Zinc status is associated with inflammation, oxidative stress, lipid, and glucose metabolism
- 4k Downloads
A number of studies have reported that zinc plays a substantial role in the development of metabolic syndrome, taking part in the regulation of cytokine expression, suppressing inflammation, and is also required to activate antioxidant enzymes that scavenge reactive oxygen species, reducing oxidative stress. Zinc also plays a role in the correct functioning of lipid and glucose metabolism, regulating and forming the expression of insulin. In numerous studies, zinc supplementation has been found to improve blood pressure, glucose, and LDL cholesterol serum level. Deeper knowledge of zinc’s properties may help in treating metabolic syndrome, thus protecting against stroke and angina pectoris, and ultimately against death.
KeywordsOxidative stress Inflammation Zinc Lipid metabolism Glucose metabolism
Zinc (Zn) is one of the most common trace elements in the human body and plays a substantial role in growth and development, acting as a signaling factor . This metal takes part in the regulation of chronic inflammatory status through the reduction of inflammatory cytokines. Zinc also reduces oxidative stress by participating in the synthesis of antioxidant enzymes and acts as a catalyzer of enzymes, taking part in lipid, carbohydrate, and protein metabolism. It is involved in the synthesis, storage, and release of insulin, which suggests the critical role of this microelement in the progression of type-2 diabetes mellitus, atherosclerosis, and metabolic syndrome (MS) [2, 3, 4, 5].
Studies of zinc concentration in the human body are scarce, and have shown inconsistent results. Zinc deficiency has been observed in patients in some counties with increased oxidative stress and generation of inflammatory status and the decrease concentrations of this element occur in patients with MS , in patients with type 2 diabetes mellitus  and with hypertension  than in healthy people.
Some studies showed that high concentration of zinc is associated with impaired lipid profile and risk of MS [8, 9, 10]. In the last study, increase in erythrocyte zinc concentration and high zincuria was observed in patients with MS . Obtained results indicate that zinc is strongly associated with oxidation stress, inflammation, and lipid and glucose status and it can be assumed that zinc status may be a predictor of metabolic disorders.
Taking together, current knowledge reflects the need for a critical overview of the zinc role in metabolic disorders. The proposed review summarizes the advances of the last years (2010–2017), providing new insights into the association between zinc status and inflammation, oxidative stress, lipid, and glucose metabolism.
Zinc status in metabolic disorders
Multiple studies have demonstrated the interaction between obesity and Zn homeostasis. In particular, blood Zn levels were found to be significantly decreased in obese patients [12, 13]. Erythrocyte Zn levels were also shown to be negatively associated with anthropometric markers of obesity like BMI and waist circumference . At the same time, the decrease in serum Zn levels was accompanied by increased urinary concentrations, being indicative of increased Zn excretion in obesity . Low nutritional Zn status in obesity is also associated with aggravation of obesity-related metabolic disturbances like insulin resistance, inflammation, and altered lipid profile .
Similarly, short-term (8-week) weight loss in obese women was associated with a significant improvement of serum Zn levels, being negatively associated with body fat percentage .
The role of Zn dyshomeostasis in obesity is also confirmed by the results of supplementation trials. In particular, administration of 30 mg/day Zn gluconate for 1 month resulted in a significant decrease in body weight and BMI values as well as serum TG concentrations . Eight-week treatment with 20 mg/day zinc also resulted in a significant decrease in BMI and BMI z score in obese children, although remaining abnormally high. At the same time, Zn supplementation was also associated with improvement of lipoprotein profile (decreased ApoB/ApoA1, oxLDL, total cholesterol and LDL-cholesterol values) and reduced leptin levels .
It is also suggested that zinc deficiency may be an important risk factor of diabetes mellitus II. In several studies, decreased concentration of zinc status was observed in diabetic patients compared to healthy people [20, 21, 22, 23, 24, 25, 26]. Sinha et al.  have demonstrated that zinc plasma levels are inversely correlated with glycemic status (HbA1C) in diabetes mellitus, while in patients with MS an association between high zinc concentration in urine (zincuria) and fasting glucose level, glycated hemoglobin level, insulin resistance, and also CRP were found. In one study, inadequate zinc intake was observed and zinc deficiency was suggested in patients with MS . The relation between inadequate zinc intake and raised insulin concentration in blood was also noticed in adolescents . Some recent studies showed that zinc supplementation improved glucose metabolism and insulin sensitivity in diabetic patients [29, 30, 31]. It was also found that zinc supplementation reduced fasting plasma glucose, serum insulin and insulin resistance in gestational diabetes in women . However, in other studies, the association between zinc supply and glucose metabolism and insulin resistance was not confirmed [18, 33].
In our opinion, the association between metabolic disorders and zinc status is mainly mediated by inflammation, oxidative stress, modulation of zinc transporters, and altered lipid and glucose metabolism.
During inflammatory state, white adipose tissue produces cytokines such as (interleukin-6) IL-6, which stimulates the secretion of C-reactive protein (CRP) in the liver, which is a sensitive marker of inflammation, tissue damage, and impairs vascular endothelial function. On the other hand, TNF-α contributes to the acute-phase response by enabling IL-6, which increases proinflammatory cytokines such as adiponectin . In a double-blinded, placebo trial in elderly subjects, Bao et al.  have shown a significant increase in plasma zinc levels, a decrease in CRP, TNF-α, and Il-6 plasma concentrations in a response of the zinc supplementation. While different studies have shown the inverse association between IL-6, TNF-α, CRP, and serum zinc levels in adults aged 40 . According to the authors, zinc supplementation positively impacts inflammatory state reduction in obese patients with metabolic syndrome. Also, in type 2 diabetes mellitus patients, impaired zinc homeostasis leads to uncontrolled expression of immune mediators, such as IL-1β, IL-6, and NF-κB, which at the same time simultaneously exacerbate the immune response and lead to pathogenesis, negatively affecting β-cells. The long-term exposure of β-cells to IL-1β and IL-6 may lead to apoptosis, resulting in insulin resistance and increased glucose levels in the blood .
