Lab. of Endocrinology and Metabolism, Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, 13605, Republic of Korea; Lab. of Integrative Oncolomics, Department of Biomedical Science, University of Ulsan College of Medicine, Seoul, 05505, Republic of Korea.
Lab. of Endocrinology and Metabolism, Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, 13605, Republic of Korea; Department of Internal Medicine, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea.
Eur J Pharmacol. 2023 Oct 15;957:175946. doi: 10.1016/j.ejphar.2023.175946. Epub 2023 Aug 2.
Thiazolidinedione, an insulin sensitizer, has beneficial effects on glucose metabolism; however, there are concerns regarding weight gain and heart failure. Sodium-glucose co-transporter 2 (SGLT2) inhibitors can reduce body weight, increase diuresis, and play a protective role in heart failure. We examined the complementary effects of dapagliflozin, an SGLT2 inhibitor, and lobeglitazone, a thiazolidinedione, in high-fat diet (HFD)-induced obese mice. We treated HFD-induced obese mice with vehicle, dapagliflozin, lobeglitazone, and their combination for 12 weeks. Oral glucose tolerance and insulin tolerance tests were performed after 12-week treatment, and body composition was measured by dual-energy X-ray absorptiometry before and after treatment. We analyzed oxygen consumption rate (OCR) using 3T3-L1 cells after treatment of β-hydroxybutyrate and/or lobeglitazone. Treatment with a combination of dapagliflozin and lobeglitazone resulted in a significant decrease in postprandial hyperglycemia compared with dapagliflozin monotherapy, but not compared with lobeglitazone monotherapy. The addition of dapagliflozin to lobeglitazone treatment did not attenuate weight gain compared with lobeglitazone monotherapy in this study. However, this combination prevented the increase of organ weight of liver and heart, and OCR in 3T3-L1 cells was increased after treatment with a combination of β-hydroxybutyrate and lobeglitazone compared to lobeglitazone monotherapy. We confirmed the beneficial effect of lobeglitazone on glucose metabolism; however, we did not find any beneficial effect of dapagliflozin on body weight in HFD-induced obese mice. However, the protective effects of dapagliflozin and lobeglitazone combined therapy on the liver, heart, energy consumption, and β-cell senescence are worth investigating in clinical trials.
噻唑烷二酮类药物是一种胰岛素增敏剂，对葡萄糖代谢有有益作用；然而，人们对其导致体重增加和心力衰竭的风险存在担忧。钠-葡萄糖协同转运蛋白 2（SGLT2）抑制剂可以减轻体重、增加利尿作用，并在心力衰竭中发挥保护作用。我们研究了 SGLT2 抑制剂达格列净和噻唑烷二酮类药物罗格列酮在高脂肪饮食（HFD）诱导肥胖小鼠中的互补作用。我们用载体、达格列净、罗格列酮及其组合治疗 HFD 诱导肥胖的小鼠 12 周。在治疗 12 周后进行口服葡萄糖耐量和胰岛素耐量试验，并在治疗前后通过双能 X 射线吸收法测量身体成分。我们在治疗后用β-羟丁酸和/或罗格列酮处理 3T3-L1 细胞，分析耗氧量（OCR）。达格列净和罗格列酮联合治疗可显著降低餐后高血糖，与达格列净单药治疗相比，但与罗格列酮单药治疗相比无差异。与罗格列酮单药治疗相比，在本研究中，加用达格列净并未减轻罗格列酮治疗的体重增加。然而，这种联合治疗可防止肝脏和心脏器官重量的增加，并且与罗格列酮单药治疗相比，β-羟丁酸和罗格列酮联合治疗后 3T3-L1 细胞的 OCR 增加。我们证实了罗格列酮对葡萄糖代谢的有益作用；然而，我们并未发现达格列净对 HFD 诱导肥胖小鼠体重有任何有益作用。然而，达格列净和罗格列酮联合治疗对肝脏、心脏、能量消耗和β细胞衰老的保护作用值得在临床试验中进一步研究。
