Meika Foster

Zinc and Regulation of Inflammatory Cytokines: Implications for Cardiometabolic Disease

In atherosclerosis and diabetes mellitus, the concomitant presence of low-grade systemic inflammation and mild zinc deficiency highlights a role for zinc nutrition in the management of chronic disease. This review aims to evaluate the literature that reports on the interactions of zinc and cytokines. In humans, inflammatory cytokines have been shown both to up- and down-regulate the expression of specific cellular zinc transporters in response to an increased demand for zinc in inflammatory conditions. The acute phase response includes a rapid decline in the plasma zinc concentration as a result of the redistribution of zinc into cellular compartments. Zinc deficiency influences the generation of cytokines, including IL-1β, IL-2, IL-6, and TNF-α, and in response to zinc supplementation plasma cytokines exhibit a dose-dependent response. The mechanism of action may reflect the ability of zinc to either induce or inhibit the activation of NF-κB. Confounders in understanding the zinc-cytokine relationship on the basis of in vitro experimentation include methodological issues such as the cell type and the means of activating cells in culture. Impaired zinc homeostasis and chronic inflammation feature prominently in a number of cardiometabolic diseases. Given the high prevalence of zinc deficiency and chronic disease globally, the interplay of zinc and inflammation warrants further examination.

Zinc and Redox Signaling: Perturbations Associated with Cardiovascular Disease and Diabetes Mellitus

Cellular signal transduction pathways are influenced by the zinc and redox status of the cell. Numerous chronic diseases, including cardiovascular disease (CVD) and diabetes mellitus (DM), have been associated with impaired zinc utilization and increased oxidative stress. In humans, mutations in the MT-1A and ZnT8 genes, both of which are involved in the maintenance of zinc homeostasis, have been linked with DM development. Changes in levels of intracellular free zinc may exacerbate oxidative stress in CVD and DM by impacting glutathione homeostasis, nitric oxide signaling, and nuclear factor-kappa B-dependent cellular processes. Zinc ions have been shown to influence insulin and leptin signaling via the phosphoinositide 3′-kinase/Akt pathway, potentially linking an imbalance of zinc at the cellular level to insulin resistance and dyslipidemia. The oxidative modification of cysteine residues in zinc coordination sites in proteins has been implicated in cellular signaling and regulatory pathways. Despite the many interactions between zinc and cellular stress responses, studies investigating the potential therapeutic benefit of zinc supplementation in the prevention and treatment of oxidative stress-related chronic disease in humans are few and inconsistent. Further well-designed randomized controlled trials are needed to determine the effects of zinc supplementation in populations at various stages of CVD and DM progression.

Zinc and glycemic control: a meta-analysis of randomised placebo controlled supplementation trials in humans.

BACKGROUND Impaired zinc metabolism is prominent in chronic disorders including cardiovascular disease and diabetes. Zinc has the potential to affect glucose homeostasis in animals and humans and hence impact the risk of type 2 diabetes mellitus. METHODS A systematic review and meta-analysis of randomised placebo controlled trials was conducted to determine the effect of zinc supplementation on fasting blood glucose, HbA1c, serum insulin and serum zinc concentrations. Relevant studies for inclusion were identified from a literature search of electronic databases up to July 2011. RESULTS Fourteen reports (n=3978 subjects) were included in the meta-analysis. In the overall analysis, a small but statistically significant reduction in fasting glucose concentrations was observed (-0.19±0.08mmol/L, P=0.013) after zinc supplementation. HbA1c tended to decrease in zinc-supplemented individuals (-0.64±0.36%, P=0.072). No significant effect was observed for serum insulin concentrations. Plasma zinc concentrations increased significantly following supplementation (+4.03±0.81μmol/L, P=0.001). In secondary analyses of participants with chronic metabolic disease (types 1 and 2 diabetes mellitus, metabolic syndrome and obesity), zinc supplementation produced a greater reduction in glucose concentrations (-0.49±0.11mmol/L, P=0.001) compared to the effect that was observed in healthy participants. CONCLUSION The significant albeit modest reduction in glucose concentrations and tendency for a decrease in HbA1c following zinc supplementation suggest that zinc may contribute to the management of hyperglycemia in individuals with chronic metabolic disease.

Evaluation of the Micronutrient Composition of Plant Foods Produced by Organic and Conventional Agricultural Methods

The aim of the present analysis was to evaluate the micronutrient content of plant foods produced by organic and conventional agricultural methods. Studies were identified from a search of electronic databases (1980–2007, inclusive) as well as manual searches. A total of 66 studies (describing 1440 micronutrient comparisons) were identified. Thirty-three studies (908 comparisons) satisfied the screening criteria which considered cultivar, harvesting, and soil conditions. In studies that satisfied the screening criteria, the absolute levels of micronutrients were higher in organic foods more often than in conventional foods (462 vs 364 comparisons, P = 0.002), and the total micronutrient content, expressed as a percent difference, was higher in organic (+ 5.7%, P < 0.001) as compared to conventionally grown produce. The micronutrient content of food groups was more frequently reported to be higher for organic vegetables and legumes compared to their conventional counterparts (vegetables, 267 vs 197, P < 0.001; legumes, 79 vs 46, P = 0.004). This trend was supported by a mean percent difference in micronutrient content favoring organic vegetables (+ 5.9%, P < 0.001) and legumes (+ 5.7%, P < 0.001). Further research is required to determine the effect of organic agricultural methods on a broader range of nutrients and their potential impact on health.

