Comparative Study of the Effects of GLP1 Analog and SGLT2 Inhibitor against Diabetic Cardiomyopathy in Type 2 Diabetic Rats: Possible Underlying Mechanisms

Abstract

The present study investigated the possible cardioprotective effects of GLP1 and SGLT2i against diabetic cardiomyopathy (DCM) in type 2 diabetic rats and the possible underlying mechanisms. Methods: Thirty-two male Sprague Dawley rats were randomly subdivided into 4 equal groups: (a) control group, (b) DM group, type 2 diabetic rats with saline daily for 4 weeks, (c) DM + GLP1, as DM group with GLP1 analogue (liraglutide) at a dose of 75 µg/kg for 4 weeks, and (d) DM + SGLT2i as DM group with SGLT2 inhibitor (dapagliflozin) at a dose of 1 mg/kg for 4 weeks. By the end of treatment (4 weeks), serum blood glucose, homeostasis model assessment insulin resistance (HOMA-IR), insulin, and cardiac enzymes (LDH, CK-MB) were measured. Also, the cardiac histopathology, myocardial oxidative stress markers (malondialdehyde (MDA), glutathione (GSH) and CAT) and norepinephrine (NE), myocardial fibrosis, the expression of caspase-3, TGF-β, TNF-α, and tyrosine hydroxylase (TH) in myocardial tissues were measured. Results: T2DM caused significant increase in serum glucose, HOMA-IR, serum CK-MB, and LDH (p < 0.05). Also, DM caused significant myocardial damage and fibrosis; elevation of myocardial MDA; NE with upregulation of myocardial caspase-3, TNF-α, TGF-β, and TH; and significant decrease in serum insulin and myocardial GSH and CAT (p < 0.05). Administration of either GLP1 analog or SGLT2i caused a significant improvement in all studied parameters (p < 0.05). Conclusion: We concluded that both GLP1 and SGLT2i exhibited cardioprotective effects against DCM in T2DM, with the upper hand for SGLT2i. This might be due to attenuation of fibrosis, oxidative stress, apoptosis (caspase-3), sympathetic nerve activity, and inflammatory cytokines (TNF-α and TGF-β).

Dapagliflozin activates AMPK to attenuate cardiac dysfunction and oxidative stress under hypoxia/reoxygenation-caused damage

“…Data from echocardiography revealed that DAPA administration improved the measurement of LV function (such as EF and FS) affected by I/R injury, and this was in line with a recent study revealing the positive effect of DAPA on the enhancement of LV function of Type II DM patients with stable heart failure [9]. Moreover, we showed that treatment of DAPA attenuated the rise in the levels of two AMI-associated enzymes (CK-MB and LDH) in response to I/R injury, which was in conformity with a study showing SGLT2 inhibitor exhibited cardioprotective effects and downregulated the serum CK-MB and LDH in DM rats [42]. Taken together, DAPA may have protective effect of cardiac function in the setting of AMI.…”

<p>SGLT2 Inhibitors: A Novel Player in the Treatment and Prevention of Diabetic Cardiomyopathy</p>

“…Several studies have demonstrated that SGLT2Is lessened cardiac macrophage infiltration and decreased inflammatory cytokines (TNFα and TGFβ) in diabetic mice. 93,96,105 Insulin resistance and hyperglycemia can activate a molecular marker, NLRP3, in DCM, leading to activation of procaspase 1, IL1β, and IL18. 106 A study proved that dapagliflozin attenuated NLRP3, ASC, IL1β, IL6, and caspase 1, as well as TNFα mRNA levels, markedly through the activation of AMPK in hearts of diabetic mice.…”

“…133 Dapagliflozin decreases tyrosinehydroxylase density and myocardial norepinephrine content, contributing to attenuation of myocardial damage and fibrosis, indicating that improved sympathetic nerve activity is a potential mechanism for the cardiac protection of SGLT2Is in DCM. 105 Chronic activation of the hexosamine biosynthetic pathway and subsequent excessive O-GlcNAcylation is associated with DM and affects heart function in hyperglycemia. O-GlcNAcylation impairs cardiac Ca 2+ homeostasis, mitochondrial function, and ERS by modulating key protein targets, such as phospholamban, calmodulin kinase II, and FOXO1, in the diabetic heart.…”

The Impact of Antidiabetic Therapies on Diastolic Dysfunction and Diabetic Cardiomyopathy

“…• Decreased oxidative stress and cardiac myocyte apoptosis Hussein et al, 2020 Exenatide (24 nmol/kg once daily IP)…”

“…The systolic and diastolic dysfunction were much more severe in the latter study, likely due to increased islet β-cell death and worsened T2DM with higher doses of STZ utilized (treatment for 5 days vs. 1 day). In male Sprague-Dawley rats subjected to T2DM via HFD supplementation for 8-weeks with STZ (35 mg/kg) administered at the 4-week time point, treatment with liraglutide (75 μg once daily) for the final 4-weeks increased both myocardial catalase activity and reduced glutathione levels, while decreasing caspase 3 expression (Hussein et al, 2020 ). This suggests that GLP-1R agonism attenuates T2DM-related increases in myocardial oxidative stress and cardiac myocyte apoptosis, respectively, key mediators of diabetic cardiomyopathy, though diastolic function was not assessed in this particular study.…”