Micronutrients play a crucial role in maintaining overall metabolic health, with deficiencies often linked to the onset of chronic diseases such as obesity, diabetes, and cardiovascular disorders (Romani, 2016). Among these essential micronutrients, Zinc has garnered significant attention due to its wide-ranging physiological functions, from its role in antioxidant defense to its influence on hormonal regulation (Prasad, 2014). Zn is an essential trace element that plays a pivotal role in numerous physiological processes, including enzymatic functions, immune responses, and metabolic regulation. It is widely recognized for its involvement in the structural and functional integrity of antioxidant enzymes, such as superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPX), as well as its regulatory influence on hormonal systems like leptin signalling (Prasad, 2008; Chausmer, 1998). However, while Zn deficiency has been extensively studied, the potential adverse effects of excessive Zn intake remain underexplored. Recent trends in Zn supplementation in agriculture, animal husbandry, and human diets have raised concerns about its overconsumption.

Zn’s widespread use, particularly in Zn-enriched diets and multivitamin supplements, has led to unintentional exposure to levels exceeding physiological requirements. Such chronic overexposure may disrupt metabolic homeostasis, contributing to oxidative stress, dyslipidemia, and hormonal imbalances (Das et al., 2023). These disruptions are known to underlie the pathophysiology of chronic conditions such as obesity, diabetes mellitus, hypertension, and cardiovascular diseases (CVD). Given the global burden of these non-communicable diseases, it is crucial to investigate the molecular and biochemical effects of excessive Zn intake and its contribution to disease mechanisms.

This review aims to integrate findings from recent studies, including data from our investigation on excessive Zn supplementation in Wistar rats, to elucidate its correlation with the pathophysiological factors resulting in obesity, diabetes, hypertension, and CVD.

Zn is indispensable for numerous biological processes, particularly enzymatic functions, cellular signalling, and gene expression. However, excessive Zn intake can disrupt these processes, leading to detrimental physiological outcomes. Evidence from our research on Wistar rats has demonstrated that chronic Zn overload significantly affects antioxidant enzyme activity, lipid metabolism, and leptin receptor expression, providing a basis for understanding its broader implications.

According to globally accepted dietary guidelines, the Recommended Dietary Allowance (RDA) is 8 mg/day for adult women and 11 mg/day for adult men, with a Tolerable Upper Intake Level (UL) of 40 mg/day. These limits are defined by major regulatory bodies, including the European Food Safety Authority (EFSA, 2014) and the World Health Organization/Food and Agriculture Organization (WHO/FAO, 2004). In experimental research, excessive Zn exposure usually involves doses three to five times higher than normal physiological needs, often amounting to 50–150 mg/kg in rodent models. In human studies, long-term Zn consumption exceeding the UL (≥40 mg/day) is regarded as potentially harmful, particularly due to its association with copper depletion, adverse lipid alterations, and suppressed immune function. These established thresholds provide the basis for interpreting the findings summarized in this review.

Short-term therapeutic doses (50–150 mg/day) are sometimes prescribed for acute infections or deficiency management, but such high doses should not be continued chronically due to the risk of oxidative stress, disruptions in lipid and glucose metabolism, and mineral imbalance. Moreover, emerging clinical observations suggest that continuous high-dose supplementation may contribute to metabolic disturbances, highlighting the importance of cycling zinc supplementation—using it intermittently rather than continuously—to avoid long-term adverse effects. Human-specific dosage ranges, along with temporal patterns of supplementation, therefore play a crucial role in determining whether zinc exerts beneficial or detrimental effects.

This review was conducted to summarize current evidence on the effects of excessive Zn intake on obesity, diabetes, hypertension, and cardiovascular diseases. A structured search was performed in PubMed, Scopus, Google Scholar, and Web of Science for studies published between 1990 and 2025. The keywords used in various combinations included “Zn supplementation,” “Zn toxicity,” “obesity,” “diabetes mellitus,” “hypertension,” “cardiovascular diseases,” “oxidative stress,” “leptin resistance,” and “metabolic disorders.”

Excessive Zn supplementation has been linked to significant biochemical and physiological alterations that contribute to the development of obesity, diabetes mellitus (DM), hypertension (HTN), and cardiovascular diseases (CVD). These chronic diseases often share overlapping pathophysiological pathways, including dyslipidemia, oxidative stress, inflammation, and hormonal dysregulation. These adverse effects are mediated through complex biochemical pathways involving oxidative stress, insulin resistance, dyslipidemia, and renal impairment. This section discusses the molecular and clinical implications of Zn overload in the context of these conditions, integrating findings from the present study and supporting literature, along with recent advancements in the field. Table 1 provides a consolidated overview of the major pathophysiological consequences of excessive Zn supplementation, highlighting its multi-systemic impact on metabolic, endocrine, oxidative, inflammatory, renal, and cardiovascular processes. It summarizes how Zn overload disrupts lipid and glucose homeostasis, impairs antioxidant defenses, induces chronic inflammation, alters mineral balance, and contributes to conditions such as obesity, insulin resistance, diabetes, hypertension, and cardiovascular disease. Each condition is accompanied by the corresponding mechanisms and key literature, offering a clear evidence-based understanding of Zn-induced metabolic and physiological dysregulation.

