Concentrations of trace metals in serum: Implications for type 2 diabetes mellitus and gender difference

Article information

Environ Anal Health Toxicol. 2025;40.e2025001

Publication date (electronic) : 2025 January 21

doi : https://doi.org/10.5620/eaht.2025001

Jae Min Lee¹, An Na Jung², Sujeong Han³, Jae Woong Sull², Chunhwa Ihm⁴, Jin Hyun Jun^2,

¹Department of Internal Medicine, Eulji University School of Medicine, Daejeon, Korea

²Department of Biomedical Laboratory Science, Graduate School, Eulji University, Seongnam, Korea

³Department of Public Health Science, Graduate School of Public Health, Seoul National University, Seoul, Korea

⁴Department of Laboratory Medicine, Eulji University School of Medicine, Daejeon, Korea

^*Correspondence: junjh55@eulji.ac.kr

Received 2024 July 8; Accepted 2024 December 27.

Abstract

Introduction

Human exposure to heavy and trace metals primarily occurs through air, water, and food sources. Uncontrolled pollution and industrialization can be a potential source of exposure to toxic heavy metals such as lead (Pb), nickel (Ni), cadmium (Cd), mercury (Hg), and arsenic (As) in humans [1]. These metals are commonly found in soluble salt forms, which can influence the composition of body fluids [1]. Inorganic elements, such as magnesium (Mg), zinc (Zn), chromium (Cr), iron (Fe), manganese (Mn), and copper (Cu), are naturally present in trace amounts in living tissues and play vital roles in various physiological processes essential for overall health [2]. However, non-physiological concentration of many trace and heavy metals can have alteration effects on enzymatic activities and elicit various detrimental health effects [3-5].

Trace metals are involved in critical physiological processes, acting as prosthetic groups of many proteins, cofactors for numerous enzymes, and regulators of water balance [5]. Even slight alterations in trace metal concentrations can lead to various health complications, some of which can be life-threatening [6]. They exert their effects by serving as activators or inhibitors of enzymatic reactions, competing with other metals and proteins for binding sites, or influencing cell membrane permeability and other mechanisms [7]. Thus, maintaining normal and physiological concentrations of trace metals in various body tissues is crucial for proper metabolic function [8].

Environmental exposure to heavy metals, including Pb, Hg, and Cd, commonly used in industrial processes, has been linked to an increased incidence of ischemic vascular and cardiovascular disease and diabetes [9-11]. Furthermore, overexposure to heavy metals can lead to many adverse health effects [6]. Disorders in heavy metal metabolism often result from impaired absorption and digestion, stemming from factors such as improper diet, environmental and occupational exposure, and cirrhosis [12].

Among these disorders, diabetes, a non-communicable disease, has been rapidly increasing worldwide [13]. Especially, type 2 diabetes mellitus (T2DM) poses a significant public health and socioeconomic challenge globally [13]. Aside from the health issues directly associated with T2DM, severe complications such as nervous system disorders, diabetic nephropathy, heart diseases, stroke, and cardiovascular complications can also occur in diabetic patients [14]. T2DM is characterized as a metabolic disorder that leads to insulin receptor insensitivity or deficient insulin secretion, resulting in fasting hyperglycemia [15]. Both pre-diabetic and diabetic states were marked by inflammation and oxidative stress, stemming from an imbalance between the production of free radicals and their scavenging by various antioxidant systems [16, 17].

Oxidative stress also plays a critical role in the development of metabolic syndrome, a complex disorder characterized by various metabolic abnormalities, including abdominal obesity, hypertension, glucose intolerance, and atherogenic dyslipidemia [18, 19]. Trace metals are known to influence glucose homeostasis and insulin sensitivity [6]. In contrast to essential metals, some toxic trace metals have been found to accumulate in various biological samples of T2DM patients [1]. Therefore, maintaining an appropriate balance of trace metals is crucial for the overall well-being of individuals [2].

Furthermore, gender differences in trace metal concentrations and their potential implications for T2DM have been increasingly recognized, suggesting that men and women might experience distinct metabolic responses due to variations in trace metal homeostasis. It was reported that serum ferritin concentration was associated with insulin resistance in men, but not in women in Korean [20]. Abnormal metabolic processes in T2DM patients with increased urinary loss and malabsorption of trace metals due to various causes may differ by gender. In addition, higher ceruloplasmin levels and lower transferrin levels observed in T2DM patients may increase free Cu and Fe levels, respectively [21, 22]. Increased levels of these transition metals further increase oxidative stress, which in turn increases insulin resistance and T2DM [23].

