于高水平)的背景下，影响可能会如何改变 口服胰岛素的浓度。具体地说，我们研究了婴儿胰腺调节的两种全身效应。 功能和局部肠道影响。重要的是，我们将记录在新生儿出生期间的两种急性影响 更“慢性”暴露的时间和影响。我们将招募这两个正常的纯母乳喂养的婴儿 体重/正常血糖(NW；n=28)和患有胰岛素抵抗的母亲(n=36)，并在新生儿期(2-4)进行研究 在更“长期”地接触母乳之后(5个月)。我们的目标是： 目标1-横断面研究-调查新陈代谢发育和肠道成熟的差异 NW纯母乳喂养的婴儿与IR母亲在2-4周和5个月时的婴儿之间的差异。我们假设 IR母亲哺乳的婴儿将表现出：代谢谱改变，表明 碳水化合物处理和胰岛素信号传递；肠道微生物群中微生物组成的改变； 肠脱落细胞中胰岛素靶基因的相对转录丰度增加 肠细胞水平的胰岛素信号活跃；2-4周时肠道通透性降低。 目的2-血糖研究-确定是否从IR母亲(具有高浓度的 胰岛素)与2-4周时内源性胰腺反应的差异有关。我们假设 接受高胰岛素的HM将导致较低的内源性胰腺胰岛素反应。 目标3-糖耐量研究-确定是否长期摄入胰岛素抵抗(高胰岛素抵抗)母亲的HM 胰岛素浓度)与5个月时胰腺对葡萄糖刺激的反应有关。我们 假设IR母亲长期暴露于HM将导致胰腺β细胞刺激不足并导致 在5个月时，内源性胰岛素对标准葡萄糖挑战的反应受抑。 我们的长期目标是充分了解口服胰岛素在发育和出生后的影响。 对母乳喂养的婴儿进行编程。随着母亲中胰岛素抵抗患病率的上升--以及 这些女性的后代自身患代谢性疾病的风险增加了-这项研究迄今- 对我们如何建议妇女和照顾她们的婴儿以将疾病风险降至最低的影响。

Project Summary/Narrative (ORIGINAL APPLICATION) This proposal utilizes cutting-edge mechanistic approaches to investigate the clinically meaningful but hard- to-study question of HOW insulin in human milk (HM) affects infant development. This research question is particularly relevant to the growing and under-studied population of infants receiving HM from mothers with obesity and/or insulin resistance (IR) - who produce milk with significantly greater insulin concentrations. Animal models show that oral insulin delivered to the infant via breast milk has far-reaching effects on normal offspring development and maturation. This proposal documents these effects in human infants and investigates how effects may be altered in the context of maternal IR (and sustained infant exposure to high concentrations of oral insulin. Specifically, we examine both systemic effects regulated by infant pancreatic function and local intestinal effects. Importantly, we will document both acute effects during the neonatal period AND effects of more “chronic” exposure. We will recruit 64 exclusively breastfed infants of both normal weight/normoglycemic (NW; n=28) and mothers with IR (n=36) and study them during the neonatal period (2-4 weeks) and after more “chronic” exposure to mother's milk (5 months). Our aims are: Aim 1 – Cross-Sectional Study – Investigate differences in metabolic development and intestinal maturation between infants exclusively breastfed by NW vs IR mothers at: 2-4 weeks and 5 months. We hypothesize that infants breastfed by IR mothers will exhibit: an altered metabolomic profile indicating differences in carbohydrate handling and insulin signaling; an altered microbial composition in the intestinal microbiome; increased relative transcript abundance of insulin-target genes in exfoliated intestinal cells indicating more active insulin signaling at the level of the enterocyte; and decreased intestinal permeability at 2-4 weeks. Aim 2 – Glycemic Study - Determine if consumption of HM from an IR mother (with high concentrations of insulin) is correlated with differences in endogenous pancreatic response at 2-4 weeks. We hypothesize that receipt of HM with high insulin will result in a lower endogenous pancreatic insulin response. Aim 3 – Glucose Tolerance Study - Determine if chronic consumption of HM from an IR mother (with high concentrations of insulin) is correlated with pancreatic response to a glucose challenge at 5 months. We hypothesize that chronic exposure to HM from an IR mother will under-stimulate pancreatic β-cells and result in a dampened endogenous insulin response to a standard glucose challenge at 5 months. Our long-term objective is to fully understand the impact of oral insulin in the development and postnatal programming of the breastfed infant. As the prevalence of insulin resistance rises among mothers – and as these women's offspring have increased risk of developing metabolic disease themselves – this work has far- reaching implications regarding how we counsel women and care for their infants to minimize disease risk.