Excessive Zn intake profoundly impacts molecular pathways, disrupting homeostasis and contributing to the pathogenesis of chronic diseases (Figure 1). This section provides a detailed discussion of key mechanisms, including antioxidant enzyme dysregulation, leptin receptor overexpression and resistance, and the impact on inflammatory markers such as C-reactive protein (CRP).

This review synthesizes current evidence on the dual role of Zn in human metabolic and cardiovascular health, highlighting both its essential physiological functions and its potential toxicity when consumed in excess. While optimal Zn intake supports antioxidant defense, immune regulation, glucose metabolism, and lipid homeostasis, chronic overconsumption disrupts these same systems, contributing to obesity, insulin resistance, hypertension, and cardiovascular diseases. The findings reiterate the importance of dose-dependent effects of Zn, yet they also expose significant gaps in the translation of mechanistic findings into clinically meaningful human outcomes.

Zn’s protective role at optimal levels is multifaceted and involves significant contributions to antioxidant defense, immune function, and insulin sensitivity. For instance, Zn activates enzymes like Cu/Zn superoxide dismutase (SOD), which play a critical role in reducing oxidative stress and protecting against cellular damage (Figure 1). Research by Maret and Sandstead (2006) underscores Zn’s ability to mitigate oxidative injury, particularly in chronic conditions such as diabetes and cardiovascular diseases (CVD). Additionally, Zn’s involvement in immune regulation is evident through its impact on cytokine production and T-cell activity, as highlighted in clinical trials where Zn supplementation reduced the duration and severity of infections. Zn also enhances insulin receptor signaling, improving glucose uptake and reducing the risk of type 2 diabetes (Chausmer, 1998). Despite these benefits, evidence from Zn supplementation studies reveals conflicting findings. While animal models provide valuable mechanistic insight into oxidative stress, leptin signaling, and mineral imbalance, their physiological responses do not fully replicate human metabolic processes. Rodent studies often use Zn doses several-fold higher than typical human exposures and exhibit faster metabolic turnover, making direct extrapolation difficult. Human studies show similar trends—such as altered lipid metabolism and impaired copper homeostasis—but the magnitude of effect is smaller. Therefore, findings from animal studies must be interpreted with caution, particularly regarding dosage thresholds and long-term toxicity in humans.

Across included studies, excessive Zn intake consistently induced oxidative stress through dysregulation of antioxidant enzymes, particularly reduced Cu/Zn SOD, CAT, and GPX activities (Furukawa et al., 2004; Singh, 2012). The resulting accumulation of reactive oxygen species (ROS) contributes to endothelial dysfunction, metabolic inflexibility, and increased cardiovascular risk (Harrison and Gongora, 2009; Mackenzie and Bergdahl, 2022). Zn overload also interferes with glucose–insulin homeostasis. Elevated Zn levels impair insulin receptor phosphorylation and GLUT4 translocation (Jayawardena et al., 2012), contributing to insulin resistance and hyperglycemia. Human studies corroborate these associations, showing increased risk of prediabetes and diabetes with higher circulating Zn (Zhang et al., 2021; Yang et al., 2023). In terms of lipid metabolism, excessive Zn promotes dyslipidemia characterized by elevated triglycerides, VLDL-C, and total cholesterol alongside reduced HDL-C (Das et al., 2023; Shabana et al., 2020). Such alterations are mechanistically linked to hepatic enzyme dysregulation affecting lipid synthesis and clearance (Klop et al., 2013), thereby augmenting atherosclerotic risk (Gordon et al., 1977). Inflammatory biomarkers, particularly CRP, were consistently elevated in Zn-overloaded states, aligning with epidemiological evidence that CRP predicts future coronary events and hypertension (Koenig et al., 1999). Finally, Zn-induced mineral imbalance—especially reductions in copper and magnesium—further amplifies oxidative stress and vascular dysfunction (Plum et al., 2010; Li et al., 2019). These combined effects suggest a multilevel disruption of metabolic and cardiovascular physiology under Zn excess.

Despite strong mechanistic evidence for Zn toxicity, findings across the literature remain context-specific. Moderate Zn supplementation improves insulin sensitivity, immune function, and antioxidant capacity (Prasad, 2014; Maret and Sandstead, 2006). Beneficial effects are particularly noted in populations with baseline Zn deficiency, malabsorption, or chronic inflammation. Conversely, adverse effects predominantly occur in Zn-sufficient individuals with chronic high intake, high dietary Zn-to-copper ratios (Kärberg et al., 2022), or intake from multiple fortified sources. These discrepancies reflect differences in baseline nutritional status, genetic and environmental modifiers, Zn formulation (e.g., ZnSO₄ vs. ZnO nanoparticles), duration of exposure, and study design. They also highlight the need for individualized and population-specific guidelines rather than universal supplementation strategies.

