| Autor: |
Ilegems, Erwin, Bryzgalova, Galyna, Correia, Jorge, Yesildag, Burcak, Berra, Edurne, Ruas, Jorge L., Pereira, Teresa S., Berggren, Per-Olof |
| Předmět: |
|
| Zdroj: |
Science Translational Medicine; 3/30/2022, Vol. 14 Issue 638, p1-17, 17p |
| Abstrakt: |
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. Inhibiting HIF-1α improves glucose homeostasis: Type 2 diabetes (T2D) places insulin-secreting beta cells under sustained metabolic stress. Ilegems et al. reasoned that such stress might result in a hypoxic state and thereby impair β cell function. The authors confirmed a glucose metabolism–mediated increase in hypoxia in multiple mouse models with metabolic dysfunction and showed that a HIF-1α inhibitor improved β cell function in db/db and streptozotocin-induced mouse models of diabetes. Human islet organoids cultured under high-glucose conditions also showed improved β cell function in response to HIF-1α inhibitor treatment, suggesting that these findings may translate to humans. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
|
