574 - Early Neonatal Hyperglycemia: Implications for Pulmonary and Pancreatic Function Revealed through Translational Functional Analysis and Transcriptomics

Poster Number: 574
Publication Number: 574.1358

Background: Hyperglycemia is a common condition in premature infants. Its effects at critical periods of development remain poorly understood.

Objective: We examined the association between hyperglycemia and bronchopulmonary dysplasia (BPD) in extremely low birth weight (ELBW) humans. We examined functional and mechanistic effects of hyperglycemia in our novel non-human primate (NHP) model.

Design/Methods: Human cohort: A retrospective analysis of ELBW infants utilizing propensity score matching for gender, gestation and date of birth was conducted. Our primary outcome was BPD based on Shannon criteria or mortality before discharge. We constructed a logistic regression model for BPD using variables of significance through univariate analysis. Model performance was evaluated using odds of developing BPD.

NHP cohort: Preterm baboons born at 67% gestation and mechanically ventilated were randomly assigned to five days of hyperglycemia (HG, n=7) or normoglycemia (Ctrl, n=6). Hyperglycemic clamp to assess pancreatic function was calculated on day 6 and 12. Differential gene expression analysis was carried out using EdgeR on RNASeq data extracted from baboon lung tissue.

Results: Human cohort: In 137 ELBW infants, 58.4% (n=80) had BPD. The BPD group had more males (69% vs 42%, p=0.002), lower birthweight (740 g vs 830 g BW, p=0.007), and a higher percentage of patients in the top tertile of average serum glucose in the first 72 HOL (105 mg/dL vs 84 mg/dL; 44% vs 19%, p=0.003). After controlling for gender and BW, patients with elevated glucose had an increased odds of developing BPD (OR: 2.97 [95% CI, 1.26 - 7.02]).

NHP cohort: HG and Ctrl groups were similar in gestational age and birthweight. HG baboons had increased oxygenation and ventilation indices during hyperglycemia (Fig 1A). Animals with hyperglycemia had decreased pancreatic insulin secretion 1 week after hyperglycemic insult (Fig 1B). Top upregulated genes were associated with cellular respiration (COX1), surfactant production (SFTPC), cytoskeletal connection (MACF1), and pulmonary-vascular development (EPAS1) (Fig 2). Ontologic processes different between the groups included regulation of cellular adhesion, apoptosis, and developmental maturation.

Conclusion(s): Early hyperglycemia in prematurity is associated with BPD in humans and alters pancreatic and lung development in baboons. Our differentially expressed genes from the NHP model contribute to our understanding of the complex molecular interplay occurring in lung tissues affected by hyperglycemia, lending biologic plausibility to the correlation between early hyperglycemia and BPD in ELBW neonates.