ObjectiveHypoxic injuries occurring during the perinatal period can lead to persistent hyperinsulinism and profound hypoglycemia in newborns. We studied the impact of hypoxia-inducible pathway on the postnatal β-cell function.MethodsRat pups were treated daily between postnatal day (P)7 to P10 with adaptaquin (AQ), an inhibitor of prolyl hydroxylases, leading to stabilization of hypoxia-inducible factor 1A (HIF1A). In parallel, mouse pups were placed in a hypoxic chamber between embryonic day (E)19 to P6. Dynamic insulin secretion was assessed in both models by islet perifusions. Changes in gene expression were assessed by whole-islet RNA sequencing.ResultsAQ-treated rat pups and hypoxic mouse pups were hypoglycemic and had higher levels of serum insulin. The AQ-/hypoxia-treated islets showed a decreased glucose threshold for insulin secretion compared to controls, indicative of a delay in β-cell postnatal functional maturation. Islet morphometric analysis in the AQ-treated pups showed an increase in insulin area per pancreas, but no change in the number of islets or in the number of β-cells per islet, consistent with a higher average size of β-cells. Differential transcriptomic analysis showed upregulation of the expected HIF1A target genes. AQ-treated rat pups had decreased expression of cell cycle genes and decreased numbers of proliferating β-cells.ConclusionWe showed that hypoxia and pharmacologic activation of the hypoxia inducible pathway in early postnatal period leads to hyperinsulinism, due to the persistence of a low glucose threshold for insulin secretion. This exaggerated activation of hypoxia pathway also decreased early postnatal β-cell proliferation, suggesting it can impact adult β-cell mass and diabetes risk.
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