While a substantial portion of the mechanistic evidence in this review is derived from animal models, particularly rodent studies, it is important to acknowledge the inherent limitations of extrapolating these findings directly to humans. Rats are valuable models for studying metabolic regulation, oxidative stress pathways, and trace-element interactions due to their physiological similarity and controllable experimental conditions. However, species-specific differences in zinc absorption, hepatic metabolism, endocrine regulation, and inflammatory responses may influence the magnitude or direction of zinc’s effects. Therefore, while animal studies provide critical insights into underlying biochemical pathways, these findings should be interpreted cautiously when considering human physiology. Inclusion of human observational and interventional studies helps strengthen the translational relevance, but further controlled clinical trials are needed to clarify zinc’s dose-dependent effects in humans. Also a key concern in the reviewed literature is the heavy reliance on animal models, many of which employ supraphysiological doses unlikely to be encountered in typical human diets. Their metabolic rate, gastrointestinal absorption, and trace mineral kinetics differ substantially from humans, limiting external validity. Furthermore, long-term human trials assessing chronic Zn toxicity are scarce, often small in sample size, heterogenous in dosage, and short in duration.

The limited number of rigorous observational or randomized controlled trials (RCTs) evaluating chronic, moderate Zn excess constrains the strength of causal inference in humans. Additionally, publication bias toward positive or mechanistic outcomes may overrepresent harmful or beneficial effects in isolation. Recent epidemiological and clinical studies have provided additional support for the role of zinc dysregulation in metabolic disorders. For example, higher serum zinc concentrations have been associated with increased risks of prediabetes and diabetes in large human cohorts (Zhang et al., 2021; Yang et al., 2023), suggesting that zinc overload may be clinically relevant even in free-living populations. Similarly, population-based studies evaluating dietary and supplemental zinc intake have shown that excessive zinc consumption, particularly from long-term supplementation, may contribute to altered lipid profiles, impaired glucose regulation, and increased inflammatory burden. These findings underscore the need to contextualize animal-derived mechanistic data within human physiological variability and highlight the importance of further human trials to clarify optimal intake thresholds.

Because the evidence in this review was derived from systematically searched studies, the strength of conclusions is influenced by variability in study design, zinc doses, and population characteristics. Animal studies were abundant, whereas human trials were fewer and often short-term, limiting direct translation. Nonetheless, systematic inclusion of all eligible studies minimized selection bias and allowed for a balanced assessment of both beneficial and adverse effects. Future research should prioritize (i) long-term human cohort studies evaluating chronic moderate Zn exposure, (ii) dose–response analyses integrating Zn–copper interactions, (iii) mechanistic studies exploring the interplay between Zn and gut microbiota, and (iv) refined models that better account for human physiological Zn kinetics. Nutrigenomic research may also clarify inter-individual variability in Zn metabolism and disease susceptibility.

Given increasing use of fortified foods, dietary supplements, and agricultural Zn enrichment, the potential for unintentional chronic Zn excess warrants public health attention. Supplementation strategies should prioritize at-risk groups while avoiding excessive or indiscriminate use in the general population. Incorporating Zn intake monitoring and regulation of fortification programs could mitigate long-term risks. Precision nutrition approaches, leveraging genetic and metabolic profiling, may guide safer and more effective Zn use.

This systematic review underscores the dual-edged nature of Zn supplementation in human health. While Zn is essential for numerous physiological processes, including antioxidant defense, immune regulation, and metabolic homeostasis, excessive intake disrupts these functions and contributes to the pathogenesis of obesity, diabetes mellitus, hypertension, and cardiovascular diseases. The mechanistic insights presented reveal how Zn overload dysregulates antioxidant enzymes, exacerbates inflammation, and induces hormonal resistance, creating a cascade of adverse health outcomes. Conflicting evidence regarding Zn’s protective and detrimental effects highlights the importance of dose-dependent and context-specific considerations. Optimal Zn levels confer significant health benefits, such as enhanced antioxidant capacity and improved insulin sensitivity, while excessive intake poses risks, including oxidative stress, dyslipidemia, and systemic inflammation. These findings emphasize the need for individualized approaches to Zn supplementation, taking into account genetic, dietary, and environmental factors. Addressing the knowledge gaps in Zn research requires longitudinal studies to evaluate its long-term effects, as well as mechanistic investigations to clarify its interactions with other trace elements. Public health policies must balance the risks and benefits of Zn supplementation by establishing clear dietary guidelines, promoting targeted interventions for at-risk populations, and regulating Zn fortification in foods. Therapeutic applications of Zn, particularly in combination with other antioxidants, hold promise for mitigating chronic disease burden and improving health outcomes globally.

In conclusion, zinc’s role in health and disease is a dynamic interplay of its essentiality and potential toxicity. Excessive zinc intake has been shown to contribute to obesity, diabetes, hypertension, and cardiovascular risks through multiple biochemical mechanisms, including oxidative stress, insulin resistance, dyslipidemia, and renal dysfunction. While moderate zinc intake is essential for maintaining metabolic and cardiovascular health, excessive zinc supplementation may lead to adverse effects. Therefore, caution is advised when considering zinc supplementation, and further research is needed to determine the optimal dosage and duration of zinc intake for different populations. A nuanced understanding of this trace element is crucial for harnessing its benefits while minimizing its risks, paving the way for precision nutrition and evidence-based public health strategies.