NF-κB is one of the major immune response transcription factors in the development of atherosclerosis . This inflammatory pathway takes part in the expression of pro-inflammatory cytokines, CRP, MMPs, and controls genes, which regulate proliferation, apoptosis, cell adhesion, tissue remodeling, inflammatory processes, immune responses, and cellular-stress responses . Some authors have shown that zinc ions lead to signal transduction, thus making zinc involved in NF-κB inhibition . Another negative impact of zinc regarding NF-κB activity appears through inhibition of lipopolysaccharide-induced activation of NF-κB, which in the same time suppresses TNF-α secretion in monocytes . Also, zinc ions imported to macrophages or monocytes by ZIP8 (zinc transporter) during inflammatory state provokes NF-κB inhibition . It seems that ZIP8 plays a crucial role in inflammation.
The main negative regulator of NF-κB activity is zinc finger protein (A20), which is known as a cell protector against TNF-α-induced NF-κB toxicity, decreasing its level, along with IL-1β. Prasad et al.  have demonstrated that this zinc–protein complex suppress TNF-α and IL-1β production, inhibiting the activity of NF-κB in endothelial cells. It has been reported that zinc supplementation reduces the level of these cytokines, reactive oxygen species (ROS), and polysaccharides by increasing the concentration of A20 and PPAR-α. Zinc influences the expression of peroxisome proliferator-activated receptors α (PPARs-α), which plays a significant role in lipoprotein and glucose metabolism. These receptors also suppress NF-κB activity. The inhibition of NF-κB by zinc via A20 and PPARs signaling pathways are the most important mechanism because zinc decreases pro-inflammatory cytokines in atherosclerosis .
Zinc also plays a key role in regulating the function of MMP2 and MMP9 named gelatinases whose expression increases during inflammation with artery damage. They belong to the group of zinc-dependent matrix metalloproteinases (MMPs), which bind zinc ions to the catalytic site for their activation, forming coenzymes. MMPs cause the degradation of various components of ECM and they mediate its remodeling, which enables cell migration, and facilitates the pathogenesis processes. Thus, they play an important role in immunity and angiogenesis, whereby their dysregulation may contribute to inflammation or atherosclerosis [42, 43]. Jagadeesha et al.  have reported that the activation of zinc-dependent endopeptidase MMP9 enables cell migration, while other authors have shown significant increasing of the MMP9 serum levels and lower zinc concentration in patients with unstable atherosclerotic plaque . According to research, high MMP9 serum concentrations may increase the risk of atherosclerosis. Instead, some studies have revealed that zinc supplementation with a high-fat diet inhibits MMP2 and MMP9, decreases the inflammatory state, and lowers TG, LDL, IL-6, and CRP and increases HDL, as well as protecting the liver in rabbits . Obtained results highlight the protective role of zinc against artery damage and atherosclerosis.
Oxidative stress plays a significant role in MS development, being tightly associated with inflammation, and providing a link between certain MS components like obesity, diabetes, dyslipidemia, and hypertension. Moreover, recent studies proposed that oxidative stress may be considered as one of the components of MS .
Physiological concentration of zinc inhibits the production of reactive oxygen species, such as superoxide anion (·O−), hydrogen peroxide (H2O2), and radical hydroxyl (OH·)  as well as reactive nitrogen species including peroxynitrite (Fig. 1) . The antioxidant effect of zinc may be mediated through direct action of zinc ion, its structural role in antioxidant proteins, and modulation metallothionein induction. Direct antioxidant activity of Zn ions is associated with its binding to thiol groups, thus protecting them from oxidation [50, 51].
Zinc is a cofactor of antioxidant enzyme Cu,Zn-superoxide dismutase (SOD1), which is suppressed under Zn-deficient conditions . It has also been demonstrated that Zn may indirectly affect the activity of other antioxidant enzymes. In particular, Zn supplementation significantly increased GPx activity through modulation of Se status . It has also been demonstrated that nanoformulated Cu,Zn-SOD is capable of decreasing adipose tissue  and vascular  inflammation in obese mice.
According to Manea et al. , the inhibition of NF-κB, in whose regulation zinc plays a critical role, holds up the expression of NOX1 and NOX4, which play an important role in redox status determination in blood vessels. They cause damage to vessels through by increasing the number of thrombins, causing NOX activation and elevated production of ROS, which leads to DNA and lipid oxidation, concurring to atherosclerosis , which has also been confirmed in Jagadeesha et al.’s  research. It is also notable that free zinc deficiency contributes to the inhibition of the N-methyl-d-aspartate receptor (NMDAR), which leads to an increased level of ROS [35, 58, 59, 60].
As stated earlier, Zn-dependent modulation of the antioxidant system is at least partially mediated by its influence on transcription factors. Nuclear factor erythroid 2-related factor 2 (Nrf2) is one of the key transcription factors regulating antioxidant system activity. It protects against oxidative stress at an early stage, scavenging reactive oxygen and nitrogen species, while zinc regulates its expression and transcription . Li et al.  have demonstrated that zinc deficiency suppresses Nrf2 activity in diabetes-induced renal oxidative damage in mice. The intracellular concentration of zinc is partly regulated through MTs and closely linking the redox status of the cell to cellular availability of zinc ions .
