TO THE EDITOR
This letter to the editor is related to the study titled “L-arginine administration exacerbates myocardial injury in diabetics via prooxidant and proinflammatory mechanisms along with myocardial structural disruption” by Mansouri et al[1], which investigated the effects of L-arginine (L-Arg) supplementation on cardiac health in diabetic rats. Prior studies have predominantly focused on L-Arg’s vasodilatory and insulin-sensitizing benefits in diabetes[2], often overlooking its dose-dependent cardiotoxicity. For instance, Forzano et al[3] highlighted L-Arg’s role in improving endothelial function but did not explore its long-term cardiac risks in diabetic models. Mansouri et al[1] bridge this gap by demonstrating that hyperglycemia amplifies L-Arg’s proinflammatory effects, a phenomenon not observed in non-diabetic cohorts. They uniquely identify a dose threshold beyond which L-Arg exacerbates diabetic cardiomyopathy. The integration of histopathological, biochemical, and molecular analyses (e.g., alpha-smooth muscle actin, desmin disruption) provides unprecedented evidence of structural cardiac damage linked to high-dose L-Arg. This aligns with emerging research on metabolic reprogramming in diabetic cardiomyopathy, where excess nitric oxide (NO) disrupts mitochondrial bioenergetics[4]. Furthermore, the study’s emphasis on nuclear factor E2-related factor (Nrf-2) depletion connects to broader oxidative stress mechanisms in aging and cardiovascular diseases, suggesting shared pathways across metabolic and neurodegenerative disorder[5]. The study by Mansouri et al[1] is a significant contribution to the diabetic community, as it highlights the potential risks of high doses of L-Arg in diabetic individuals, particularly related to myocardial injury, cautioning against the indiscriminate use of L-Arg in diabetic patients.
The study’s methodological rigor and the detailed analysis of oxidative stress and inflammatory markers provide valuable insights into the mechanisms by which L-Arg may exacerbate cardiac damage in diabetic rats. The findings suggest that while low doses of L-Arg (0.5 g/kg) may offer some benefits, such as improved lipid profiles and reduced body weight. On the contrary, higher doses at 1 g/kg and 1.5 g/kg significantly increase oxidative stress, inflammation, and myocardial injury. These results are particularly concerning given the widespread use of L-Arg as a dietary supplement, especially among athletes and individuals with metabolic disorders[3,6].
CLARIFICATION OF MECHANISMS INVOLVING NRF-2 AND INDUCIBLE NO SYNTHASE
The study by Mansouri et al[1] demonstrates that high-dose L-Arg exacerbates oxidative stress via Nrf-2 depletion and inducible NO synthase (iNOS) upregulation. Nrf-2 is a critical regulator of antioxidant defense, binding to antioxidant response elements to activate genes encoding superoxide dismutase (SOD), catalase, and glutathione peroxidase. In diabetic cardiomyopathy, chronic oxidative stress disrupts Nrf-2/Keap1 dissociation, impairing cellular detoxification. Concurrently, L-Arg supplementation in diabetics amplifies iNOS expression, leading to excessive NO production. Elevated NO reacts with superoxide to form peroxynitrite, a potent oxidant that further depletes Nrf-2 and exacerbates mitochondrial dysfunction. This vicious cycle of Nrf-2 suppression and iNOS-driven oxidative stress highlights a key mechanism by which high-dose L-Arg worsens myocardial injury, suggesting that targeting these pathways could mitigate harm in diabetic patients. Although these mechanisms align with prior findings that hyperglycemia-induced iNOS upregulation disrupts redox balance, while Nrf-2 depletion exacerbates oxidative injury in diabetic cardiomyopathy[7], the study’s focus on short-term rodent models limits insights into chronic L-Arg effects in humans. Additionally, the molecular pathways linking L-Arg to Nrf-2 suppression (e.g., Keap1-mediated degradation) and iNOS hyperactivation remain incompletely defined. Future studies should investigate whether combining L-Arg with Nrf-2 activators (e.g., sulforaphane) or iNOS inhibitors could mitigate these effects, offering therapeutic synergies to optimize L-Arg’s safety in diabetic patients.
The study by Mansouri et al[1] focuses on a rodent model and its retrospective design. While rodent models provide valuable insights, key physiological differences between species must be acknowledged. Humans exhibit slower L-Arg clearance rates and distinct arginase activity compared to rodents, which may alter oxidative stress responses[8,9]. Additionally, human diabetic cardiomyopathy often involves comorbidities (e.g., hypertension, atherosclerosis) absent in rodent models, potentially modulating L-Arg’s effects[10]. Furthermore, the retrospective design did not account for potential confounding factors such as gut microbiota-derived arginine metabolism, which influences systemic NO levels. Therefore, translational research to validate dose-response relationships and establish safe thresholds in human subjects; large-scale, multicenter prospective studies are needed to validate these findings and to explore the potential risks and benefits of L-Arg supplementation in diabetic patients. Additionally, it would be beneficial to investigate whether the observed effects of L-Arg are consistent across different types of diabetes and other metabolic conditions. Given these limitations and the potential for adverse effects, it is crucial to consider the clinical implications of L-Arg supplementation in diabetic patients and provide specific guidelines for safe usage.
