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

项目概要/摘要 1该提案利用尖端的机械方法来研究临床上有意义但难以实现的 2研究问题人乳中的胰岛素如何影响婴儿发育。这一研究课题尤其 3例与接受肥胖和/或胰岛素治疗的母乳喂养的婴儿的不断增长和研究不足的人群相关 4位抵抗（IR）的母亲-生产的乳汁中胰岛素浓度显著较高。动物模型显示 通过母乳给婴儿口服胰岛素对后代的正常发育有深远的影响 6、成熟该提案记录了人类婴儿的这些影响，并调查了这些影响可能是如何产生的。 7在母体IR的背景下发生改变-从而使婴儿持续暴露于高浓度口服胰岛素。 8具体来说，我们检查了婴儿胰腺功能以及局部肠道功能调节的全身效应 9效果重要的是，我们将记录新生儿时期的两种急性效应， 10不成熟和影响更多的“慢性”曝光。我们将招募64名纯母乳喂养的婴儿， 11名正常体重/血糖正常（NW; n=28）和IR（n=36）母亲，并在新生儿期对其进行研究 12（2-4周）和更多的“慢性”接触母乳（5个月）。我们的目标是： 13目的1 -横断面研究-研究代谢发育和肠道成熟的差异 在两个关键时间点（2-4周和5周），NW与IR母亲纯母乳喂养的婴儿之间的差异为14 15个月我们假设IR母亲母乳喂养的婴儿将表现出：代谢组学特征改变 16表明碳水化合物处理和胰岛素信号传导（H1.1）的差异; 17肠道微生物组（H1.2）;脱落细胞中胰岛素靶基因的相对转录丰度增加 18个肠细胞，表明在肠上皮细胞水平上更活跃的胰岛素信号传导（H1.3）; 19 2-4周时的肠道渗透性（肠道成熟的功能指标）（H1.4）。 20目标2 -糖基化研究-确定摄入IR母亲的人乳（高浓度） 21的胰岛素）与2-4周时内源性胰腺反应的差异相关。我们假设 22接受高胰岛素人乳将导致内源性胰腺胰岛素反应较低（H2.1）。 目标3 -葡萄糖耐量研究-确定长期食用IR母亲的人乳（具有 24高浓度胰岛素）与5个月时胰腺对葡萄糖激发的反应相关。我们 25假设长期暴露于IR母亲的人乳将刺激胰腺β细胞不足， 26导致在5个月时对标准葡萄糖激发的内源性胰岛素应答减弱（H3.1）。 27我们的长期目标是充分了解口服胰岛素对发育和产后的影响。 28母乳喂养的婴儿的编程。随着母亲中胰岛素抵抗的患病率上升， 这些妇女的后代本身患代谢疾病的风险增加-这项工作已经远远- 关于我们如何为妇女提供咨询和照顾她们的婴儿以最大限度地减少疾病风险的30个影响。

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.