Rosa Camila Moreno, Campos Dijon Henrique Salome, Reyes David Rafael Abreu, Damatto Felipe Cesar, Kurosaki Lucas Yamada, Pagan Luana Urbano, Gomes Mariana Janini, Corrêa Camila Renata, Fernandes Ana Angelica Henrique, Okoshi Marina Politi, Okoshi Katashi
Department of Internal Medicine, Botucatu Medical School, Sao Paulo State University, UNESP, Botucatu 18618-687, SP, Brazil.
Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Antioxidants (Basel). 2022 May 17;11(5):982. doi: 10.3390/antiox11050982.
Clinical trials have shown that sodium glucose co-transporter 2 (SGLT2) inhibitors improve clinical outcomes in diabetes mellitus (DM) patients. As most studies were performed in Type 2 DM, the cardiovascular effects of SGLT2 inhibition still require clarification in Type 1 DM. We analyzed the effects of SGLT2 inhibitor dapagliflozin on cardiac remodeling in rats with streptozotocin-induced diabetes, an experimental model of Type 1 DM. Methods: Male Wistar rats were assigned into four groups: control (C, n = 14); control treated with dapagliflozin (C + DAPA, n = 14); diabetes (DM, n = 20); and diabetes treated with dapagliflozin (DM + DAPA, n = 20) for 8 weeks. Dapagliflozin dosage was 5 mg/kg/day. Statistical analyses: ANOVA and Tukey or Kruskal−Wallis and Dunn. Results: DM + DAPA presented decreased blood pressure and glycemia and increased body weight compared to DM (C 507 ± 52; C + DAPA 474 ± 50; DM 381 ± 52 *; DM + DAPA 430 ± 48 # g; * p < 0.05 vs. C; # p < 0.05 vs. C + DAPA and DM + DAPA). DM echocardiogram presented left ventricular and left atrium dilation with impaired systolic and diastolic function. Cardiac changes were attenuated by dapagliflozin. Myocardial hydroxyproline concentration and interstitial collagen fraction did not differ between groups. The expression of Type III collagen was lower in DM and DM + DAPA than their controls. Type I collagen expression and Type I-to-III collagen ratio were lower in DM + DAPA than C + DAPA. DM + DAPA had lower lipid hydroperoxide concentration (C 275 ± 42; C + DAPA 299 ± 50; DM 385 ± 54 *; DM + DAPA 304 ± 40 # nmol/g tissue; * p < 0.05 vs. C; # p < 0.05 vs. DM) and higher superoxide dismutase and glutathione peroxidase activity than DM. Advanced glycation end products did not differ between groups. Conclusion: Dapagliflozin is safe, increases body weight, decreases glycemia and oxidative stress, and attenuates cardiac remodeling in an experimental rat model of Type 1 diabetes mellitus.
临床试验表明，钠-葡萄糖协同转运蛋白2（SGLT2）抑制剂可改善糖尿病（DM）患者的临床结局。由于大多数研究是在2型糖尿病患者中进行的，SGLT2抑制对心血管的影响在1型糖尿病中仍有待阐明。我们分析了SGLT2抑制剂达格列净对链脲佐菌素诱导的糖尿病大鼠心脏重塑的影响，链脲佐菌素诱导的糖尿病大鼠是1型糖尿病的实验模型。方法：将雄性Wistar大鼠分为四组：对照组（C，n = 14）；接受达格列净治疗的对照组（C + DAPA，n = 14）；糖尿病组（DM，n = 20）；以及接受达格列净治疗的糖尿病组（DM + DAPA，n = 20），为期8周。达格列净剂量为5 mg/kg/天。统计分析：方差分析和Tukey检验或Kruskal-Wallis检验和Dunn检验。结果：与糖尿病组相比，DM + DAPA组血压和血糖降低，体重增加（C组507±52；C + DAPA组474±50；DM组381±52*；DM + DAPA组430±48# g；与C组相比p < 0.05；#与C + DAPA组和DM + DAPA组相比p < 0.05）。糖尿病组超声心动图显示左心室和左心房扩张，收缩和舒张功能受损。达格列净可减轻心脏变化。各组间心肌羟脯氨酸浓度和间质胶原分数无差异。DM组和DM + DAPA组III型胶原的表达低于其对照组。DM + DAPA组I型胶原表达和I型与III型胶原比值低于C + DAPA组。DM + DAPA组脂质过氧化产物浓度较低（C组275±42；C + DAPA组299±50；DM组385±54；DM + DAPA组304±40# nmol/g组织；*与C组相比p < 0.05；#与DM组相比p < 0.05），超氧化物歧化酶和谷胱甘肽过氧化物酶活性高于糖尿病组。各组间晚期糖基化终产物无差异。结论：在1型糖尿病实验大鼠模型中，达格列净安全，可增加体重，降低血糖和氧化应激，并减轻心脏重塑。
