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

摘要 早产儿的营养需求增加，因此他们的人乳（HM）饲料必须强化。 从历史上看，强化因子是以牛为基础的。最近HM衍生的强化剂已经可用。在2017年， 我们的NICU从为体重<1250 g或妊娠<30周的婴儿提供牛源性强化剂转向HM源性强化剂。 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， 其影响尚未研究。提供者观察到新生儿低血糖增加， 需要干预的高钙血症，我们在初步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）在HM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， 我们的试点数据首次表明，这也发生在母乳喂养的新生儿中。PTHrP有助于 骨和钙（Ca）调节。推测HM PTHrP促进Ca吸收和骨骼Ca ~（2+） 通过全身吸收和/或局部肠道相互作用在健康新生儿中增加。HM衍生增强子 浓缩HM蛋白。由于胰岛素和PTHrP是蛋白质，它们可能进一步集中在这些蛋白质中。 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。为了研究这一现象，我们建议： 1.历史比较：比较婴儿血糖调节和血清钙的措施 接受HM衍生的强化剂（2017-2019）与那些有资格接受这些强化剂但接受牛- 基于强化剂（2015-2017）。假设1：低血糖和高钙血症在HM中会更高- 导出强化子群新生儿的葡萄糖将降低，钙将增加强化增加。 2. HM强化剂和诱导代谢事件的前瞻性观察性研究：A）记录分布 HM衍生强化剂的每个水平（碱/20、24、28、30 kcal/oz）中HM胰岛素和PTHrP浓度， 表征强化水平之间和单个批次内的差异。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）预防性研究75 接受HM衍生强化剂的婴儿，保存每日制备的饲料的等分试样，直到任何强化停止。 比较胰岛素和PTHrP的饲料从天时，代谢紊乱的记录与没有。 假设2b：婴儿胰岛素和PTHrP的剂量在低血糖和低血糖发生时较高， 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所需的紧迫问题，并提高了我们的 了解未强化的人乳对足月儿代谢的影响。这项尖端研究 与杨博士的K 01奖相结合的方式，将协同她走向独立的进步。

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.