CLINICAL IMPLICATIONS AND RECOMMENDATIONS FOR INDUSTRY AND POPULATION-SPECIFIC GUIDELINES
For diabetic patients using L-Arg supplements, doses exceeding 0.5 g/kg (human equivalent: Approximately 5.6 g/day) may pose cardiac risks, particularly in those with preexisting myocardial dysfunction. Type 1 diabetic patients, characterized by absolute insulin deficiency, may face heightened susceptibility to L-Arg-induced hyperglycemia compared to type 2 diabetics, where residual insulin secretion might buffer glucose fluctuations. Clinicians should prioritize monitoring biomarkers such as cardiac troponin I and malondialdehyde in high-risk populations. The detrimental effects of high-dose L-Arg (≥ 1 g/kg) observed by Mansouri et al[1] align with mechanistic insights from earlier studies. Excessive L-Arg supplementation in diabetics overwhelms arginase-mediated metabolism, diverting substrate toward iNOS-driven NO overproduction[11]. This excess NO reacts with superoxide to form peroxynitrite, a potent oxidant that nitrates cardiac proteins (e.g., mitochondrial complexes I and III), impairing adenosine triphosphate synthesis and triggering cardiomyocyte apoptosis[12]. Concurrently, L-Arg suppresses Nrf-2, disabling antioxidant defenses (e.g., SOD, catalase) and exacerbating lipid peroxidation[13]. Furthermore, hyperactivation of iNOS promotes inflammatory cytokine release (e.g., tumor necrosis factor-alpha, interleukin-1β), which disrupts desmin filaments and promotes myocardial fibrosis[14]. These cascades collectively explain the dose-dependent cardiac injury reported in this study.
Given these findings, there is an urgent need for regulatory frameworks to standardize L-Arg dosing in commercial supplements, particularly those marketed to diabetic populations. Supplement manufacturers should consider incorporating antioxidant adjuvants (e.g., coenzyme Q10, vitamin E) to mitigate prooxidant effects at higher L-Arg doses. Functional foods targeting lipid profile improvements should leverage low-dose L-Arg (≤ 0.5 g/kg) while avoiding formulations that exceed this threshold. Transparent labeling and consumer education about dose-dependent risks are imperative to ensure safe usage. These strategies align with recent efforts to optimize nutraceutical safety in metabolic disorders[15,16]. These strategies must be further tailored to specific population subgroups. For adults over 50 years-especially those with diabetes-doses exceeding 0.3 g/kg/day (human equivalent: Approximately 4.8 g/day) may heighten cardiac risks due to age-related declines in antioxidant capacity[17]. Conversely, athletes engaged in endurance sports (e.g., marathon runners) might tolerate short-term high-dose L-Arg (1–1.5 g/kg) during intensive training, provided cardiac biomarkers (e.g., troponin I, malondialdehyde) are rigorously monitored[18]. However, vulnerable groups such as pregnant women and children should avoid unregulated L-Arg supplementation until robust safety data from gestational and pediatric studies are available. These recommendations echo the National Institutes of Health’s call for personalized nutraceutical strategies, bridging industry standards with individualized health needs[19].
CONCLUSION
In conclusion, the study by Mansouri et al[1] provides a timely reminder of the complexity and important insights into the potential risks of high-dose L-Arg supplementation in diabetic individuals because it may have unintended consequences. These findings urge clinicians to exercise caution when recommending L-Arg supplements to diabetic patients, particularly at unregulated doses. Prioritizing human trials to establish safe thresholds could assist to inform guidelines for the safe use of L-Arg as a dietary supplement, particularly in individuals with diabetes and other metabolic disorders. Further research is needed to validate these findings in human subjects and to explore the implications for clinical practice.
Provenance and peer review: Invited article; Externally peer reviewed.
Peer-review model: Single blind
Specialty type: Endocrinology and metabolism
Country of origin: China
Peer-review report’s classification
Scientific Quality: Grade B, Grade B, Grade B, Grade C
Novelty: Grade B, Grade B, Grade B, Grade E
Creativity or Innovation: Grade B, Grade B, Grade B, Grade E
Scientific Significance: Grade B, Grade B, Grade B, Grade D
P-Reviewer: Huang J; Jozanović M; Shi Q S-Editor: Luo ML L-Editor: Filipodia P-Editor: Xu ZH
