Developmental infant effects of exposure to high doses of oral insulin in human milk

项目摘要/摘要 这项建议利用尖端的机械学方法来研究临床上有意义但难以 2母乳中的胰岛素如何影响婴儿发育的研究问题。这一研究问题尤为突出 3与因肥胖和/或胰岛素而接受母乳喂养的婴儿人数不断增长和研究不足有关 4抵抗(IR)母亲--她们生产的牛奶中胰岛素浓度明显较高。动物模型秀 通过母乳给婴儿口服胰岛素对正常后代的发育有深远的影响 6和成熟度。这项建议记录了这些对人类婴儿的影响，并调查了这些影响可能是如何 7在母亲IR的背景下发生变化--从而使婴儿持续暴露在高浓度的口服胰岛素中。 8具体地说，我们研究了婴儿胰腺功能和局部肠道调节的全身效应。 9效应。重要的是，我们将记录在器官仍在的新生儿期的两种急性影响 10.不成熟和更“慢性”暴露的影响。我们将招募，两人都是纯母乳喂养的婴儿 11名正常体重/正常血糖(NW；n=28)和IR(n=36)母亲，并在新生儿期对她们进行研究 12个月(2-4周)和更“长期”接触母乳后(5个月)。我们的目标是： 13目标1-横断面研究-调查新陈代谢发育和肠道成熟的差异 14在两个关键时间点：2-4周和5周，由NW和IR母亲纯母乳喂养的婴儿之间 15个月。我们假设，由IR母亲哺乳的婴儿将表现出：代谢谱改变 16表示碳水化合物的处理和胰岛素信号的不同(H1.1)； 17肠道微生物组(H1.2)；脱落的胰岛素靶基因的相对转录丰度增加 18个肠道细胞，表明胰岛素信号在肠细胞水平上更活跃(H1.3)； 19肠道通透性(衡量肠道成熟的功能指标)2-4周(H1.4)。 20目标2-血糖研究-确定是否从IR母亲(高浓度)摄入母乳 胰岛素的21%)与2-4周内源性胰腺反应的差异有关。我们假设 22接受高胰岛素的母乳将导致较低的内源性胰腺胰岛素反应(H2.1)。 23目标3-葡萄糖耐量研究-确定是否长期摄入IR母亲的母乳(有 24高浓度胰岛素)与5个月时胰腺对葡萄糖刺激的反应有关。我们 25假设长期暴露在IR母亲的母乳中将不能刺激胰腺β细胞和 26在5个月时，内源性胰岛素对标准葡萄糖刺激的反应减弱(H3.1)。 27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 28母乳喂养婴儿的程序设计。随着母亲中胰岛素抵抗患病率的上升--以及 29这些妇女的后代自身患代谢性疾病的风险增加--这项研究迄今-- 30对我们如何为妇女提供咨询并照顾她们的婴儿以将疾病风险降至最低的影响。

PROJECT SUMMARY/ABSTRACT 1 This proposal utilizes cutting-edge mechanistic approaches to investigate the clinically meaningful but hard-to- 2 study question of HOW insulin in human milk affects infant development. This research question is particularly 3 relevant to the growing and under-studied population of infants receiving breast milk from obese and/or insulin 4 resistant (IR) mothers - who produce milk with significantly greater insulin concentrations. Animal models show 5 that oral insulin delivered to the infant via breast milk has far-reaching effects on normal offspring development 6 and maturation. This proposal documents these effects in human infants and investigates how effects may be 7 altered in the context of maternal IR - and thus sustained infant exposure to high concentrations of oral insulin. 8 Specifically, we examine systemic effects regulated by infant pancreatic function as well as local intestinal 9 effects. Importantly, we will document both acute effects during the neonatal period when organs are still 10 immature AND effects of more “chronic” exposure. We will recruit 64 exclusively breastfed infants of both 11 normal weight/normoglycemic (NW; n=28) and IR (n=36) mothers and study them during the neonatal period 12 (2-4 weeks) and after more “chronic” exposure to mother’s milk (5 months). Our aims are: 13 Aim 1 – Cross-Sectional Study – Investigate differences in metabolic development and intestinal maturation 14 between infants exclusively breastfed by NW vs IR mothers at two critical time points: 2-4 weeks and 5 15 months. We hypothesize that infants breastfed by IR mothers will exhibit: an altered metabolomic profile 16 indicating differences in carbohydrate handling and insulin signaling (H1.1); an altered microbial composition in 17 the intestinal microbiome (H1.2); increased relative transcript abundance of insulin-target genes in exfoliated 18 intestinal cells, indicating more active insulin signaling at the level of the enterocyte (H1.3); and decreased 19 intestinal permeability (a functional measure of intestinal maturation) at 2-4 weeks (H1.4). 20 Aim 2 – Glycemic Study - Determine if consumption of human milk from an IR mother (with high concentrations 21 of insulin) is correlated with differences in endogenous pancreatic response at 2-4 weeks. We hypothesize that 22 receipt of human milk with high insulin will result in a lower endogenous pancreatic insulin response (H2.1). 23 Aim 3 – Glucose Tolerance Study - Determine if chronic consumption of human milk from an IR mother (with 24 high concentrations of insulin) is correlated with pancreatic response to a glucose challenge at 5 months. We 25 hypothesize that chronic exposure to human milk from an IR mother will under-stimulate pancreatic β-cells and 26 result in a dampened endogenous insulin response to a standard glucose challenge at 5 months (H3.1). 27 Our long term objective is to fully understand the impact of oral insulin in the development and postnatal 28 programming of the breastfed infant. As the prevalence of insulin resistance rises among mothers – and as 29 these women’s offspring have increased risk of developing metabolic disease themselves – this work has far- 30 reaching implications regarding how we counsel women and care for their infants to minimize disease risk.