Targeting cardiac remodeling and sirtuin gene expression in type 1 diabetes mellitus: role of dapagliflozin

Introduction Inhibition of sodium-glucose co-transporter 2 (SGLT2) induces well established cardiovascular benefits in high-risk patients with Type 2 diabetes mellitus (DM). However, only a few studies have evaluated the cardiovascular effects of SGLT2 inhibition in individuals with Type 1 DM. The mechanisms involved in beneficial effects have not yet been fully clarified. Studies suggest that SGLT2 inhibitors interact with sirtuins, proteins that modulate cellular survival and apoptosis, autophagy, mitochondrial function, and stress response. Objective To analyze the effects of the SGLT2 inhibitor dapagliflozin (Dapa) on cardiac structure, left ventricular function, and myocardial gene expression of sirtuins 1, 3, 5, 6 e 7 in rats with streptozotocin-induced DM. Methods Male Wistar rats were assigned into control (C), C treated with Dapa (C-Dapa), DM, and DM treated with Dapa (DM-Dapa) groups. DM was induced by a single streptozotocin injection, 50 mg/kg. Dapa was added to rat chow at a dosage of 10 mg/kg/day for 16 weeks. Cardiac remodeling was evaluated by echocardiogram at the end of the study and gene expression by RT-qPCR. Statistical analysis: ANOVA complemented by Tukey or Kruskal–Wallis and Dunn tests (p<0.05). Results Final body weight was lower in DM and DM-Dapa than their controls and higher in DM-Dapa than DM. Glycemia and echocardiogram data are shown in the Table. Gene expressions of sirtuins 1 and 5 were lower in DM than C and gene expressions of sirtuins 3, 6 and 7 did not differ between groups. Conclusion Long-term dapagliflozin attenuates body weight loss, hyperglycemia, left cardiac chambers dilation, left ventricular hypertrophy, and systolic and diastolic dysfunction in rats with Type 1 diabetes mellitus. Gene expression of sirtuins 1 and 5 is also modulated by dapagliflozin.