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

接触高剂量口服母乳胰岛素 (HM) 对婴儿发育的影响

• 批准号: 10557142
• 负责人: Bridget Victoria Young
• 金额: $ 11.55万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10557142
• 关键词: Address; Agreement; Aliquot; Animal Model; Birth; Blood Glucose; Bone Development; Breast Feeding; Breastfed infant; Calcium; Calories; Cattle; Dangerousness; Data; Development; Dose; Event; Exhibits; Exposure to; Feeds; Glucose; Health; Hormones; Human Milk; Hypercalcemia; Hypoglycemia; Individual; Infant; Insulin; Insulin Resistance; Intervention; Intestines; Lactation; Measures; Medical; Mentored Research Scientist Development Award; Metabolic; Metabolism; Methods; Milk; Milk Proteins; Mothers; Nature; Necrotizing Enterocolitis; Neonatal; Neonatal Hypoglycemia; Newborn Infant; Nutrient; Nutritional Study; Obesity; Observational Study; Oral; Outcome; Parathyroid gland; Plasma; Population; Pregnancy; Premature Infant; Prevalence; Prospective Studies; Proteins; Provider; Public Health; Qualifying; Regulation; Research; Risk; Science; Serum; Time; Woman; Work; absorption; base; blood glucose regulation; bone; calcium absorption; clinical care; fortification; infant nutrition; mammary; neonate; novel; parathyroid hormone-related protein; premature; prospective; skeletal; synergism

SUMMARY ABSTRACT Premature infants have elevated nutrient needs, so their human milk (HM) feeds must be fortified. Historically, fortifiers have been bovine-based. Recently HM-derived fortifiers have become available. In 2017, our NICU switched from providing bovine to HM-derived fortifiers to infants <1250g or <30 weeks gestation. While these products protect against necrotizing enterocolitis, they are still novel enough that metabolic implications remain unstudied. Providers anecdotally observed increases in neonatal hypoglycemia and hypercalcemia necessitating intervention, an observation we statistically confirm in our pilot data. Unlike other hormones, insulin and parathyroid-related protein (PTHrP) are uniquely concentrated in HM vs maternal plasma. Animal models demonstrate that milk insulin contributes to blood glucose regulation in the newborn and our pilot data is the first to suggest this also occurs in breastfed neonates. PTHrP contributes to bone and calcium (Ca) regulation. It is hypothesized that HM PTHrP promotes Ca absorption and skeletal Ca accretion in the healthy neonate via systemic absorption and/or local intestinal interaction. HM-derived fortifiers concentrate HM protein. As insulin and PTHrP are proteins, they are likely further concentrated in these fortifiers (our pilot data agrees) and remain active, potentially impacting infant metabolism and resulting in the hypoglycemia and hypercalcemia observed. To study this concerning phenomenon, we propose: 1. Historical Comparison: Compare measures of blood glucose regulation and serum Ca among infants receiving HM-derived fortifiers (2017-2019) with those who qualified for these fortifiers but received bovine- based fortifiers (2015-2017). Hypotheses 1: Hypoglycemia and hypercalcemia will be higher in the HM- derived fortifier group. Neonatal glucose will be lower and Ca will increase as fortification increases. 2. Prospective, observational study of HM fortifiers and induced metabolic events: A) Document the distribution of HM insulin and PTHrP concentrations in each level of HM-derived fortifier (base/20, 24, 28, 30 kcal/oz), characterizing differences between fortification levels and within individual lots. Hypothesis 2a: Insulin and PTHrP concentrations will increase as fortifier protein concentration increases. B) Prospectively study 75 infants receiving HM-derived fortifiers, saving aliquots of daily prepared feeds until any fortification ceases. Compare insulin and PTHrP in feeds from days when metabolic disturbances were documented vs not. Hypotheses 2b: Infant dose of insulin and PTHrP will be higher on days when hypoglycemia and hypercalcemia are observed, respectively. Daily insulin dose will correlate with average daily blood glucose. This proposal addresses urgent questions necessary to optimize premature infants' nutrition and enhances our understanding of unfortified HM's impact on term infant metabolism. This cutting-edge research uniquely integrates with Dr Young's K01 award in a manner that will synergize her progress towards independence.

摘要摘要 过早的婴儿的营养需求升高，因此必须加强其人牛奶（HM）饲料。 从历史上看，堡垒一直以牛为基础。最近，HM衍生的堡垒已上市。 2017年， 我们的NICU从提供牛到HM衍生的堡垒转换为<1250g或<30周妊娠的婴儿。 尽管这些产品可以防止坏死性小肠结肠炎，但它们仍然足够新颖，以至于代谢 含义仍然没有研究。提供者轶事观察到新生儿低血糖和 高钙血症需要干预，这是我们在试点数据中统计确认的观察结果。 与其他激素不同，胰岛素和甲状旁腺相关蛋白（PTHRP）在HM VS中独特地集中 母体血浆。动物模型表明，牛奶胰岛素有助于血糖调节 新生儿和我们的试验数据是第一个提出这也发生在母乳喂养的新生儿中的数据。 PTHRP为 骨和钙（CA）调节。假设HM PTHRP促进CA吸收和骨骼CA 通过全身吸收和/或局部肠道相互作用在健康新生儿中积聚。 HM来源的堡垒 浓缩HM蛋白。由于胰岛素和PTHRP是蛋白质，因此它们可能进一步集中在这些 堡垒（我们的飞行员数据同意）并保持活跃，可能影响婴儿代谢，并导致 观察到低血糖和高钙血症。为了研究有关现象的这种现象，我们提出： 1。历史比较：比较婴儿血糖调节和血清CA的度量 接受HM衍生的Fortifiers（2017-2019），有资格获得这些堡垒但收到牛的人 基于堡垒（2015-2017）。假设1：在HM-中低血糖和高钙血症将更高 派生的堡垒集团。新生儿葡萄糖将较低，并且随着强化的增加，CA将增加。 2。对HM堡垒和诱导代谢事件的前瞻性，观察性研究：a）记录分布 HM衍生堡垒的HM胰岛素和PTHRP浓度（基本/20、24、28、30 kcal/oz）， 表征强化水平和单个批次之间的差异。假设2a：胰岛素和 随着Fortifier蛋白浓度的增加，PTHRP浓度将增加。 b）前瞻性研究75 接收HM衍生的堡垒的婴儿，节省了每日准备好的饲料的等分试样，直到任何强化停止。 从记录代谢性疾病与未记录的几天相比，比较源中的胰岛素和PTHRP。 假设2B：胰岛素和PTHRP的婴儿剂量在低血糖症和 分别观察到高钙血症。每日胰岛素剂量将与平均每日血糖相关。 该提案解决了优化早产儿营养并增强我们的紧急问题 了解不幸的HM对术语婴儿代谢的影响。这项尖端的研究独特 与Young博士的K01奖相结合的方式将使她朝着独立性协同作用。