Effects of zinc on plasma lipoprotein cholesterol concentrations in humans: A meta-analysis of randomised controlled trials

BACKGROUND Studies in humans and animals suggest that zinc has the potential to affect lipoprotein metabolism and hence impact cardiovascular disease risk. METHODS A meta-analysis of controlled clinical trials was conducted to determine the effect of zinc supplementation on plasma cholesterol and triglyceride concentrations in humans. Potentially relevant studies were identified from a literature search covering the period 1980-2008 (inclusive), and additional citation searches. RESULTS Thirty three interventions (n=14,238 subjects) were included in the random effects meta-analysis. No overall significant effects of zinc supplementation were observed for plasma cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol or plasma triglyceride concentrations. Plasma zinc concentrations increased significantly (+2.42+/-0.25 micromol/L, P<0.001; n=14,047). Secondary analyses in individuals classified as healthy revealed that zinc supplementation is associated with a significant decrease in plasma HDL cholesterol concentrations (-0.10+/-0.02 mmol/L, P<0.001; n=13,215), equivalent to a 7% decrease from baseline. CONCLUSION No effect of zinc supplementation on plasma lipoproteins was detected in the overall analysis. In individuals classified as healthy, zinc supplementation is associated with a decrease in HDL cholesterol concentrations and thus contributes to an increased risk of coronary heart disease.

Zinc Transporter Genes Are Coordinately Expressed in Men and Women Independently of Dietary or Plasma Zinc

The zinc transporter (ZnT; SLC30) and Zrt- and Irt-like protein (Zip, SLC39) zinc transporter families are integral to the maintenance of intracellular zinc concentrations. Few studies have examined the expression patterns of zinc transporter genes in human primary tissues. This study investigated the expression levels of a range of zinc transporter mRNA in the peripheral blood mononuclear cells of healthy men and women (n = 40) using quantitative real-time PCR. It also explored the relationships among zinc transporter expression levels, plasma zinc concentrations, and dietary zinc intake. The relative expression of the zinc transporter mRNA varied considerably, with ZnT7, ZnT1, and Zip1 being the most abundantly expressed. ZnT1 and Zip1 mRNA were highly correlated with one another (r = 0.9; P < 0.001) and with ZnT5, ZnT7, Zip3, and Zip10 (P < 0.001). When analyzed by gender, a correlation between the mRNA of ZnT7 and Zip3 (r = 0.6; P < 0.01) was demonstrated only in women. Zip10 mRNA was correlated with ZnT1 and Zip1 (r = 0.9; P < 0.001) in men only. In a regression analysis, plasma zinc variability was not significantly explained by dietary zinc intake, gender, age, or any individual or combination of zinc transporters. This study expands what is known about both the levels of zinc transporter gene transcription in humans and the extent of its variation in healthy men and women. The positive association between the mRNA of ZnT1 and Zip1, which have reciprocal roles in zinc transport across the plasma membrane, provides insight into the coordinated control of zinc homeostasis in humans.

Effect of vegetarian diets on zinc status: a systematic review and meta‐analysis of studies in humans

Plant-based diets contain less saturated fat and cholesterol and more folate, fibre and phytochemicals than omnivorous diets, but some micronutrients, especially zinc, are poorly bioavailable. The findings of studies exploring the zinc intake and zinc status in populations that habitually consume vegetarian diets are inconsistent. This study aims to investigate the effects of plant-based diets on dietary zinc intake and status in humans using systematic review and meta-analysis techniques. Thirty-four studies were included in the systematic review. Of these, 26 studies (reporting 48 comparisons) compared males and/or females consuming vegetarian diets with non-vegetarian groups and were included in meta-analyses. Dietary zinc intakes and serum zinc concentrations were significantly lower (-0.88 ± 0.15 mg day(-1), P < 0.001 and -0.93 ± 0.27 µmol L(-1), P = 0.001 respectively; mean ± standard error) in populations that followed habitual vegetarian diets compared with non-vegetarians. Secondary analyses showed greater impact of vegetarian diets on the zinc intake and status of females, vegetarians from developing countries and vegans. Populations that habitually consume vegetarian diets have low zinc intakes and status. Not all vegetarian categories impact zinc status to the same extent, but a lack of consistency in defining vegetarian diets for research purposes makes dietary assessment difficult. Dietary practices that increase zinc bioavailability, the consumption of foods fortified with zinc or low-dose supplementation are strategies that should be considered for improving the zinc status of vegetarians with low zinc intakes or serum zinc concentrations at the lower end of the reference range.

