2型糖尿病(T2DM)是一种快速增长的流行病,导致发病率增加,死亡率,和飙升的医疗费用。前列腺素E2(PGE2),一个重要的脂质介质,据报道可以预防肝脏脂肪变性,炎症,内质网(ER)应激,和胰岛素抵抗,表明其在T2DM中的潜在治疗作用。PGE2可被15-羟基前列腺素脱氢酶(15-PGDH)降解。SW033291,15-PGDH的抑制剂,据报道,PGE2水平升高,然而,SW033291在T2DM中的作用还有待探索。本研究旨在评估SW033291是否对T2DM具有保护作用,并探讨其潜在机制。通过高脂饮食/链脲佐菌素注射建立T2DM小鼠模型,而棕榈酸处理的小鼠原代肝细胞被用作胰岛素抵抗细胞模型。SW033291治疗减轻体重,脂肪重量,空腹血糖,改善T2DM小鼠糖耐量受损和胰岛素抵抗。更重要的是,SW033291减轻脂肪变性,炎症,T2DM小鼠肝脏内质网应激。机械上,SW033291降低了T2DM小鼠SREBP-1c和ACC1的表达,增加了PPARα的表达。此外,SW033291抑制T2DM小鼠NF-κB和eIF2α/CHOP信号传导。Further,我们表明,SW033291对上述病理生理过程的保护作用可以通过抑制PGE2受体EP4而受到阻碍。总的来说,我们的研究揭示了SW033291在缓解T2DM方面的新作用,并提示其作为T2DM新治疗策略的潜力.
Type 2 diabetes mellitus (T2DM) is a rapidly growing epidemic that results in increased morbidity, mortality, and soaring medical costs. Prostaglandin E2 (PGE2), a vital lipid mediator, has been reported to protect against hepatic steatosis, inflammation, endoplasmic reticulum (ER) stress, and insulin resistance, indicating its potential therapeutic role in T2DM. PGE2 can be degraded by 15-hydroxyprostaglandin dehydrogenase (15-PGDH). SW033291, an inhibitor of 15-PGDH, has been reported to increase PGE2 levels, however, the effect of SW033291 in T2DM remains to be explored. This study aims to evaluate whether SW033291 protects against T2DM and explore its potential mechanisms. A T2DM mouse model was established through high-fat diet/streptozotocin injection, while palmitic acid-treated mouse primary hepatocytes were used as insulin-resistant cell models. SW033291 treatment reduced body weight, fat weight, fasting blood glucose, and improved impaired glucose tolerance and insulin resistance in T2DM mice. More importantly, SW033291 alleviated steatosis, inflammation, and ER stress in the liver of T2DM mice. Mechanistically, SW033291 decreased the expressions of SREBP-1c and ACC1, and increased the expression of PPARα in T2DM mice. Additionally, SW033291 inhibited NF-κB and eIF2α/CHOP signaling in T2DM mice. Further, we showed that the protective effects of SW033291 on the above-mentioned pathophysiological processes could be hindered by inhibition of the PGE2 receptor EP4. Overall, our study reveals a novel role of SW033291 in alleviating T2DM and suggests its potential as a new therapeutic strategy for T2DM.