Chronic metabolic diseases, such as cardiovascular diseases (CVD) and Type 2 diabetes mellitus (DM), represent a significant proportion of non-communicable disease (NCD) deaths around the world [1
]. In 2012, 17.5 million and 1.5 million deaths were attributed to CVD and Type 2 DM, respectively. Deaths due to NCD are projected to increase, with the majority occurring in low- and middle-income countries (LMIC). The role of diet and physical activity in the prevention and management of chronic metabolic diseases is recognised by numerous health organisations [2
]. While there is substantial evidence for optimal dietary patterns and macronutrient compositions for the prevention of diseases, the influence of micronutrient intakes, such as zinc, on the risk of developing chronic metabolic diseases remains to be elucidated.
Zinc is an essential trace element with antioxidant activity and functions related to energy metabolism and growth [4
]. In addition, zinc has been shown to serve a regulatory role in many signalling pathways, including potentiation of leptin and insulin signalling [5
]. The involvement of zinc in immunity has been demonstrated consistently in cellular studies [6
]; specifically, a protective role of zinc was shown for autoimmune diseases, including multiple sclerosis [7
] and Type 1 DM [8
]. Recent genome-wide association studies identified the potential roles of Zinc Transporter-8 (ZnT8; SLC30A8) and zinc status in the pathogenesis and management of Type 2 DM [9
]. Meta-analyses of randomised controlled trials (RCT) involving patients with Type 2 DM revealed improvements in measures of glycaemic control [10
] and dyslipidaemia [11
] following zinc supplementation. The mechanisms of action have been proposed to involve improvements in the stability of insulin within pancreatic β-cells and insulin sensitivity in peripheral tissues. While the therapeutic effects of zinc in Type 2 DM have been proposed [10
], the associations between zinc status and the prospective risks of developing CVD and Type 2 DM have not been evaluated.
Findings in cell and animal studies support the protective role of zinc against the risk factors of CVD, such as the development of atherosclerosis. The modulating effects of zinc on the formation of atherosclerotic plaque are primarily attributed to the role of zinc in supporting the structural integrity of endothelial cells and attenuating lipid peroxidation through zinc-regulated redox signalling pathways [5
]. In cultured endothelial cells, the aberrant expression of inducible nitric oxide synthase (iNOS) forms the basis of endothelial dysfunction and pathogenesis of atherosclerosis. Zinc has been shown to regulate the activity of iNOS, reversing the adverse effects of inflammation on the endothelium [13
]. In addition, zinc supplementation has been shown to reduce atheroma formation and plasma and arterial wall lipid peroxidation in rabbits fed a high cholesterol diet [14
]. Taken together, the growing evidence derived from experimental models provides biological plausibility for a potential role of zinc in CVD prevention.
Furthermore, the association between zinc deficiency, low grade inflammation and immune response supports the importance of optimal zinc status in modulating the inflammatory events required for atherosclerosis development in humans [15
]. While RCT designed to study the effects of zinc supplementation on the development of CVD are limited, a number of observational studies have explored the relationship between zinc status and CVD outcomes [17
]. In a Finnish nested case-control study, the highest tertile of serum zinc concentration was associated with 43% reduction in the relative risk (RR) of CVD death compared to those in the lowest tertile of serum zinc [17
]. Similar trends were observed in an urban Indian population, where higher dietary zinc intakes and higher concentrations of serum zinc concentrations were correlated with reduced prevalence of coronary artery disease and Type 2 DM [18
To date, no systematic review has explored the link between zinc status and the risk of developing chronic metabolic diseases, specifically Type 2 DM and CVD. Therefore, our aim is to determine the relationship between zinc intake, plasma/serum zinc concentrations and prospective incidence of CVD and Type 2 DM in cohort studies.
