Metformin and glibenclamide may have beneficial effects on the levels of trace elements in diabetic patients. The aim of the current study was to assess the effects of metformin and glibenclamide on the concentrations of copper (Cu), zinc (Zn) and magnesium (Mg) in patients with type 2 diabetes mellitus. The metformin-treated patients showed significantly lower serum Cu levels compared with the untreated and glibenclamide groups. In addition, treatment with metformin was associated with a significant increase in serum concentrations of Zn compared to the newly diagnosed patients, whereas it did not show a noticeable alteration in the serum level of Mg. In contrast, the glibenclamide treated group revealed significantly higher Zn and Mg levels compared with the newly diagnosed group, while the serum level of Cu was not significantly modified. In conclusion, treatment with metformin led to a reduction in serum Cu and an increase in serum Zn concentrations, whereas glibenclamide treatment displayed enhancement in serum Zn and Mg levels.

Copper, Glibenclamide, Magnesium, Metformin, Zinc

Trace elements are divalent cations that play essential roles in the human body. These cations, including copper (Cu), zinc (Zn) and magnesium (Mg), are necessary for different cellular functions and the alterations in their concentrations can contribute to the development of many diseases, such as T2DM (Dosa et al., 2011, Viktorinova et al., 2009). Cu and Zn have a crucial role in the mechanisms of oxidation-reduction reactions. Cu has both prooxidant and antioxidant effects through the generation of free radicals and catalyzation of the superoxide dismutase enzyme, which protects cells from superoxide radicals, respectively. In contrast, Zn has only an antioxidant effect by preventing reactive oxygen species from causing damage to proteins and enzymes (DiSilvestro, 2000). So, an oxidant/antioxidant imbalance can result from a disturbance in the level of these elements, which in turn induces diabetes and its complications (Soinio et al., 2007). In addition, low Zn levels can negatively affect the production and secretion of insulin from the islet cells of the pancreas (Quraishi et al., 2005). Mg is another important trace element that has a vital role in glucose homeostasis. It has been found that its deficiency can contribute to decreased insulin sensitivity and secretion (Huerta et al., 2005).

Although numerous studies have been carried out to determine the serum levels of trace elements in type 2 diabetic patients receiving metformin, contradictory results have been obtained (Chakraborty et al., 2011, Peters et al., 2013). Moreover, little known data is available on the effect of glibenclamide on the concentrations of various divalent cations in type 2 diabetic patients. Hence, taking into consideration the aforementioned findings, the present study was performed to investigate the effects of metformin versus glibenclamide on the concentrations of some trace elements (Cu, Zn, and Mg) in T2DM patients.

Demographic characteristics of the study groups:

Age, duration of diabetes and BMI of diabetic patients and controls are shown in Table 1. Non-significant differences were found between the groups.

While the role of glibenclamide and metformin in the treatment of diabetes has been well assessed, little evidence about their activity on trace elements in type 2 diabetic patients exists. This study aimed to investigate the effects of glibenclamide and metformin on Cu, Zn and Mg levels in type 2 diabetic patients.

The findings of the current study revealed that newly diagnosed diabetic patients have much higher Cu levels and lower Zn and Mg levels than healthy controls. In addition, newly diagnosed diabetic patients showed higher FSG and lower insulin levels compared to the control. These results were consistent with previously reported studies, indicating the impact of these trace elements on the pathogenesis of T2DM as well as the effect of glycemic status on their levels (Khan et al., 2015, Viktorinova et al., 2009). However, Basaki et al. (2012) showed that diabetic patients have a lower Cu level compared to the control, whereas Terrés-Martos et al. (1998) exhibited no significant differences in the Cu level between diabetic patients and the control. Higher levels of Cu in type 2 diabetic patients are possibly associated with hyperglycemia due to disruption of the Cu-binding proteins (Talaei et al., 2011), whereas lower levels of Zn and Mg may be attributed to hyperglycemia induced disturbances in the factors that maintain their balance, such as intestinal absorption and urinary excretion (Mishra and Mishra, 2017, Yerlikaya et al., 2013).

Figure 1. 