This study was conducted to investigate the relationship between trace metal serum concentrations and T2DM by comparing and analyzing serum samples from healthy controls and T2DM patients. In addition, we aimed to explore the potential association between trace metal concentrations and gender differences in T2DM patients.

Materials and Methods

Results

Characteristics and categorized variables of two groups were presented in Table 1. The two groups between healthy controls and T2DM patients had a statistical significance associated with age, HbA1c, FBG, TC, HDL-C, and LDL-C. The T2DM patients were confirmed by diagnostic serum parameters (Table 1). However, there was no significant difference in TG and CRP between two groups.

Table 1.

Comparison of clinical characteristics between healthy controls and type 2 diabetes mellitus (T2DM) patients

In Table 1, the serum concentrations of total trace metals were compared in overall T2DM patients to healthy controls. The Se and Cu concentration in the T2DM group was significantly lower than those of the control group (P < 0.01 and P < 0.05 respectively). Logistic regression analysis in all unadjusted, adjusted model 1 for age and model 2 for age and sex indicated that Mn concentration was significantly higher in overall T2DM patients than in healthy controls (Table 2).

Table 2.

Odds ratios and 95% confidence intervals of type 2 diabetes mellitus (T2DM) according to serum concentration of trace metals

When examining trace metal concentrations by gender difference, Cu and Se levels were significantly lower in diabetic men (P < 0.05; Table 3). In separate analysis of women, T2DM group exhibited significantly higher levels of Zn, Se and Mn than those of healthy control group (P < 0.05; Table 3).

Table 3.

Comparison of clinical characteristics between healthy controls and type 2 diabetes mellitus (T2DM) patients in men and women

In logistic regression analysis of Table 4, there was no significant difference between healthy controls and T2DM patients in adjusted model 1 for age in men. However, in women, the Cu, Se, and Mn concentrations in T2DM patients were significantly different compared with healthy controls in the logistic regression analysis in both the unadjusted and adjusted model 1 for age (Table 4).

Table 4.

Odds ratios and 95 % confidence intervals of type 2 diabetes mellitus (T2DM) according to serum concentration of trace metals in men and women

Discussion

To our knowledge, this is the first study to separately examine the association between trace metals and T2DM by gender difference. In this study, trace metal accumulation was found to be associated with T2DM in women, but no significant relationship was found in men. We found that higher concentrations of Se, Zn and Mn, and lower concentrations of Cu were associated with increased prevalence of T2DM in women. This association was stronger in women compared to men. Accumulation and deficiency of certain trace metals in women’s serum may have negative health effects, and monitoring them may be useful for the prevention and treatment of T2DM patients.

The Cu is an essential and important mineral for many biological functions, and contributes to the catalytic activity of superoxide dismutase, which protects cells from superoxide radicals [26]. It also activates cytochrome oxidase, which is involved in the electron transport chain of mitochondria. When Cu is deficient, cytochrome oxidase activity decreases, which can impair mitochondrial activity in metabolically active tissues such as pancreatic beta cells [27]. For this reason, abnormalities in serum Cu and other trace metals concentrations have been reported to be associated with alterations in the metabolic pathways of T2DM and its complications [28].

The Se is one of the essential trace elements for human health and is part of Se-dependent glutathione peroxidase family. It contributes to redox action by converting lipid and phospholipid hydrogen peroxide and hydrogen peroxide into harmless products [29]. Diabetes is caused by insufficient insulin secretion and insulin resistance. Hyperglycemia can induce excessive levels of free radicals, leading to oxidative stress, which has a significant impact on the development and complications of diabetes [30]. However, Se may play a protective role against diabetes. Overexpression of Se-dependent glutathione peroxidase can protect pancreatic beta cells from the onset of oxidative stress and improve pancreatic function by stimulating pancreatic beta cell gene expression [31]. Conversely, the mechanisms by which high levels of Se affect diabetes are controversial. This is because research has shown that high selenium levels in the body can cause diabetes by interfering with insulin signaling [32].

