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bioRxiv · 10.1101/2021.06.09.447705

Postnatal activation of hypoxia pathway disrupts β-cell functional maturation

Yang, J.·Hammoud, B.·Ridler, A.·Ackermann, A. M.·Won, K.-J.·Hoshi, T.·Stanley, C. A.·Stanescu, D. E.
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Abstract

Hypoxic insults in the perinatal period can lead to persistent hyperinsulinism and profound hypoglycemia in newborns. We studied the impact of the hypoxia-inducible factor 1A (HIF1A) pathway on postnatal {beta}-cell function. Rat pups were treated daily between postnatal day (P)7 to P10 with adaptaquin (AQ), an inhibitor of prolyl hydroxylases, which stabilizes HIF1A. AQ-treated pups were hypoglycemic and had higher plasma insulin concentrations. Their islets had a decreased glucose threshold for insulin secretion, indicative of a delay in {beta}-cell postnatal functional maturation. Histology analyses revealed that AQ-treated pups had increased pancreatic insulin-positive area but no changes in the number of islets or number of {beta}-cells per islet, suggesting larger average {beta}-cell size. AQ-treated rat pups had decreased expression of cell cycle genes and decreased numbers of proliferating {beta}-cells. In conclusion, pharmacologic activation of the HIF1A pathway in the early postnatal period leads to hyperinsulinism, due to the persistence of a low glucose threshold for insulin secretion, and to decreased early postnatal {beta}-cell proliferation, suggesting it can impact adult {beta}-cell mass and diabetes risk.

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Yang, J., Hammoud, B., Ridler, A., Ackermann, A. M., Won, K.-J., Hoshi, T., Stanley, C. A., Stanescu, D. E.. 2021-06-09. Postnatal activation of hypoxia pathway disrupts β-cell functional maturation. https://doi.org/10.1101/2021.06.09.447705

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