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 早产儿的营养需求较高，因此必须强化其母乳 (HM) 喂养。 从历史上看，强化剂一直以牛为原料。最近，HM 衍生的强化剂已经上市。 2017年， 我们的新生儿重症监护病房 (NICU) 从向 <1250 克或 <30 周妊娠的婴儿提供牛强化剂改为 HM 衍生强化剂。 虽然这些产品可以预防坏死性小肠结肠炎，但它们仍然足够新颖，以至于代谢 其影响尚未得到研究。据传闻，医疗服务提供者观察到新生儿低血糖和 高钙血症需要干预，我们在试点数据中统计证实了这一观察结果。 与其他激素不同，胰岛素和甲状旁腺相关蛋白 (PTHrP) 独特地集中在 HM 中 母体血浆。动物模型证明牛奶胰岛素有助于调节血糖 新生儿，我们的试点数据首次表明母乳喂养的新生儿也会出现这种情况。 PTHrP 有助于 骨骼和钙 (Ca) 调节。据推测，HM PTHrP 促进钙吸收和骨骼钙 通过全身吸收和/或局部肠道相互作用在健康新生儿体内积聚。 HM 衍生强化剂 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 强化剂（我们的试点数据同意）并保持活跃，可能会影响婴儿的新陈代谢并导致 观察到低血糖和高钙血症。为了研究这一相关现象，我们建议： 1. 历史比较：比较婴儿血糖调节和血清钙的测量值 接受 HM 衍生强化剂（2017-2019），以及那些有资格获得这些强化剂但接受牛源强化剂的人 基于强化剂（2015-2017）。假设1：低血糖和高钙血症在HM-中会更高 衍生强化剂组。随着强化的增加，新生儿血糖会降低，钙会增加。 2. HM 强化剂和诱导代谢事件的前瞻性观察研究：A) 记录分布 HM 衍生强化剂各水平中的 HM 胰岛素和 PTHrP 浓度（基础/20、24、28、30 kcal/oz）， 描述设防水平之间和各个批次内的差异。假设 2a：胰岛素和 PTHrP 浓度将随着强化蛋白浓度的增加而增加。 B) 前瞻性研究 75 接受 HM 衍生强化剂的婴儿，保存每日准备的饲料的等分部分，直到任何强化停止。 比较记录代谢紊乱的日子与未记录代谢紊乱的日子饲料中的胰岛素和 PTHrP。 假设 2b：在低血糖和 PTHrP 发生的日子里，婴儿胰岛素和 PTHrP 的剂量会更高。 分别观察到高钙血症。每日胰岛素剂量与每日平均血糖相关。 该提案解决了优化早产儿营养所需的紧迫问题，并增强了我们的能力。 了解未强化的 HM 对足月婴儿代谢的影响。这项前沿研究独一无二 与杨博士的 K01 奖相结合，将协同她走向独立的进程。