The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, SE-171 76 Stockholm, Sweden.
Department of Physiology and Pharmacology, Molecular and Cellular Exercise Physiology, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
Sci Transl Med. 2022 Mar 30;14(638):eaba9112. doi: 10.1126/scitranslmed.aba9112.
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.
在 2 型糖尿病进展过程中，胰岛β细胞会受到持续的代谢超负荷的影响。我们假设这种状态介导了由缺氧诱导因子-1α（HIF-1α）驱动的缺氧表型，并且 HIF-1α 抑制剂 PX-478 的治疗可以改善β细胞功能。我们的研究表明，HIF-1α 蛋白存在于糖尿病小鼠模型的胰岛β细胞中。在高葡萄糖代谢的小鼠胰岛中，用 HIF-1α 抑制剂 PX-478 处理可抑制细胞内 Ca 振荡在低糖浓度下的出现和胰岛素的异常高基础释放，表明β细胞功能得到改善。用 PX-478 治疗 db/db 小鼠可通过维持升高的血浆胰岛素浓度来防止血糖升高和糖尿病进展。在链脲佐菌素诱导的糖尿病小鼠中，PX-478 改善了葡萄糖稳态的恢复。从这些小鼠中分离出的胰岛表现出改善的β细胞功能的特征，包括胰岛素含量升高、参与β细胞功能和成熟的基因表达增加、分化标志物抑制和成熟胰岛素颗粒的形成。对长期暴露于高葡萄糖的人胰岛类器官进行 PX-478 处理后，葡萄糖诱导的胰岛素分泌刺激指数得到改善。这些结果表明，HIF-1α 抑制剂 PX-478 有可能作为一种抗糖尿病治疗药物，在代谢超负荷下保留β细胞功能。