Effects of metformin versus glibenclamide on serum concentrations of A) Cu, B) Zn, and C) Mg in type 2 diabetic patients.* indicates statistically significant differences compared to the control group (**p < 0.01; ***p < 0.001; ****p < 0.0001); # indicates statistically significant differences compared to the newly diagnosed group (#p < 0.05; ###p < 0.001); $ indicates statistically significant differences between the metformin and glibenclamide treated groups, as determined by the Kruskal-Wallis test followed by a Dunn’s multiple comparisons post-hoc test.

The present study showed that patients treated with metformin have a significantly lower serum Cu level compared with glibenclamide and newly diagnosed diabetic patients, while treatment with glibenclamide had no significant effect. Our results are inconsistent with those of Dosa et al. (2011), who reported a non-significant effect of metformin on the plasma concentration of Cu in type 2 diabetic patients. In contrast, our data is in line with Zargar et al. (1998), who revealed that glibenclamide does not affect plasma copper levels. In the current study, the difference between the effects of the treated groups on serum Cu may be related to glycaemic control. Metformin treated patients showed a significantly lower FSG level compared to the newly diagnosed group. This could be, in part, explained by the increasing affinity of Cu for ceruloplasmin due to decreased glycation by metformin (Roxborough et al., 1995, Sarkar et al., 2010). However, the results of our study showed no difference between the metformin and glibenclamide treated groups in terms of their effects on FSG. Another reason for a decrease in serum Cu may be due to the ability of metformin to abstract Cu ions from the biological system, resulting in complex formation (Quan et al., 2015).

With respect to Zn, both the metformin and glibenclamide treated groups showed significantly higher levels compared to the newly diagnosed group. Previous studies about the effect of metformin on the serum Zn level in type 2 diabetic patients have shown conflicting and even contrary results. Dosa et al. (2011) showed that metformin administration does not lead to significant changes in the plasma concentration of Zn in patients with non-insulin-dependent diabetes mellitus. In contrast, Naik et al. (2019) revealed that metformin alone or in combination with glimiperide causes a significant decrease in serum zinc levels in type 2 diabetic patients. Regarding glibenclamide, our findings of higher serum concentration of Zn compared to the untreated group is in line with those obtained in a previous study on streptozotocin-induced diabetic rats (Shawky et al., 2018). In the present study, the increment in the serum Zn level in the treated groups may be related to the improvement in the glycaemic parameters, including FSG. A significant decrease in FSG might result in a decrease in Zn urinary loss and an increase in its active transport to tubular cells (Praveeena and Sameera, 2013). However, the glibenclamide treated group, unlike its metformin counterpart, did not show significant low FSG levels compared to the newly diagnosed group. In contrast, patients treated with glibenclamide showed comparable insulin levels to the control. Zn is important for synthesis and release of insulin, and its shortage appears to affect insulin release (Lobo et al., 2010). Therefore, the ability of glibenclamide to increase Zn levels could be related to its role in stimulation of insulin release from the pancreatic β-cells.

In the current study, the use of glibenclamide resulted in an increase in serum magnesium to a level comparable to the control and significantly higher than the newly diagnosed group. By contrast, metformin did not significantly change serum Mg levels, leading to significantly lower levels than the control. Our results are in accordance with the findings of previous studies (Chakraborty et al., 2011, Wahlen et al., 2017). Even though the glibenclamide treated group in the present study had worse glycaemic control, they showed better serum Mg levels than the patients treated with metformin. This outcome can be attributed to the ability of glibenclamide to increase insulin levels. This is in agreement with previous studies showing that insulin has an essential role in the renal reabsorption of Mg (Kurstjens et al., 2017) by stimulating the renal Mg channel TRPM6 (Nair et al., 2012). In contrast to our findings, Peters et al. (2013) reported lower serum magnesium concentrations in patients receiving metformin monotherapy or in combination with a sulfonylurea compared to those on diet alone.

It is necessary to emphasise that this study has several limitations due to restricted funds. Glycated haemoglobin (HbA1c) and intracellular magnesium were not measured. Moreover, collection of samples occurred at a single point, and no follow-up data is available.

The present study demonstrated an elevation in serum Cu and a reduction in serum Zn and Mg in T2DM. It also showed that metformin treatment is associated with decreased serum Cu and increased serum Zn. In contrast, glibenclamide treated patients revealed improvement in serum levels of Mg and Zn.

The authors thankfully acknowledge the University of Mosul and the College of Pharmacy for their continuous support and encouragement to all researchers.