Double-edged sword of L-arginine in diabetes: Exploring anti-inflammatory and antioxidant strategies

Abstract

The article by Mansouri et al provides a comprehensive investigation into the effects of L-arginine (L-Arg) on diabetic cardiomyopathy. The authors conclude that while a low dose (0.5 g/kg) of L-Arg improves lipid profiles and reduces body weight, higher doses (≥ 1 g/kg) exacerbate oxidative stress, inflammation, and myocardial damage. In this letter, we aim to expand on the potential role of anti-inflammatory and antioxidant strategies in mitigating these adverse effects. Specifically, we focus on nuclear factor erythroid 2-related factor 2 activation and nitric oxide synthase modulation. These strategies could enhance the clinical utility of L-Arg by preserving its metabolic benefits while reducing its cardiotoxic risks. We believe this perspective will stimulate future research on L-Arg-based therapies in patients with diabetes, with an emphasis on optimizing dosage and exploring synergistic co-therapies.

Key Words: L-arginine; Diabetic cardiomyopathy; Oxidative stress; Nuclear factor erythroid 2-related factor 2; Nitric oxide synthase

Core Tip: L-arginine (L-Arg) exhibits dose-dependent effects in diabetic cardiomyopathy, with low doses improving lipid profiles and high doses exacerbating oxidative stress and inflammation. This letter emphasizes the need for targeted interventions, such as nuclear factor erythroid 2-related factor 2 activation, nitric oxide synthase modulation, and combination therapies, to mitigate these adverse effects and enhance L-Arg’s clinical safety, offering safer therapeutic options for diabetic patients at risk of cardiovascular complications.

TO THE EDITOR

We read with great interest the recent article by Mansouri et al[1] on the effects of L-arginine (L-Arg) in diabetic cardiomyopathy, which elucidates its dose-dependent dual effects. The study demonstrates that low doses (0.5 g/kg) improve lipid profiles and reduce body weight, highlighting metabolic benefits, whereas higher doses (≥ 1 g/kg) exacerbate myocardial injury through proinflammatory and prooxidant pathways. This dose-dependent response underscores L-Arg's therapeutic potential while raising concerns about its safety at higher doses. Although the authors thoroughly discuss the mechanisms of oxidative stress and inflammation triggered by high-dose L-Arg, they insufficiently address the role of anti-inflammatory and antioxidant strategies to counteract these adverse effects. Expanding on these approaches is critical for optimizing L-Arg’s clinical applications, particularly in the context of diabetes-related cardiovascular complications.

Current gaps and challenges

The study by Mansouri et al[1] demonstrates that high doses of L-Arg exacerbate oxidative stress and inflammation in diabetic rats, primarily through elevated nitric oxide (NO) production and inducible NO synthase (NOS) activation. This process leads to the formation of peroxynitrite and other reactive nitrogen species (RNS), resulting in significant myocardial damage. While these findings underscore the risks of high-dose L-Arg, the study does not address several critical questions. Notably, the therapeutic potential of enhancing antioxidant defense mechanisms, particularly through the activation of the nuclear factor erythroid 2-related factor 2 (Nrf-2) pathway, remains unexplored. Nrf-2 plays a crucial role in regulating antioxidant enzymes, such as superoxide dismutase (SOD)[2], catalase (CAT)[3], and glutathione peroxidase[4], which are vital for countering oxidative damage.

Additionally, while the study mentions reduced antioxidant enzyme activity, it does not discuss interventions aimed at restoring or enhancing this defense system. Furthermore, the potential for combining L-Arg with antioxidant and anti-inflammatory agents to mitigate its adverse effects remains unexamined. Addressing these gaps could facilitate the development of safer and more effective L-Arg supplementation strategies, particularly for diabetic populations with elevated cardiovascular risk. These efforts would also emphasize the importance of integrated therapeutic approaches.

Proposed anti-inflammatory and antioxidant strategies

Nrf-2 activation: Nrf-2 is a critical regulator of cellular antioxidant responses, controlling the expression of genes involved in detoxifying reactive oxygen species. Activation of Nrf-2 has been shown to enhance the expression of antioxidant enzymes, such as SOD and CAT, which could counteract the oxidative damage induced by high-dose L-Arg. Clinically, Nrf-2 activators such as sulforaphane and resveratrol have shown promise in reducing oxidative stress and inflammation in chronic diseases, including diabetes and cardiovascular diseases[5-7]. Clinical trials have demonstrated their potential in mitigating disease progression, and combining these agents with L-Arg supplementation may offer a synergistic approach to protect against myocardial injury in diabetic patients.

NOS modulation: Balancing NO production is essential to mitigate L-Arg-induced cardiotoxicity. Co-administration of NOS inhibitors, particularly selective inducible NOS (iNOS) inhibitors, could reduce excessive NO production and subsequent RNS formation. This strategy may preserve the beneficial vasodilatory effects of NO produced by endothelial NOS while minimizing inflammation and tissue damage associated with iNOS overactivation[8,9]. However, prolonged or excessive inhibition of NO synthesis may pose risks. NO is essential for vascular function, immune response regulation, and neurotransmission. Overuse of NOS inhibitors may impair these functions, potentially exacerbating cardiovascular diseases or immune dysregulation. Therefore, careful dosing and monitoring are crucial when combining NOS inhibitors with L-Arg therapy to ensure safety and maximize therapeutic benefits.

Combined antioxidant and anti-inflammatory co-therapies: Combining L-Arg with antioxidants (e.g., vitamins C and E, N-acetylcysteine)[10,11] and anti-inflammatory agents (e.g., statins or omega-3 fatty acids)[12] could offer a dual protective mechanism. This approach may reduce oxidative stress and inflammation while enhancing the metabolic benefits of L-Arg, such as improvements in lipid profiles and reductions in body weight.

Clinical implications and future directions

Given the widespread use of L-Arg supplements, particularly among diabetic patients and athletes, understanding its safety profile is crucial. Future research should prioritize the following areas.

Dose optimization: Investigate a broader range of doses between 0.5 g/kg and 1 g/kg to identify the maximum therapeutic dose with minimal side effects.

Co-therapy validation: Conduct preclinical and clinical trials to evaluate the efficacy of combining L-Arg with Nrf-2 activators or NOS inhibitors in reducing myocardial injury, and attention should be paid to the adverse effects of Nrf-2 activators or NOS inhibitors.

Mechanistic studies: Examine the precise molecular mechanisms by which L-Arg induces oxidative stress and inflammation, with a particular focus on its effects on pancreatic β-cells and insulin secretion.

Clinical trials: Conduct human trials to confirm the safety and efficacy of these combination therapies for managing diabetes-related cardiovascular complications.

Conclusion

Mansouri et al[1] have provided valuable insights into L-Arg’s dual effects in diabetic cardiomyopathy. Incorporating anti-inflammatory and antioxidant strategies could enhance its therapeutic potential while minimizing adverse effects. These combined approaches may redefine L-Arg’s role in diabetes management, offering safer and more effective solutions for preventing cardiovascular complications.