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

摘要摘要 早产儿的营养需求增加，因此他们的母乳(HM)饲料必须强化。 从历史上看，防御工事一直是以牛为基础的。最近，HM衍生的强化剂已经上市。2017年， 我们的NICU从向孕期1250克或30周的婴儿提供牛源性强化剂转向HM来源的强化剂。 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，足以使新陈代谢 其影响仍未得到研究。供应商零星地观察到新生儿低血糖和 高钙血症需要干预，我们在飞行员数据中从统计上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和 母体血浆。动物模型表明，牛奶胰岛素对糖尿病大鼠的血糖调节有贡献 我们的试点数据首次表明这种情况也发生在母乳喂养的新生儿身上。PTHrP有助于 骨和钙(Ca)调节。推测HM PTHrP促进钙吸收和骨钙素 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累。HM衍生强化剂 浓缩HM蛋白。由于胰岛素和PTHrP是蛋白质，它们很可能进一步集中在这些 强化剂(我们的试验数据一致)，并保持活跃，潜在地影响婴儿的新陈代谢，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：婴儿血糖调节和血钙指标的比较 接受HM衍生的强化剂(2017-2019年)，与那些有资格获得这些强化剂但获得牛- 基于防御工事(2015-2017)。假设1：低血糖和高钙血症将在HM- 衍生强化剂组。随着营养素的增加，新生儿血糖会降低，而钙会增加。 2.HM增强剂和诱发代谢事件的前瞻性观察性研究：a)记录其分布 HM胰岛素和甲状旁腺素在每一水平的HM衍生增强剂中的浓度(BASE/20、24、28、30千卡/盎司)， 描述防御工事水平之间和个别地段内的差异。假设2a：胰岛素和 PTHrP浓度会随着增强剂蛋白浓度的增加而增加。B)前瞻性研究75 婴儿接受HM衍生的强化剂，节省每日准备的等量饲料，直到任何强化剂停止。 比较代谢紊乱时期饲料中的胰岛素和甲状旁腺素水平。 假设2b：婴儿的胰岛素和PTHrP剂量在低血糖和 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。 这项建议解决了优化早产儿营养所必需的紧迫问题，并增强了我们的 了解非强化HM对足月儿代谢的影响。这项尖端研究是独一无二的 与杨博士的K01奖相结合，将协同她在独立方面的进展。

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.