The present synthesis of prospective cohort studies has identified an incomplete evidence-base to establish a relationship between zinc intake, CVD and Type 2 DM risk in apparently healthy populations. However, higher serum zinc level appears to be associated with lower risk of CVD in vulnerable populations, such as those with Type 2 DM [23
] and patients referred to coronary angiography [31
The prospective cohort studies included in the current review, although limited in number, show no effect of serum zinc levels on CVD risk in nonclinical populations, except in the study of British elderly populations where higher dietary zinc intake was associated with decreased risk of vascular disease mortality following minimal statistical adjustments of age and sex only. In contrast, significant protective effects of zinc status on CVD deaths were shown in those with significant CVD risk factors. Soinio et al. identified that patients with Type 2 DM with serum zinc levels <14.1 μmol/L were at higher risk of MI [23
]. Similarly, for patients who were referred to coronary angiography, those with serum zinc <11.9 μmol/L experienced greater risk of CVD mortality [31
]. The serum zinc thresholds identified for increased CVD risk from these studies are within the typical reference range of 10–18 μmol/L [37
]. This suggests that the optimal level of serum zinc concentrations for the reduction of CVD risk exists at the upper end of the reference range for those with pre-existing risk factors. There is good evidence for improving zinc status in individuals with pre-existing Type 2 DM as an adjunct treatment strategy for the reduction of DM complications, such as CVD [38
]. Optimal zinc status, achieved by supplementation or dietary means, is associated with improvements in intermediate markers of Type 2 DM disease progression, such as glycaemic control [10
] and lipidemia [11
], in addition to reduced rates of complications secondary to DM [23
All studies exploring the relationship between zinc intake and prospective risks of CVD and Type 2 DM were conducted in the general population. The evidence of relationship between dietary/supplemental zinc on risk of CVD and Type 2 DM provided by the prospective cohort studies are complicated by inherent confounding factors, such as sex differences. Significant decrease in Type 2 DM incidences were found with higher dietary zinc intake in female participants [32
], studies involving both sexes with statistical adjustments for sex reported no association [30
], and in a male study population, higher serum zinc levels were associated with increased risk of Type 2 DM [36
The collation of prospective cohort studies in this review highlights the inconsistency of statistical models utilised in the current literature; this is exemplified by the majority of unclear to high risk of bias ratings for the adequate control of confounding factors. While the majority of the papers included adjustments for confounding factors, the combinations of factors used are largely varied, with some models lacking adjustments that are widely accepted in the literature. For example, while there is good evidence that dietary trans
-fatty acids are positively associated with CVD risk and events [40
], some studies have omitted trans
-fatty acids as a covariate variable in their models [25
]. The lack of adjustments for confounding factors can introduce bias in the reported results, especially taken together with the inherent limitations of prospective cohort studies, such as potential selection bias [41
]. Furthermore, the included studies reported diverse metrics of outcome measures, for example the report of hazard ratios as continuous variable (HR per SD decrease) [25
], or comparisons of quartiles [27
] and tertiles [28
] of serum zinc. The small number of studies, in addition to inconsistencies in statistical models and covariate adjustments, added differences in the determination and presentation of the effects of zinc status on CVD and Type 2 DM rendering meta-analysis of effect inappropriate currently.
The majority of the studies reporting total zinc intake used FFQ to estimate habitual dietary zinc intake of the study population [24
]. In validation studies that compared different methods of dietary assessment, long term zinc intake derived from FFQ and dietary records were well correlated [43
]. In contrast, variability in results reported for serum zinc levels may be attributed to differences in methods of measurement. Three of the five included studies [23
] used AAS to determine serum zinc concentration, as the “gold standard” method recommended by the International Zinc Nutrition Consultative Group (IZiNCG) [37
]. The other studies [25
] utilised colorimetric assays for serum zinc analyses, which are liable to significant systematic and fixed bias when compared to zinc analysis by AAS [44
]. The intrinsic differences in zinc analysis methods, highlighted in the ratings of risk of biases relating to valid measurements of exposure and outcome, should be considered in the interpretation of variations in the results presented currently.