It has been demonstrated that obesity-associated induction of MT expression in adipose tissue is a protective response, being at least partially mediated through modulation of oxidative and endoplasmic reticulum stress . However, another group of authors has linked increased adipose tissue MT expression with the rate of insulin resistance . Corresponding to the earlier-discussed role of Zn in MT synthesis, Zn intake and Zn status in obese patients were significantly associated with peripheral blood mononuclear cell MT levels . Experimental studies have also demonstrated the impact of Zn status on antioxidant systems in obesity. In particular, Chen et al.  have assessed the effect of zinc deficiency and zinc supplementation on antioxidant expression in high-fat diet mice, inducing vascular inflammation and oxidative stress, demonstrating that zinc insufficiency exacerbates antioxidant expression, whereas zinc supplementation improves that expression.
It is worth mentioning that zinc does not always act as an antioxidant. In terms of high intracellular zinc levels, it can possess prooxidant properties. In particular, it has been demonstrated that zinc oxide nanoparticles significantly increased oxidative stress in 3T3-L1 adipocytes in a dose-dependent manner , although increasing the expression of antioxidant enzymes .
Some studies have demonstrated a tight interaction between metabolic syndrome and its components and the activity of Zn-dependent antioxidant systems. In particular, low serum SOD activity and zinc intake were shown to be associated with an incidence of MS in Shanghai, China .
Taheri et al.  reported decreasing activities of SOD and increases in GSH-Px (glutathione peroxide) and GR activities in diabetic patients. Correspondingly, serum Zn and SOD levels are significantly inversely correlated with HbA1c levels . Hayens et al.  and Ogawa et al.  have demonstrated an elevated concentration of metallothionein 2a gene expression in diabetes individuals  and rats . In contrast, Bellomo et al.  reported decreases in MT mRNA levels in response to high glucose concentration in β-cells in a mice model. Numerous experimental studies have demonstrated that Zn supplementation causes increased MT expression [69, 70]. However, it has been noted that in type 2 diabetics with normal Zn status, supplementation did not improve oxidative status and glucose metabolism .
Cu,Zn-SOD was also shown to play a significant role in altered lipid profile in diabetic patients . Decreased activity of Cu,Zn-SOD in relation to Zn-deficiency was observed in hypertensive patients. Certain studies have demonstrated increased SOD activities in metabolic syndrome and its components. In particular, Vávrova et al.  have shown altered antioxidant enzymes levels in patients with metabolic syndrome, including significantly increased Cu,Zn-SOD and glutathione reductase (GR) activities, and lower activities of CAT and PON1 (paraoxonase) in association with low GSH levels. Similarly, erythrocyte SOD activity was increased in type 2 diabetics, being significantly associated with Zn levels and glycemic control. The authors state that the increased enzyme activity is a response to counteract oxidative stress in terms of adequate zinc supply .
Therefore, zinc has a protective potential against metabolic syndrome-associated oxidative stress through induction of transcription factors (including (ARE)-Nrf2 signaling) and a subsequent up-regulation of enzymatic and non-enzymatic antioxidants, induction of metallothionein synthesis, its structural role in Cu,Zn-SOD (SOD1), and, finally, its direct antioxidant activity. It seems that metabolic stress during obesity and metabolic syndrome induces a compensatory response, being characterized by increased Zn-mediated mechanisms of antioxidant protection. However, in terms of poor Zn status due to increased Zn excretion or insufficient intake, their mechanisms may not be activated, resulting in aggravation of metabolic disturbances.
Adipose tissue is the main depot of the lipids in the human organism and expanded adipose tissue mass due to overaccumulation of lipids is the morphological substrate of obesity. Therefore, a tight interaction between Zn and adipose tissue dysfunction is of particular interest. Numerous studies have indicated an association between serum zinc levels and lipid metabolism . In clinical and experimental studies, it has been reported that zinc supplementation results in the total cholesterol, LDL cholesterol, and triglycerides decreasing, and the HDL cholesterol increasing in patients [29, 52]. Instead, Weigand and Egenolf  have shown that moderate zinc deficiency did not alter lipid concentration and fatty acid composition in the liver of rats fed a high-fat diet. In other studies, zinc deficiency exacerbates hepatic lipid metabolism, while Zn supplementation increases hepatocyte activity and improves lipid metabolism in the liver [77, 78]. Moreover, short-term zinc supplementation in obese patients decreases weight and TG levels without significant change in lipid and glucose profile [18, 79, 80].
Numerous studies have demonstrated that the state of adipose tissue in obesity and other pathologies is tightly associated with Zn status. Experimental studies have demonstrated a significant decrease in adipose tissue Zn content and its negative correlation with insulin, HOMA-IR, and TNF-α values in obese animals . A significant decrease in adipose tissue Zn levels was detected in animals fed both Zn-adequate and Zn-deficient high-fat diets. At the same time, dietary Zn deficiency in overfed animals resulted in a significant increase in serum leptin levels, being accompanied by a more intensive macrophage infiltration as compared to the HFD-Zn-adequate group . In opposite, other studies showed that a high-fat diet significantly elevated the zinc level in plasma in rats .
It seems that Zn does not passively react to the changes in adipose tissue mass. Although being rather contradictory, the existing data demonstrate that the metabolic effects of Zn in obesity may be associated with its interference with leptin production.
Experimental studies demonstrate that adequate adipose tissue Zn status is required for normal adipocyte functioning and leptin synthesis to provide a leptin-mediated negative feedback. Taking into account the fact that Zn supplementation was associated with a further increase of serum leptin levels in obese leptin-resistant subjects, being accompanied by improvement of weight and metabolic parameters, one can propose that Zn may also decrease the rate of leptin resistance. At the same time, Baltaci and Mogulkoc have proposed that leptin may act as a possible link between zinc and immunity .
Zinc has a significant impact on other adipokines. In particular, it has been demonstrated that Zn stimulates oligomerization of higher molecular weight forms of adiponectin through modulation of disulfide bond formation . These findings are in agreement with the clinical observation of a positive correlation between serum Zn and adiponectin levels in obese patients with polycystic ovary syndrome . Moreover, 50 mg/day of Zn supplementation for 12 weeks in obese examinees was associated with a significant more than twofold increase in serum adiponectin concentration .
