HIF-1 alpha inhibitor PX-478 preserves pancreatic. cell function in diabetes

Erwin Ilegems, Galyna Bryzgalova, Jorge Correia, Burcak Yesildag, Edurne Berra, Jorge L. Ruas, Teresa S. Pereira, Per-Olof Berggren

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

Abstract

During progression of type 2 diabetes, pancreatic β cells are subjected to sustained metabolic overload. We postulated that this state mediates a hypoxic phenotype driven by hypoxia-inducible factor-1α (HIF-1α) and that treatment with the HIF-1α inhibitor PX-478 would improve β cell function. Our studies showed that the HIF-1α protein was present in pancreatic β cells of diabetic mouse models. In mouse islets with high glucose metabolism, the emergence of intracellular Ca oscillations at low glucose concentration and the abnormally high basal release of insulin were suppressed by treatment with the HIF-1α inhibitor PX-478, indicating improvement of β cell function. Treatment of db/db mice with PX-478 prevented the rise of glycemia and diabetes progression by maintenance of elevated plasma insulin concentration. In streptozotocin-induced diabetic mice, PX-478 improved the recovery of glucose homeostasis. Islets isolated from these mice showed hallmarks of improved β cell function including elevation of insulin content, increased expression of genes involved in β cell function and maturity, inhibition of dedifferentiation markers, and formation of mature insulin granules. In response to PX-478 treatment, human islet organoids chronically exposed to high glucose presented improved stimulation index of glucose-induced insulin secretion. These results suggest that the HIF-1α inhibitor PX-478 has the potential to act as an antidiabetic therapeutic agent that preserves β cell function under metabolic overload.
Original languageEnglish
Article numberaba9112
JournalScience Translational Medicine
Volume14
Issue number638
Early online date30 Mar 2022
DOIs
Publication statusE-pub ahead of print - 30 Mar 2022

Bibliographical note

Publisher Copyright:
© 2022 The Authors.

Keywords

  • Animals
  • Diabetes Mellitus, Experimental/drug therapy
  • Diabetes Mellitus, Type 2/drug therapy
  • Insulin-Secreting Cells
  • Mice
  • Mustard Compounds/metabolism
  • Phenylpropionates

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