Inflammation markers predict zinc transporter gene expression in women with type 2 diabetes mellitus

The pathology of type 2 diabetes mellitus (DM) often is associated with underlying states of conditioned zinc deficiency and chronic inflammation. Zinc and omega-3 polyunsaturated fatty acids each exhibit anti-inflammatory effects and may be of therapeutic benefit in the disease. The present randomized, double-blind, placebo-controlled, 12-week trial was designed to investigate the effects of zinc (40 mg/day) and α-linolenic acid (ALA; 2 g/day flaxseed oil) supplementation on markers of inflammation [interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α, C-reactive protein (CRP)] and zinc transporter and metallothionein gene expression in 48 postmenopausal women with type 2 DM. No significant effects of zinc or ALA supplementation were observed on inflammatory marker concentrations or fold change in zinc transporter and metallothionein gene expression. Significant increases in plasma zinc concentrations were observed over time in the groups supplemented with zinc alone or combined with ALA (P=.007 and P=.009, respectively). An impact of zinc treatment on zinc transporter gene expression was found; ZnT5 was positively correlated with Zip3 mRNA (P<.001) only in participants receiving zinc, while zinc supplementation abolished the relationship between ZnT5 and Zip10. IL-6 predicted the expression levels and CRP predicted the fold change of the ZnT5, ZnT7, Zip1, Zip7 and Zip10 mRNA cluster (P<.001 and P=.031, respectively). Fold change in the expression of metallothionein mRNA was predicted by TNF-α (P=.022). Associations among inflammatory cytokines and zinc transporter and metallothionein gene expression support an interrelationship between zinc homeostasis and inflammation in type 2 DM.

Vegetarian Diets Across the Lifecycle: Impact on Zinc Intake and Status

Optimal zinc status is an important consideration when evaluating the nutritional adequacy of vegetarian diets. In the absence of animal tissue sources of zinc and with increased intake of inhibitors of zinc absorption, phytic acid in particular, the bioavailability of zinc is thought to be lower from vegetarian as compared to omnivorous diets. The aim of this chapter is to review the research that examines the effects of vegetarian compared to omnivorous diets on zinc intake and zinc status in the elderly, adults, children, pregnancy, and lactation. A narrative review of the published literature was undertaken, focusing on observational studies in humans that reported zinc intake and biomarkers of zinc status at various stages of the life cycle. Compared to their respective nonvegetarian control groups, adult male and female vegetarians have lower dietary zinc intakes and serum zinc concentrations. However in the elderly, children, and in women during pregnancy and lactation, there is insufficient evidence to determine whether zinc intake and status are lower in vegetarians compared to omnivores. Inconsistencies in study findings reflect variations inherent in the definition of vegetarian diets, and in many instances compromised statistical power due to a small sample size. Improved methods for the assessment of zinc status are required to determine whether homeostatic responses are sufficient to maintain an adequate zinc status in vegetarians, particularly during times of increased requirement. Appropriate dietary advice to increase the zinc content and bioavailability of vegetarian diets throughout the life cycle is prudent.

Zinc transporter gene expression and glycemic control in post-menopausal women with Type 2 diabetes mellitus.

Type 2 diabetes mellitus (DM) is associated often with underlying zinc deficiency and nutritional supplements such as zinc may be of therapeutic benefit in the disease. In a randomized, double-blind, placebo-controlled, 12-week trial in postmenopausal women (n=48) with Type 2 DM we investigated the effects of supplementation with zinc (40mg/d) and flaxseed oil (FSO; 2g/d) on the gene expression of zinc transporters (ZnT1, ZnT5, ZnT6, ZnT7, ZnT8, Zip1, Zip3, Zip7, and Zip10) and metallothionein (MT-1A, and MT-2A), and markers of glycemic control (glucose, insulin, glycosylated hemoglobin [HbA1c]). The homeostasis model assessment of insulin resistance (HOMA-IR) was calculated. No significant effects of zinc or FSO supplementation were observed on glycemic marker concentrations, HOMA-IR or fold change over 12 weeks in zinc transporter and metallothionein gene expression. In multivariate analysis, the change over 12 weeks in serum glucose concentrations (P=0.001) and HOMA-IR (P=0.001) predicted the fold change in Zip10. In secondary analysis, marginal statistical significance was observed with the change in both serum glucose concentrations (P=0.003) and HOMA-IR (P=0.007) being predictive of the fold change in ZnT6. ZnT8 mRNA expression was variable; HbA1c levels were higher (P=0.006) in participants who exhibited ZnT8 expression compared to those who did not. The significant predictive relationships between Zip10, ZnT6, serum glucose and HOMA-IR are preliminary, as is the relationship between HbA1c and ZnT8; nevertheless the observations support an association between Type 2 DM and zinc homeostasis that requires further exploration.