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

• 批准号: 10628678
• 负责人: Bridget Victoria Young
• 金额: $ 5.6万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 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/10628678
• 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; COVID-19 pandemic; 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; Mentored Research Scientist Development Award; Messenger RNA; Metabolic; Metabolic Diseases; Metabolism; Milk; Mothers; Neonatal; Obesity; Oral; Pancreas; Parents; Pattern; Phenotype; Population; Prevalence; Regulation; Request for Applications; Research; Risk; Stimulus; Structure of beta Cell of islet; 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; programs; recruit; response; study population; urinary; virtual

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.

项目摘要/叙述（原始申请） 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 研究母乳中的胰岛素如何影响婴儿发育。这个研究问题是 特别是与接受母亲人乳的婴儿群体的增长和研究不足有关， 肥胖和/或胰岛素抵抗（IR）----这些人产奶时胰岛素浓度明显更高。 动物模型表明，通过母乳给予婴儿的口服胰岛素对正常的 后代的发育和成熟。该提案记录了人类婴儿的这些影响， 调查如何影响可能会改变的背景下，产妇IR（和持续的婴儿暴露于高 口服胰岛素浓度。具体来说，我们研究了婴儿胰腺炎调节的全身效应， 功能和局部肠道影响。重要的是，我们将记录新生儿期的急性影响， 更“慢性”接触的影响。我们将招募64名纯母乳喂养的婴儿， 体重/血糖正常（NW; n=28）和IR母亲（n=36），并在新生儿期（2-4 周）和更多的“慢性”暴露于母乳（5个月）。我们的目标是： 目的1 -横断面研究-研究代谢发育和肠道成熟的差异 在2-4周和5个月时，纯母乳喂养的NW母亲与IR母亲的婴儿之间的差异。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，表明 碳水化合物处理和胰岛素信号传导;肠道微生物组中改变的微生物组成; 脱落的肠细胞中胰岛素靶基因的相对转录丰度增加，表明 在肠上皮细胞水平上的活性胰岛素信号传导;以及在2-4周时降低的肠通透性。 目标2 -糖基化研究-确定是否消耗来自IR母体的HM（具有高浓度的糖基化）。 胰岛素）与2-4周时内源性胰腺反应的差异相关。我们假设 接受具有高胰岛素HM将导致较低的内源性胰腺胰岛素应答。 目标3 -葡萄糖耐量研究-确定是否长期消耗来自IR母亲的HM（具有高血糖）， 胰岛素浓度）与5个月时胰腺对葡萄糖激发的反应相关。我们 假设IR母亲长期暴露于HM将刺激胰腺β细胞不足， 在5个月时，内源性胰岛素对标准葡萄糖刺激的反应减弱。 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， 母乳喂养婴儿的编程。随着母亲中胰岛素抵抗的患病率上升， 这些女性的后代本身患代谢疾病的风险增加-这项工作已经远远- 对我们如何为妇女提供咨询和照顾她们的婴儿以尽量减少疾病风险产生影响。