The targets for Zn-mediated impact on energy metabolism may include PPARs (proliferator-activated receptors), which are responsible for the expression of mRNA genes that play a critical role in energy metabolism [98, 99]. Three types of PPAR can be singled out: PPARα, PPARβ/δ, and PPARγ. PPARα and PPARβ/δ are mainly responsible for regulation of fatty acid degradation, whereas PPARγ takes part in lipid storage, regulates adipocyte differentiation, and enhances adipogenesis and insulin sensitivity [100, 101, 102, 103, 104]. The significant role of zinc in the zinc-finger protein as part of the proper functioning of PPARs has been confirmed by the research of Zhou et al. .
The observed interactions between Zn status and adipokine production are dependent on the functional state of the cell. In particular, certain studies have indicated that modulation of Zn levels has a significant impact on adipose tissue differentiation. A recent study demonstrated that zinc oxide (ZnO)-treatment (1–4 mg/l) upregulated PPARγ, FABP4, C/EBPα, and SREBP1 mRNA expression and stimulated lipid accumulation in adipocytes during adipogenesis . Similar findings were obtained for zinc-chelated vitamin C . In contrast, Justus et al.  have shown that zinc deficiency does not exacerbate PPARγ gene expression in rats. At the same time, certain studies demonstrated that ZnO nanoparticles (> 10 µg/ml) may be toxic to adipose tissue-derived mesenchymal stem cells, decreasing cell viability through induction of apoptosis .
The impact of Zn on adipocyte differentiation may be related to the functioning of various Zn-containing proteins that have been recognized as early regulators of adipogenesis . In particular, it has been demonstrated that Zn-finger protein ZNF638 is induced at early stages of adipocyte differentiation and stimulates adipogenesis through C/EBPs and subsequent up-regulation of PPARy. In turn, ZNF638 knockdown inhibits adipogenesis . Another Zn-finger protein, Zfp423, was also shown to be the factor stimulating adipocyte differentiation acting via stimulation of PPARy expression. It is also notable that Zfp423 deficiency is associated with impairment of both white and brown adipose tissue development . Zfp467 stimulates progenitor cell differentiation from osteoblastic to adipocyte lineage, increasing PPARy, C/EBPa, adiponectin and resistin expression . At the same time, Zfp467 suppression stimulated osteoblast commitment and alleviated osteoporosis, being characterized by specific changes of adipogenic and osteogenic marker proteins . In turn, Zfp521 acts as a negative regulator of adipogenesis at least partially through inhibition of Zfp423 expression . Other Zn-finger proteins involved in regulation of adipocyte determination and differentiation include Znf395, Shn-2, GATA proteins, SLUG, Egr2/Egr1, ZBTB16, YY1, and Krüppel-like factors .
Zinc and insulin secretion
Zinc is an essential trace element required for the normal synthesis, storage and secretion of insulin in pancreatic β-cells. It has been reported in a recent study that the depletion of zinc negatively impacts insulin sensitivity and glucose tolerance . Instead, Jayawardena et al.  have shown that zinc supplementation improves glucose homeostasis in patients with diabetes. Ahn et al.  have reported that zinc concentrations are inversely associated with insulin resistance but not correlated with metabolic syndrome. This metal also stimulates glycolysis, inhibits gluconeogenesis, and plays a role in glucose transport in adipocytes .
Insulin is co-stored and co-crystallized in granules in pancreatic β-cells with free cytosolic zinc. Six insulin monomers congregate in β-cells into a hexamer with two zinc ions in the center, and this form is stored and transported across the cell membrane as an insulin-zinc crystal in the normal functioning of β-cells. Slepchenko et al.  have shown inhibition of the zinc feature upon further glucose-stimulated secretion of insulin. After the zinc–insulin complexes have been secreted, they start to dissociate; only the insulin monomer is an active form of the hormone. The elevated extracellular concentration of free zinc is related to the increase in insulin secretion [60, 120, 121, 122].
Along with insulin, zinc also takes part in the inhibition of glucagon secretion in response to high glucose concentrations. Glucagon is a hormone secreted by α-cells of the pancreas, which increase the glucose blood level during hypoglycemia. When the glucose concentration decreases, zinc is released from the β-cells with insulin, triggering glucagon secretion . These findings were confirmed in the research conducted by Slucca et al.  and Myers . These authors have confirmed the inhibitive properties of zinc released with insulin on glucagon function in mice. Glucagon also regulates glycogen breakdown and gluconeogenesis and decreases at the same time triglyceride synthesis by the liver .
The interaction between zinc status and obesity may be at least partially mediated by obesity-induced modulation of zinc transporters that regulate cellular and intracellular Zn fluxes . In particular, in obese women, the highest expression was observed for ZnT1 followed by Zip1, whereas no significant expression of Zip3 was found . It has been revealed that obese patients were characterized by a significantly lower expression of Zip14 in subcutaneous adipose tissue, whereas a 10-week weight loss period significantly increased gene expression. Zip14 expression directly correlated with PPARy expression and HDL-C concentration, although being negatively associated with anthropometric markers of obesity, body fat percentage, HOMA-IR, blood glucose, insulin, and TG levels .
It was also observed that the deficiency of zinc-transporter protein 7 (ZnT7) plays a substantial role in lipid metabolism . It was found that the ZnT7 expression was induced by lipogenic differentiation in ZnT7 knockout mice and the decreased expression of this transporter exacerbates the signal transduction pathway activity, which regulates basal and insulin-stimulated glucose uptake in adipocytes .