The interaction between zinc and other nutrients in determining the risk of cardiometabolic diseases was explored in several included studies [26
]. Alcohol consumption has been consistently associated with CVD events in a J-shaped relationship, whereby low to moderate alcohol consumption is protective against CVD mortality when compared to non-drinkers or those with high alcohol consumption [45
]. When categories of dietary zinc intakes and RR of CVD mortality were stratified by alcohol consumption, Lee et al. showed protective effect of increasing zinc intake for women consuming ≥10 g alcohol/day [26
], thereby suggesting additive and separate mechanisms of effect of zinc and alcohol on CVD risk. Interactions between zinc and other minerals, such as iron and copper, have been explored in determining the risk of CVD and Type 2 DM. Higher dietary zinc/iron ratio was associated with lower risk of developing Type 2 DM in a cohort of Australian women [32
], possibly due to the antagonist effect of dietary iron on zinc absorption [46
]. While known interactions between zinc and other nutrients were explored as ratios or stratified statistical analyses in some included studies, the mechanisms of interaction remain unclear. Furthermore, there is a lack of differentiation in the dietary sources of zinc in the included studies, with only one report of dietary zinc from red meat correlated to CVD risks (but not Type 2 DM risk), despite no association with total zinc intake [30
]. Different food groups, such as processed meats, nuts and cereals, have been shown to elicit different effects on risks of CVD and Type 2 DM [47
]; therefore, the influence of different food groups on the effects of dietary zinc intake and disease risks should be considered in the evaluation of the relationships. Future investigation should consider the inclusion of secondary analyses determining the effect of dietary sources of zinc on the prospective risks of CVD and Type 2 DM.
The generalisability of the present results may be limited to high income countries, where all included studies were conducted. Disparities in health care and management of chronic diseases stratified by socioeconomic development of countries are highlighted by differences in life expectancy and probabilities of death from NCD [1
]. For individuals with Type 2 DM, management of DM in LMIC may be suboptimal in the prevention of DM associated complications [48
]. Novel interventions, such as those that improve zinc status of patients with DM, may be an applicable, low cost strategy, in conjunction with current management therapies, for the prevention of DM complications, such as CVD. In addition, environmental factors that affect zinc levels in soil and water may be important in determining disease risk. Ecological studies have shown negative associations between zinc levels in soil and onset of autoimmune diseases, specifically Type 1 DM [49
] and multiple sclerosis [50
], suggesting that natural zinc bioavailability in different locations can influence risk of developing diseases.
Little information regarding the relationship between dietary zinc intake and serum zinc concentration was available from the included studies. A recent meta-regression of zinc supplementation/depletion studies revealed a logarithmic relationship between these two variables, whereby a doubling of zinc intake corresponded with a 6% increase in serum zinc concentration [51
]. However, this relationship is complicated by the numerous factors, other than zinc intake, that can influence serum zinc concentration [46
], for example, inflammation and zinc bioavailability. Reduced zinc bioavailability, in particular in diets with a high ratio of phytate to zinc, has been suggested to impair the absorption of zinc in the gastrointestinal tract and hence incorporation into body tissues [52
]. However, it is difficult to determine the absolute amount of zinc absorbed as it is likely that the higher zinc content in some high phytate foods, compared to products lower in phytate, may compensate for the less efficient absorption of zinc [53
Furthermore, potential interactions should be considered in regards to the effects of current preventative and treatment recommendations for obesity-related chronic diseases, such as exercise and dietary management, on zinc status. For example, higher intakes of dietary fibre are often recommended to individuals with Type 2 DM [54
] and those with increased risk for cardiometabolic diseases. Foods that are high in fibre are also high in phytate and the effects of phytate on reducing the bioavailability of zinc in the gut is well-established [55
]; thereby, the incidental effect of increased dietary fibre on risk of zinc deficiency may be a determining factor in risk of chronic diseases. Moreover, lifestyle modifications, specifically physical activity, can modulate nutrient status [56
] with implications for beneficial effects induced by exercise [57
]. Further investigations are required to examine the interactions between zinc status and current preventative and treatment recommendations, especially exercise and intakes of competing nutrients, in the management of obesity-related chronic diseases.