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Open AccessArticle

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

Biomedical Research and Innovation Platform (BRIP), South African Medical Research Council, Tygerberg 7505, South Africa
Division of Medical Physiology, Faculty of Health Sciences, Stellenbosch University, Tygerberg, Cape Town 7505, South Africa
Department of Biotechnology, University of the Western Cape, Cape Town 7505, South Africa
Department of Biochemistry, Genetics and Microbiology (BGM), Division of Biochemistry, University of Pretoria, Hatfield 0028, South Africa
Department of Biochemistry and Microbiology, University of Zululand, Kwadlangezwa, Durban 3800, South Africa
Author to whom correspondence should be addressed.
Nutrients 2019, 11(12), 2850;
Received: 23 October 2019 / Revised: 8 November 2019 / Accepted: 11 November 2019 / Published: 21 November 2019
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. View Full-Text
Keywords: oxidative stress; diabetes; apoptosis; N-acetyl cysteine; metformin; cardiovascular oxidative stress; diabetes; apoptosis; N-acetyl cysteine; metformin; cardiovascular
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Johnson, R.; Sangweni, N.F.; Mabhida, S.E.; Dludla, P.V.; Mabasa, L.; Riedel, S.; Chapman, C.; Mosa, R.A.; Kappo, A.P.; Louw, J.; Muller, C.J.F. An In Vitro Study on the Combination Effect of Metformin and N-Acetyl Cysteine against Hyperglycaemia-Induced Cardiac Damage. Nutrients 2019, 11, 2850.

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