It is suggested that also in glycemic control and glucose homeostasis transport zinc proteins play a crucial role. ZnT8 seems to be one of the most important zinc transporters in diabetes. Zinc-protein (ZnT8) is mainly expressed in pancreatic INS-1 β-cells, which contain the largest amount of zinc; this complex induces glucose-stimulated insulin secretion. ZnT8 plays an important role in zinc transport from the cytoplasm into insulin secretory granules within islets, and is thus an essential transporter in the synthesis, storage, and function of insulin [124, 132, 133]. Wijesekara et al.  and Pound et al.  have shown that zinc deficiency in mice may lead to ZnT8 depletion and may contribute to perturbed function of the islets of Langerhans and increased of insulin, leading to a greater risk of type 2 diabetes mellitus. These authors also reported that ZnT8 depletion may trigger the formation of atypical insulin-zinc secretory granules [133, 134]. Furthermore, Merriman et al.  have found that even mutations in ZnT8 may cause greater risk of type 2 diabetes.
Zinc also plays a crucial role in insulin degradation in the liver. It has been found that mutation in ZnT8 may contribute to dysregulation in insulin in the first passage through the liver and increase risk of type 2 diabetes mellitus development . Huang et al. [137, 138] demonstrated that ZnT7 transporter is also implicated in glucose–insulin homeostasis.
Βeta-cells contain larger amounts of zinc ions than are required for the formation of the zinc–insulin granules. After the co-crystallization and secretion of the insulin–zinc granules, the remaining quantities of zinc are redistributed to the cytosol by Zip transporters [139, 140]. Hardy et al.  have demonstrated increased levels of free cytosolic zinc in response to a higher level of Zip-4 in mice, whereas Liu et al.  reported an elevated concentration of zinc ions in response to increased activity of Zip-6 and Zip-7 transporters. Myers et al.  attempted to find a connection between Zip-7 activity and carbohydrate homeostasis; they demonstrated the contribution of Zip-7 to glucose uptake and the storage of glycogen in skeletal muscles. They also conclude that this transporter may be used in insulin resistance treatment. Feitosa et al.  have shown that Zip-14 also takes part in zinc homeostasis during inflammation caused by obesity. They also reported elevated plasma concentrations of IL-6, leading to the increased expression of Zip-14 in obese women.
Recent studies have brought attention to the fact that zinc acts as a signaling factor. The mechanism of zinc’s insulin-mimetic activity has been observed in several studies on glucose and lipid metabolism . The signal–transduction mechanism of ZIP10 reflects the role of Zn signaling in B cell function. Zip10-KO mice study showed evidence that ZIP10 signaling regulates caspase activity, promotes the survival of pro-B cells, and regulates the function of mature B-cells .
Conclusions and perspectives
Zinc is an essential trace element that plays a substantial role in the prevention of metabolic syndrome, including atherogenic dyslipidemia, hyperglycemia, insulinemia, and elevated blood pressure through the inhibition of proinflammatory cytokine expression, which suppresses ROS production, protecting against oxidative stress damage. Zinc takes part in ROS neutralization as well as in glucose and lipid metabolism. Zinc is thus highly significant in the pathogenesis of metabolic syndrome, which suggests that zinc supplementation would have a positive effect in regressing metabolic syndrome.
Further investigations of the relationship between Zn and cytokines, adipokines, antioxidants, and receptors are needed to explain the role of zinc in health and diseases. Modulation of zinc status may become a new target in the prevention and treatment of metabolic disorders. It has been shown that Zn transporters play the crucial role in zinc homeostasis in the body . It seems that deeper knowledge about physiological functions of Zn transporters and the ability to control their activity may be an important factor in developing new therapies for Zn-related diseases.
All authors have read and approved the final manuscript.
JO collected literature and drafted the manuscript; AT and AS drafted the manuscript and prepared the figures; JS developed the concept and drafted the manuscript; JO, AT, AS, and JS edited and revised the manuscript and approved the final version of the manuscript.
Compliance with ethical standards
This article was not funded by any grants.
This article does not contain any studies with human participants or animals performed by any of the authors.
Conflict of interest
The authors declare that they have no competing interests.
- 1.Hara T, Takeda TA, Takagishi T, Fukue K, Kambe T, Fukada TJ (2017) Physiological roles of zinc transporters: molecular and genetic importance in zinc homeostasis. J Physiol Sci 67(2):283–301Google Scholar
