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Published March 30, 2022 | Version v1
Journal article Open

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

  • 1. The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, SE-171 76 Stockholm, Sweden
  • 2. Department of Physiology and Pharmacology, Molecular and Cellular Exercise Physiology, Karolinska Institutet, SE-171 77 Stockholm, Sweden
  • 3. InSphero AG, Wagistrasse 27a, 8952 Schlieren, Switzerland
  • 4. CIC bioGUNE, Derio, Spain

Description

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 Ca2+ 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.

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2022 Ilegems Sci Transl Med.pdf

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Additional details

Funding

EYELETS – A regenerative medicine approach in diabetes. 834860
European Commission