An In Vitro Study on the Combination Effect of Metformin and N-Acetyl Cysteine against Hyperglycaemia-Induced Cardiac Damage

Abstract

Chronic hyperglycaemia is a major risk factor for diabetes-induced cardiovascular dysfunction. In a hyperglycaemic state, excess production of reactive oxygen species (ROS), coupled with decreased levels of glutathione, contribute to increased lipid peroxidation and subsequent myocardial apoptosis. N-acetylcysteine (NAC) is a thiol-containing antioxidant known to protect against hyperglycaemic-induced oxidative stress by promoting the production of glutathione. While the role of NAC against oxidative stress-related cardiac dysfunction has been documented, to date data is lacking on its beneficial effect when used with glucose lowering therapies, such as metformin (MET). Thus, the aim of the study was to better understand the cardioprotective effect of NAC plus MET against hyperglycaemia-induced cardiac damage in an H9c2 cardiomyoblast model. H9c2 cardiomyoblasts were exposed to chronic high glucose concentrations for 24 h. Thereafter, cells were treated with MET, NAC or a combination of MET and NAC for an additional 24 h. The combination treatment mitigated high glucose-induced oxidative stress by improving metabolic activity i.e. ATP activity, glucose uptake (GU) and reducing lipid accumulation. The combination treatment was as effective as MET in diminishing oxidative stress, lipid peroxidation and apoptosis. We observed that the combination treatment prevented hyperglycaemic-induced cardiac damage by increasing GLUT4 expression and mitigating lipid accumulation via phosphorylation of both AMPK and AKT, while decreasing nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB), as well as protein kinase C (PKC), a known activator of insulin receptor substrate-1 (IRS-1), via phosphorylation at Ser307. On this basis, the current results support the notion that the combination of NAC and MET can shield the diabetic heart against impaired glucose utilization and therefore its long-term protective effect warrants further investigation.

Antioxidants Supplementation Reduces Ceramide Synthesis Improving the Cardiac Insulin Transduction Pathway in a Rodent Model of Obesity

“…The precise mechanism of the NAC action is still unclear, but it is known that the development of inflammation during obesity induced by an HFD is associated with increased oxidative stress, which also worsens insulin signaling and accelerates myocardial damage. Thus, in our research, NAC probably resulted in reduced ROS generation that interfere with cellular processes, i.e., the degradation of membrane lipids (lipid peroxidation) and thereby increasing the metabolic activity of the tissue and reducing cellular apoptosis [36,37]. Similarly, we also observed that ALA reversed HFD-induced insulin resistance.…”

“…Rodrigues et al, in their study on obese mice, showed that NAC raised the protein level of phosphorylated Akt in the cardiac tissue, and thus the pAkt level was restored to values close to that of the control mice [36]. A study conducted by Johnson et al revealed that cardiomyocytes exposed to a high-glucose concentration with n-acetylcysteine showed improved glucose utilization caused by enhanced GLUT4 redistribution to the membrane allowing regulation and maintained proper glucose homeostasis [37]. In our study, we demonstrated that the dietinduced decrease in the heart pAkt(Ser473)/Akt ratio was completely reestablished.…”

“…Several studies conducted on animal models demonstrated that metabolites of fatty acids interfere in decreasing insulin transduction at multiple levels, especially the decline in phosphorylation of Akt as a consequence of the development of obesity in heart tissue in rodents [35][36][37]. In our study, we evaluated the Akt pathway as a pivotal marker of insulin signaling, which is regulated by not only insulin but also nutrition and redox status.…”

Metformin protects against diabetes-induced heart injury and dunning prostate cancer model

“…15 Recent studies suggest that chronic hyperglycaemia is associated with ROS-induced oxidative stress, which in turn plays a crucial role in the development and progression of impaired cardiac function. 16 –18 In a population-based study, cancer patients were found to have a higher risk of dying from cardiovascular disease and the risk is negatively related to the diagnosis at an early stage. 19…”

Hypoglycemic effect of Taraxacum officinale root extract and its synergism with Radix Astragali extract

“…Currently, researchers have begun to concern about drug combination treatment in diabetes (Johnson et al., 2019; Li & Zhang, 2016; Schlosser, 2019). Studies have shown that the components and contents of the biologically active compounds will change after combination, and the interactions between these compounds may make better therapeutic effects, with fewer side effects due to the decrease in dose of each drug (Cui et al., 2019).…”