- 2.Ahn BI, Kim MJ, Koo HS, Seo N, Joo NS, Kim YS (2014) Serum zinc concentration is inversely associated with insulin resistance but not related with metabolic syndrome in nondiabetic Korean adults. Biol Trace Elem Res 160(2):169–175Google Scholar
- 4.Otto MCCD, Alonso A, Lee DH, Delclos GL, Jenny NS, Jiang R, Lima JA, Symanski E, Jacobs DR, Nettleton JA (2011) Dietary micronutrient intakes are associated with markers of inflammation but not with markers of subclinical atherosclerosis. J Nutr 141(8):1508S–1515SGoogle Scholar
- 6.Daradkeh G, Zerie M, Othman M, Chandra P, Jaiosi A, Mahmood L, Alowainati B, Mohammad I, Daghash M (2014) Zinc status among type (2) diabetes mellitus in the State of Qatar. Public Health Front 3(1):4–10Google Scholar
- 8.Ghasemi A, Zahediasl S, Hosseini-Esfahani F, Azizi F (2014) Gender differences in the relationship between serum zinc concentration and metabolic syndrome. Ann Hum Biol 41(5):436–442Google Scholar
- 9.Yu Y, Cai Z, Zheng J, Chen J, Zhang X, Huang XF, Li D (2012) Serum levels of polyunsaturated fatty acids are low in Chinese men with metabolic syndrome, whereas serum levels of saturated fatty acids, zinc, and magnesium are high. Nutr Res 32(2):71–77Google Scholar
- 12.de Luis DA, Pacheco D, Izaola O, Terroba MC, Cuellar L, Cabezas G (2013) Micronutrient status in morbidly obese women before bariatric surgery. Surg Obes Relat Dis 9(2):323–327Google Scholar
- 13.Suliburska J, Cofta S, Gajewska E, Kalmus G, Sobieska M, Samborski W, Bogdanski P (2013) The evaluation of selected serum mineral concentrations and their association with insulin resistance in obese adolescents. Eur Rev Med Pharmacol Sci 17(17):2396–2400Google Scholar
- 14.Ferro FED, de Sousa Lima VB, Mello Soares NR, Franciscato Cozzolino SM, Nascimento Marreiro DD (2011) Biomarkers of metabolic syndrome and its relationship with the zinc nutritional status in obese women. Nutr Hosp 26(3):650–654Google Scholar
- 18.Payahoo L, Ostadrahimi A, Mobasseri M, Bishak YK, Farrin N, Jafarabadi MA, Ostadrahimi A (2013) Effects of zinc supplementation on the anthropometric measurements, lipid profiles and fasting blood glucose in the healthy obese adults. Advan Pharm Bull 3(1):161–165Google Scholar
- 19.Kelishadi R, Hashemipour M, Adeli K, Tavakoli N, Movahedian-Attar A, Shapouri J, Rouzbahani A (2010) Effect of zinc supplementation on markers of insulin resistance, oxidative stress, and inflammation among prepubescent children with metabolic syndrome. Metab Syndr Relat Disord 8(6):505–510Google Scholar
- 20.Sinha S, Sen S (2014) Status of zinc and magnesium levels in type 2 diabetes mellitus and its relationship with glycemic status. Int J Diabetes Dev Ctries 34(4):220–223Google Scholar
- 21.Olaniyan OO, Awonuga MAM, Ajetunmobi AF, Adeleke IA, Fagbolade OJ, Olabiyi KO, Oyekanmi BA, Osadolor HB (2012) Serum copper and zinc levels in Nigerian type 2 diabetic patients. Afr J Diabetes Med 20(2):36–38Google Scholar
- 22.Devi TR, Hijam D, Dubey A, Debnath S, Oinam P, Devi NGT, Singh WG (2016) Study of serum zinc and copper levels in type 2 diabetes mellitus. Int J Contem Med Res 3(4):2454–7379Google Scholar
- 23.Kaur J, Singh T (2015) Estimation of serum magnesium and zinc levels in type-2 diabetes mellitus. Int J Bioassays 4(1):3654–3656Google Scholar
- 24.Yahya H, Yahya KM, Saqib A (2011) Minerals and type 2 diabetes mellitus—levels of zinc, magnesium and chromium in diabetic and nondiabetic population. J UMDC 2:1Google Scholar
- 25.Jyothirmayi B, Vasantha M (2015) Study of zinc and glycated Hb levels in diabetic complications. Int J Pharm Clin Res 7(5):360–363Google Scholar
- 26.Kumar DA, Priya VS, Jaiprabhu J, Ramalingam K (2014) Serum copper and zinc levels significance in type 2 diabetic patients. J Med Sci Tech 3(2):79–81Google Scholar
- 27.Bao B, Prasad AS, Beck FWJ, Fitzgerald JT, Snell D, Bao GW, Singh T, Cardozo LJ (2010) Zinc decreases C-reactive protein, lipid peroxidation, and inflammatory cytokines in elderly subjects: a potential implication of zinc as an atheroprotective agent. Am J Clim Nutr 91(6):1634–1641Google Scholar
- 28.Ho M, Baur LA, Cowell CT, Samman S, Garnett SP (2016) Zinc status, dietary zinc intake and metabolic risk in Australian children and adolescents; Nepean Longitudinal Study. Eur J Nutr 30:1–8Google Scholar
- 29.El-Ashmony SMA, Morsi HK, Abdelhafez AM (2012) Effect of zinc supplementation on glycemic control, lipid profile, and renal functions in patients with type II diabetes: a single blinded, randomized, placebo-controlled, trial. J Biol Agric Health 2(6):33Google Scholar
- 30.Kanoni S, Nettleton JA, Hivert M-F, Ye Z, van Rooij FJA, Shungin D, Sonestedt E, Ngwal JS, Wojczynski MK, Lemaitre RN, Gustafsson S, Anderson JS et al (2011) Total zinc intake may modify the glucose-raising effect of a zinc transporter (SLC30A8) variant a 14-cohort meta-analysis. Diabetes 60(9):2407–2416PubMedPubMedCentralGoogle Scholar
- 31.Islam MR, Attia J, Ali L, McEvoy M, Selim S, Sibbritt D, Akhter A, Akter S, Peel R, Faruque O, Mona T, Lona H, Milton AH (2016) Zinc supplementation for improving glucose handling in pre-diabetes: a double-blind randomized placebo controlled pilot study. Diabetes Res Clin Pract 115:39–46Google Scholar
