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

暴露于母乳中高剂量口服胰岛素对婴儿发育的影响

基本信息

批准号：
10395455
负责人：
Bridget Victoria Young
金额：
$ 11.2万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-05-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10395455
关键词：
Acute Affect Animal Model B Cell Proliferation Beta Cell Biological Biological Markers Birth Blood Circulation Blood Glucose Body mass index Breastfed infant Carbohydrates Caring Cells Characteristics Chronic Clinical Consumption Counseling Cross-Sectional Studies Data Development Diabetes Mellitus Dose Endocrine Enterocytes Epithelial Cells Exclusive Breastfeeding Exhibits Exposure to Fasting Feces Female of child bearing age Gammaproteobacteria Gastrointestinal tract structure Gene Expression Genes Glucose Human Human Milk Immune Infant Infant Development Inflammation Insulin Insulin Receptor Insulin Resistance Intestinal permeability Intestines Knowledge Lactulose Life Macronutrients Nutrition Mannitol Measures Messenger RNA Metabolic Metabolic Diseases Metabolism Milk Mothers Neonatal Obesity Oral Organ Pancreas Pattern Phenotype Population Prevalence Regulation Research Research Design Resistance Risk Stimulus Structure of beta Cell of islet Technology Testing Tight Junctions Time Transcript Weight Woman Work bacteriome cytokine disorder risk glucose tolerance gut microbiome improved insulin signaling intestinal epithelium intestinal maturation metabolic phenotype metabolomics microbial composition microbiome milk production neonatal period offspring postnatal recruit response study population urinary virtual

项目摘要

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.

项目摘要/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 - 2研究人乳中胰岛素如何影响婴儿发育的问题。这个研究问题特别是 3与肥胖和/或胰岛素接受母乳的婴儿的增长和研究不足有关 4个抗药性（IR）母亲 - 产生胰岛素浓度明显更高的牛奶。动物模型显示 5口服胰岛素通过母乳递送给婴儿的口腔胰岛素对正常后代的发展具有深远的影响 6和成熟。该提案记录了这些对人类婴儿的影响，并研究了如何影响 7在产妇IR的背景下发生了变化，因此婴儿暴露于高浓度的口服胰岛素。 8特别是，我们检查了婴儿胰腺功能和局部肠道调节的系统效应 9效果。重要的是，我们将记录在器官仍在的新生儿期间的两种急性影响 10未成熟和更多“慢性”暴露的影响。我们将招募64位两者的母乳喂养婴儿 11正常体重/正常血液（NW; n = 28）和IR（n = 36）母亲，并在新生儿期间进行研究 12（2-4周）和更多“慢性”暴露于母乳（5个月）之后。我们的目标是： 13 AIM 1 - 横断面研究 - 研究代谢发育和肠道成熟的差异 14在两个关键时间点由NW与IR母亲母乳喂养的婴儿之间：2-4周和5 15个月。我们假设将存在IR母亲母乳喂养的婴儿：代谢组的改变 16表明碳水化合物处理和胰岛素信号传导的差异（H1.1）；改变的微生物组成 17肠道微生物组（H1.2）;去角质中胰岛素靶基因基因的相对转录本的提高 18个肠道细胞，表明在肠细胞水平上更活跃的胰岛素信号传导（H1.3）；并改进 19在2-4周（H1.4）在肠道渗透性（肠成熟的功能测量）。 20 AIM 2 - 血糖研究 - 确定ir母亲的人奶消耗是否（浓度很高）胰岛素的21）与2-4周的内源性胰腺反应的差异相关。我们假设这一点 22接受高胰岛素的人奶将导致内源性胰岛胰岛素反应较低（H2.1）。 23 AIM 3 - 葡萄糖耐受性研究 - 确定IR母亲的长期消费人牛奶（与 24高浓度的胰岛素）与5个月时对葡萄糖挑战的胰腺反应相关。我们 25假设来自IR母亲的长期暴露于人类乳的暴露会刺激胰腺β细胞，并且 26导致对5个月时标准葡萄糖挑战的内源性胰岛素反应抑制（H3.1）。 27我们的长期目标是充分了解口服胰岛素在发育和产后的影响 28母乳喂养婴儿的编程。随着胰岛素抵抗的患病率在母亲之间升高， 29这些妇女后代有增加代谢疾病本身的风险 - 这项工作的风险很大 - 30对我们如何为妇女提供咨询和照顾婴儿的意义，以最大程度地减少疾病风险。