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

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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.