- 32.Karamali M, Heidarzadeh Z, Seifati SM, Samimi M, Tabassi Z, Hajijafari M, Asemi Z, Esmaillzadeh A (2015) Zinc supplementation and the effects on metabolic status in gestational diabetes: a randomized, double-blind, placebo-controlled trial. J Diabetes Complic 29(8):1314–1319Google Scholar
- 33.El Dib R, Gameiro OL, Ogata MS, Módolo NS, Braz LG, Jorge EC, do Nascimento P Jr, Beletate V (2015) Zinc supplementation for the prevention of type 2 diabetes mellitus in adults with insulin resistance. Cochrane Database Syst Rev 28(5). doi: 10.1002/14651858.CD005525.pub3
- 35.Fernández-Sánchez A, Madrigal-Santillán E, Bautista M, Jaime Esquivel-Soto J, Morales-González A, Esquivel-Chirino C, Durante-Montiel I, Sánchez-Rivera G, Valadez-Vega C, Morales-González JA (2011) Inflammation, oxidative stress, and obesity. Int J Mol Sci 12(5):3117–3132PubMedPubMedCentralGoogle Scholar
- 39.von Bülow V, Dubben S, Engelhardt G, Hebel S, Plümäkers B, Heine H, Rink L, Haase H (2017) Zinc-dependent suppression of TNF-alpha production is mediated by protein kinase A-induced inhibition of Raf-1, I kappa B kinase beta, and NF-kappa B. J Immunol 179(6):4180–4186Google Scholar
- 45.Usmanova ZA (2015) Relationship between the levels of MMP-9, TIMP-1, and zinc in biological samples of patients with carotid atherosclerosis. IJBM 5(2):60–64Google Scholar
- 49.Hadwan MH, Almashhedy LA, Alsalman ARS (2014) Study of the effects of oral zinc supplementation on peroxynitrite levels, arginase activity and NO synthase activity in seminal plasma of Iraqi asthenospermic patients. Reprod Biol Endocrinol 12:1. doi: 10.1186/1477-7827-12-1 CrossRefPubMedPubMedCentralGoogle Scholar
- 51.Korkmaz-Icöz S, Atmanli A, Radovits T, Li S, Hegedüs P, Ruppert M, Brlecic P, Yoshikawa Y, Yasui H, Karck M, Szabó GJ (2016) Administration of zinc complex of acetylsalicylic acid after the onset of myocardial injuryprotects the heart by upregulation of antioxidant enzymes. J Physiol Sci 66(2):113–125PubMedGoogle Scholar
- 52.Li HT, Jiao M, Chen J, Liang Y (2010) Roles of zinc and copper in modulating the oxidative refolding of bovine copper, zinc superoxide dismutase. Acta Biochim Biophys Sin (Shanghai) 42(3):183–194Google Scholar
- 54.Perriotte-Olson C, Adi N, Manickam DS, Westwood RA, Desouza CV, Natarajan G, Saraswathi V (2014) Nanoformulated copper/zinc superoxide dismutase reduces adipose inflammation in obesity. Obesity 24(1):148–156Google Scholar
- 57.Marseglia L, Manti S, D’Angelo G, Nicotera A, Parisi E, Rosa Di, Gitto E, Arrigo T (2015) Oxidative stress in obesity: a critical component in human diseases. Int J Mol Sci 16(1):378–400Google Scholar
- 64.Muthuraman P, Ramkumar K, Kim DH (2014) Analysis of dose-dependent effect of zinc oxide nanoparticles on the oxidative stress and antioxidant enzyme activity in adipocytes. Appl Biochem Biotechnol 174(8):2851–2863Google Scholar
- 67.Taheri E, Djalali M, Saedisomeolia A, Moghadam AM, Djazayeri A, Qorbani M (2012) The relationship between the activates of antioxidant enzymes in red blood cells and body mass index in Iranian type 2 diabetes and healthy subjects. J Diabetes Metab Disord 11(1):3. doi: 10.1186/2251-6581-11-3 CrossRefPubMedPubMedCentralGoogle Scholar
- 71.Seet RC, Lee CYJ, Lim EC, Quek AM, Huang H, Huang SH, Halliwell B (2011) Oral zinc supplementation does not improve oxidative stress or vascular function in patients with type 2 diabetes with normal zinc levels. Atherosclerosis 219(1):231–239Google Scholar
- 72.Marjani A, Moradi A, Saeedi M (2017) Plasma lipid peroxidation zinc and erythrocyte Cu-Zn superoxide dismutase enzyme activity in patients with type 2 diabetes mellitus in Gorgan City (South East of the Caspian Sea). J Med Sci 7(4):585–590Google Scholar
- 81.Tinkov AA, Popova EV, Gatiatulina ER, Skalnaya AA, Yakovenko EN, Alchinova IB, Nikonorov AA (2016) Decreased adipose tissue zinc content is associated with metabolic parameters in high fat fed Wistar rats. Acta Sci Pol Technol Aliment 15(1):99–105Google Scholar
- 86.Mazloomi S, Alizadeh N, Aminzare M, Niroomand S, Mousavi SN (2017) Serum zinc and adiponectin levels in patients with polycystic ovary syndrome, adjusted for anthropometric, biochemical, dietary intake, and physical activity measures. Biol Trace Elem Res. doi: 10.1007/s12011-017-0951-0 CrossRefPubMedGoogle Scholar
- 87.Soheylikhah SEDIGHEH, Dehestani MR, Mohammadi SM, Afkhami AM, Eghbali SA, Dehghan F (2012) The effect of zinc supplementation on serum adiponectin concentration and insulin resistance in first degree relatives of diabetic patients. Iran J Diabetes Obes 4(2):57–62Google Scholar
- 88.Bing C, Mracek T, Gao D, Trayhurn P (2012) Zinc-α2-glycoprotein: an adipokine modulator of body fat mass? Int J Obes 34(11):1559–1565Google Scholar
