Hazem Reem M, Ibrahim Ahmed Z, Ali Dina A, Moustafa Yasser M
Department of Pharmacology & Toxicology, Faculty of Pharmacy, Suez Canal University, Ismailia 41522, Egypt.
Department of clinical Pharmacology, Faculty of Medicine, Suez Canal University, Ismailia 41522, Egypt.
Int Immunopharmacol. 2022 Mar;104:108503. doi: 10.1016/j.intimp.2021.108503. Epub 2022 Jan 5.
Type-2 diabetes mellitus and NAFLD are considered as one of the greatest worldwide metabolic disorders with growing incidence. It was found that patients with T2DM have two-fold increase to develop NAFLD. Evidence that some antidiabetic agents improve NAFLD/NASH in patients with T2DM is evolving. However, there are no certain pharmacologic therapies. The current study aimed to investigate the underlying mechanisms for the hepatoprotective effect of dapagliflozin against steatohepatitis in diabetic rats. Type-2 diabetes was induced by HFD followed by a single dose of STZ (30 mg/kg I.P). Fifty rats were randomly divided into 5 groups: Group1; normal control, Group 2; diabetic control, Groups (3-5); diabetic rats received daily dapagliflozin (0.75, 1.5, 3 mg/kg, p.o.) respectively for 6 weeks. At the end of the experiment, blood glucose level and serum insulin were measured. Hepatic tissue homogenization was performed for measuring inflammatory and oxidative stress markers. In addition, histopathological investigation of the hepatic tissue was done. Diabetic rats exhibited remarkable increase in liver weight and liver enzymes, along with histopathological changes, significant elevation in MDA, IL-1 β, TGFβ levels and, NF-κB, alpha-SMA expressions. Dapagliflozin treatment decreased liver weight, liver enzymes, together with marked improvement in histopathological changes. Furthermore, dapagliflozin increased antioxidant enzymes, GSH levels. Interestingly, Dapagliflozin reduced IL-1 β, TGFβ levels and, NF-κB, alpha-SMA expressions. Present data show that dapagliflozin represent a viable approach to protect the liver against diabetes-encouraged steatohepatitis through inhibiting oxidative stress, inflammation and fibrosis progression thus conserving liver function.
2型糖尿病和非酒精性脂肪性肝病被认为是全球发病率不断上升的最严重的代谢紊乱疾病之一。研究发现，2型糖尿病患者发生非酒精性脂肪性肝病的几率增加了两倍。有证据表明，一些抗糖尿病药物可改善2型糖尿病患者的非酒精性脂肪性肝病/非酒精性脂肪性肝炎，相关证据也在不断增加。然而，目前尚无确切的药物治疗方法。本研究旨在探讨达格列净对糖尿病大鼠脂肪性肝炎肝保护作用的潜在机制。通过高脂饮食诱导2型糖尿病，随后单次腹腔注射链脲佐菌素（30 mg/kg）。将50只大鼠随机分为5组：第1组为正常对照组；第2组为糖尿病对照组；第3至5组为糖尿病大鼠，分别每日口服达格列净（0.75、1.5、3 mg/kg），持续6周。实验结束时，测量血糖水平和血清胰岛素。进行肝组织匀浆以测量炎症和氧化应激标志物。此外，还对肝组织进行了组织病理学检查。糖尿病大鼠的肝脏重量和肝酶显著增加，伴有组织病理学变化，丙二醛、白细胞介素-1β、转化生长因子β水平以及核因子κB、α-平滑肌肌动蛋白表达显著升高。达格列净治疗可降低肝脏重量和肝酶，同时组织病理学变化显著改善。此外，达格列净可增加抗氧化酶和谷胱甘肽水平。有趣的是，达格列净可降低白细胞介素-1β、转化生长因子β水平以及核因子κB、α-平滑肌肌动蛋白表达。目前的数据表明，达格列净是一种可行的方法，可通过抑制氧化应激、炎症和纤维化进展来保护肝脏免受糖尿病诱发的脂肪性肝炎的侵害，从而保护肝功能。
