内科学
内分泌学
胰岛素
糖尿病
胰岛
小岛
链脲佐菌素
胰岛素振荡
葡萄糖稳态
平衡
胰腺
生物
碳水化合物代谢
化学
医学
胰岛素抵抗
作者
Erwin Ilegems,Galyna Bryzgalova,Jorge C. Correia,Burçak Yesildag,Edurne Berra,Jorge L. Ruas,Teresa Pereira,Per Olof Berggren
出处
期刊:Science Translational Medicine
[American Association for the Advancement of Science (AAAS)]
日期:2022-03-30
卷期号:14 (638)
被引量:11
标识
DOI:10.1126/scitranslmed.aba9112
摘要
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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