Gender-specific effects of Se was reviewed and important health issues related to the Se and selenoproteins status suggested unexpected sexual dimorphisms [33]. Prospective human studies have shown that the anticancer effects of Se were greater in men than in women, suggesting that Se may exert endocrine effects, contributing to its health-promoting action [34]. Our study showed that clearly difference in detrimental effects of Se on T2DM in women. It also reported that association of elevated serum ferritin concentration with insulin resistance and impaired glucose metabolism in Korean men and women [20]. Many researchers have investigated the effects of gender difference in blood and tissue biomarker levels on various diseases, including diabetes, but the conclusions are still controversial.

Recently, Se is associated with both beneficial and detrimental health effects, thus it was suggested that deficient supply or uncontrolled supplementation raises concerns for an increased incidence of T2DM in a secondary analysis of a randomized controlled trial [35]. Another study showed the positive relationship between Se intake and the prevalence of T2DM. This association is particularly significant in younger individuals and men, especially [36]. In a study using mice model, relatively low dosages of Se supplementation (0.1 - 0.3 mg/Kg) exerted beneficial effects on glucose tolerance through regulating physiological glucose metabolism and inhibit the oxidative stress, while high dosages of Se (more than 0.9 mg/Kg) supplementation impaired glucose tolerance and aggravate oxidative stress [37].

In addition to Se, the accumulation of serum Mn also may cause diabetes. Mn is an essential nutrient required for carbohydrate, lipid, and protein metabolism and is involved in immune function, bone growth, blood sugar regulation, and cellular energy. And it is a component of Mn-SOD. Mn-SOD is a type of antioxidant and plays an important role in protecting mitochondria from elevated levels of reactive oxygen species (ROS), which can lead to diabetes [38, 39]. Excess Mn can increase Mn-SOD levels and activity, consequently increase hydrogen peroxide (H₂O₂) production. Previous studies have shown that transient exposure of pancreatic β-cells to large amounts of H₂O₂ can reduce the secretory response of β-cells to glucose, and that long-term exposure to high levels of H₂O₂ can cause insulin resistance [40]. However, more researches are needed to determine the link between Mn and diabetes.

Despite being an essential trace metal for glucose homeostasis and T2DM, but higher concentrations above the optimal physiological level of Mn can be toxic to humans [41]. A study of 1,801 people in China found that participants with higher serum Mn levels were more likely to develop diabetes [42]. Another case-control study found a U-shaped association between plasma Mn and T2DM in 3,228 subjects (1,614 diabetic patients and 1,614 controls). The odds ratio of type 2 diabetes significantly increased when plasma Mn levels were low or high [43].

Other trace and heavy metals of non-physiological concentration also have detrimental effects on systemic and metabolic homeostasis for healthy human. Higher total Ca, Mn, Zn, and Cu intake were inversely associated with the risk of diabetic retinopathy in USA diabetes adults (National Health and Nutrition Examination Survey, 2007-2018). It showed U-shaped dose-response relationships between various metals and diabetic retinopathy [44]. The relationship between plasma Ni concentration and T2DM also showed an inverted U-shaped connection with superoxide dismutase [45]. Several recent studies were suggested that role of environmental exposure Pb and Cd, Cu intake, plasma and urinary Zn, and Mg status and dietary pattern were related to development and prognosis of T2DM [46-49]. It also reported that mixture effects of trace metal concentration on cardiovascular diseases by Cd and Hg, and T2DM by Pb, Ni, Cr, and Cd risk in adults using G-computation analysis [50]. Our study found the similar effects of total concentration of trace metals, which was the sum of Zn, Cu, Se, Mn and Cr, in women T2DM patients.

This study had some limitations. Firstly, the case–control nature of our study does not allow us to infer any causality between all serum trace metals and T2DM because it was possible only representative trace metals such as Zn, Cu, Se, Mn and Cr. Secondly, although we adjusted for gender and age, which may confound the relationship between trace metals and T2DM, we could not rule out the possibility that other correlated parameters also contributed to the observed association. Thirdly, the results may be confounded by a lack of information on demographic variables such as participants' education level, occupation, and lifestyle habits.

Conclusions

This study has important implications considering pathophysiology of T2DM and high exposure to trace metals, especially Se and Mn, by gender difference. These findings suggest that excessive exposure to Se and Mn in women may increase their risk of developing T2DM. It highlights the significance of gender difference and suggests the potential benefits of regular monitoring of trace metal concentrations in the management of T2DM. Further large population studies should be needed to substantiate gender difference in the association of Se and Mn accumulation with T2DM in women but not in men.

Supplementary Material

Article information Continued