- 89.Garrido-Sánchez L, García-Fuentes E, Fernández-García D, Escote X, Alcaide J, Perez-Martinez P, Vendrell J, Tinahones FJ (2012) Zinc-alpha 2-glycoprotein gene expression in adipose tissue is related with insulin resistance and lipolytic genes in morbidly obese patients. PLoS One 7(3):e33264PubMedPubMedCentralGoogle Scholar
- 90.Russell ST, Tisdale MJ (2011) Studies on the antiobesity effect of zinc-α2-glycoprotein in the ob/ob mouse. Int J Obes 35:345–354Google Scholar
- 91.Cabassi A, Tedeschi S (2013) Zinc-α2-glycoprotein as a marker of fat catabolism in humans. Curr Opin Clin Nutr Metab Care 16(3):267–271Google Scholar
- 92.Yang M, Liu R, Li S, Luo Y, Zhang Y, Zhang L, Liu D, Wang Y, Xiong Z, Boden G et al (2013) Zinc-α2-glycoprotein is associated with insulin resistance in humans and is regulated by hyperglycemia, hyperinsulinemia, or liraglutide administration: cross-sectional and interventional studies in normal subjects, insulin-resistant subjects, and subjects with newly diagnosed diabetes. Diabetes Care 36(5):1074–1082PubMedPubMedCentralGoogle Scholar
- 93.Mracek T, Ding Q, Tzanavari T, Kos K, Pinkney J, Wilding J, Trayhurn P, Bing C (2010) The adipokine zinc-a2-glycoprotein (ZAG) is downregulated with fat mass expansion in obesity. Clin Endocrinol 72:334–341Google Scholar
- 96.Balaz M, Vician M, Janakova Z, Kurdiova T, Surova M, Imrich R, Belan V (2014) Subcutaneous adipose tissue zinc-α2-glycoprotein is associated with adipose tissue and whole-body insulin sensitivity. Obesity 22(8):1821–1829Google Scholar
- 97.Zahid H, Miah L, Lau AM, Brochard L, Hati D, Bui TT, McDermott LC (2016) Zinc-induced oligomerization of zinc α2 glycoprotein reveals multiple fatty acid-binding sites. Biochem J 473(1):43–54Google Scholar
- 102.Bergen WG, Burnett DD (2013) Topics in transcriptional control of lipid metabolism: from transcription factors to gene-promoter polymorphisms. J Genoms 20(1):13–21Google Scholar
- 116.Yanga HK, Leea SH, Hanc K, Kanga B, Leed SY, Yoona KH, Kwona HS, Parkf YM (2015) Lower serum zinc levels are associated with unhealthy metabolic status in normal-weight adults: the 2010 Korea National Health and Nutrition Examination Survey. Diabetes Metabol 41:282–290Google Scholar
- 118.Ahn B-I, Kim MJ, Koo HS, Seo N, Joo N-S, Kim Y-S (2014) Serum zinc concentration is inversely associated with insulin resistance but not related with metabolic syndrome in nondiabetic Korean adults. Biol Trace Elem Res 160:169–175Google Scholar
- 126.Maxel T, Smidt K, Larsen A, Bennetzen M, Cullberg K, Fjeldborg K, Lund S, Pedersen SB, Rungby J (2015) Gene expression of the zinc transporter ZIP14 (SLC39a14) is affected by weight loss and metabolic status and associates with PPARγ in human adipose tissue and 3T3-L1 pre-adipocytes. BMC Obes 2:46PubMedPubMedCentralGoogle Scholar
- 129.Troche C, Aydemir TB, Cousins RJ (2016) Zinc transporter Slc39a14 regulates inflammatory signaling associated with hypertrophic adiposity. Am J Physiol Endocrinol Metab 310(4):258–268Google Scholar
- 131.Fukunaka A, Fukada T, Bhin J, Suzuki L, Tsuzuki T, Takamine Y, Bin BH, Yoshihara T, Ichinoseki-Sekine N, Naito H, Miyatsuka T, Takamiya S, Sasaki T, Inagaki T, Kitamura T, Kajimura S, Watada H, Fujitani Y (2017) Zinc transporter ZIP13 suppresses beige adipocyte biogenesis and energy expenditure by regulating C/EBP-β expression. PLoS Genet 13(8):e1006950. doi: 10.1371/journal.pgen.1006950 CrossRefPubMedPubMedCentralGoogle Scholar
- 132.Solomou A, Meur G, Bellomo E, Hodson DJ, Tomas A, Li SM, Philippe E, Herrera PL, Magnan C, Rutter GA (2015) The zinc transporter Slc30a8/ZnT8 is required in a subpopulation of pancreatic α-cells for hypoglycemia-induced glucagon secretion. J Biol Chem 290(35):21432–21442PubMedPubMedCentralGoogle Scholar
- 133.Pound LD, Sarkar SA, Ustione A, Dadi PK, Shadoan MK, Lee CE, Walters JA, Shiota M, McGuinness OP, Jacobson DA et al (2012) The physiological effects of deleting the mouse SLC30A8 gene encoding zinc transporter-8 are influenced by gender and genetic background. PLoS One 7(7):40972Google Scholar
- 134.Wijesekara N, Dai FF, Hardy AB, Giglou PR, Bhattacharjee A, Koshkin V, Chimienti F, Gaisano HY, Rutter GA, Wheeler MB (2010) Beta cell-specific Znt8 deletion in mice causes marked defects in insulin processing, crystallisation and secretion. Diabetologia 53(8):1656–1668PubMedPubMedCentralGoogle Scholar
- 139.Hardy AB, Prentice KJ, Froese S, Liu Y, Andrews GK, Wheeler MB (2015) Zip4 mediated zinc influx stimulates insulin secretion in pancreatic beta cells. PLoS One 10(3):0119136Google Scholar
- 140.Liu Y, Batchuluun B, Ho L, Zhu D, Prentice KJ, Bhattacharjee A, Zhang M, Pourasgari F, Hardy AB, Taylor KM, Gaisano H, Dai FF, Wheeler MB (2015) Characterization of zinc influx transporters (ZIPs) in pancreatic β cells: roles in regulating cytosolic zinc homeostasis and insulin secretion. J Biol Chem 290(30):18757–18769PubMedPubMedCentralGoogle Scholar
- 142.Feitosa MC, Lima VB, Moita Neto JM, Marreiro DN (2013) Plasma concentration of IL-6 and TNF-α and its relationship with zincemia in obese women. Rev Assoc Med Bras 59(5):429–434Google Scholar
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.