Abstract
The maintenance of zinc homeostasis at the whole body and cellular levels is critical in optimising the biological functions of zinc. There is growing evidence suggesting interactions between zinc homeostasis, pathophysiology and clinical management of chronic diseases, including the role of exercise. The primary objective of this thesis was to explore the determinants and impact of zinc status under conditions of health, exercise and chronic disease, in particular Type 2 diabetes mellitus (DM) and cardiovascular diseases (CVD).
To evaluate the evidence of relationships between zinc status and risk of Type 2 DM and CVD, we undertook a systematic review of prospective cohort studies. The overall findings revealed a trend towards protective effects of higher dietary zinc levels on Type 2 DM risk in previously healthy populations. Higher serum zinc concentrations were related also to lower risk of CVD, particularly in those with pre-existing Type 2 DM. Currently, limited robust evidence is available to provide clinical advice regarding dietary zinc levels for the prevention of chronic diseases; further investigations into the mechanisms of zinc’s action on the pathogenesis of chronic diseases and additional evidence from observational studies are required.
Exercise training is an established management and prevention strategy for Type 2 DM and CVD. To assess the influence of exercise on zinc homeostasis, systematic reviews and meta-analyses were conducted for the quantification of changes in zinc biomarkers after an aerobic exercise bout. Acute fluctuations in systemic zinc levels were observed, specifically an increase in serum zinc concentration immediately after exercise (change from baseline: 0.45 ± 0.12 μmol/L, P < 0.001; mean ± SE), subsequently followed by a decrease of serum zinc during exercise recovery (change from baseline: -1.31 ± 0.22 μmol/L, P < 0.001). Secondary analyses revealed greater fluctuations of post-exercise serum zinc levels for untrained individuals or participants with lower baseline zinc status. Dietary advice to increase total zinc intake, at least to meet the recommended dietary zinc intake level, may be considered for at-risk populations in clinical practice.
The examination of zinc status in humans is hindered by the inherent limitations of the currently available zinc biomarkers. In a time course, randomised controlled trial, we examined the use of novel markers, specifically zinc transporters and metallothionein (MT) gene expressions as potential zinc biomarkers. Upregulation of the MT-2A gene was observed following 2 days of zinc supplementation (40 ± 18% increase from baseline, P = 0.011); significant relationships were noted between MT-2A gene and the expression of zinc transporters, suggestive of coordination within the cellular zinc transport system.
The synergy between cellular zinc homeostasis and cellular functions was demonstrated in the reported relationships between inflammatory cytokines and cellular zinc transport network for individuals with Type 2 DM. Trends towards upregulation of cytokine gene expressions, specifically TNF-α, were observed following 12 weeks of zinc supplementation. The expression of IL-1β gene was predicted by zinc transporters that are responsible for the transport of zinc ions in intracellular zinc signalling and the secretory pathway. The interaction between zinc availability and immune function shown in the reported study extends the understanding of the chronically activated innate immune system that is intrinsically linked to the pathology of Type 2 DM.
The differences in cellular zinc homeostasis within Type 2 DM are highlighted in the reported expression and interrelationships of zinc transporters and MT genes. Gene expression levels of most zinc transporters and MT were significantly lower in individuals with Type 2 DM, compared to control (P < 0.01). Multivariate statistical approaches were used to identify groupings within 10 zinc transporters and MT gene expressions. The groupings of zinc transporters and MT between healthy and Type 2 DM were largely similar, with the exception of the placement of ZnT1 and ZIP7. These transporters have potential implications for intracellular zinc levels and related functions, such as insulin signalling. Zinc transporters and MT were predictive of plasma zinc concentration in healthy participants, but not in those with Type 2 DM. This study in cellular zinc transport system supports the proposed disturbance in whole body zinc homeostasis associated with Type 2 DM pathophysiology.
In this thesis, the presented critical and quantitative evaluation of the literature revealed relationships between zinc status, chronic disease risk and exercise, providing evidence for future clinical guidelines and research direction. The experimental studies explored the coordination within cellular zinc transport system, in addition to elucidating the potential mechanisms of interactions between external stimuli, zinc transport and cellular functions. Collectively, the results extend the current understanding of zinc homeostasis, at the whole body and cellular levels, in health, exercise and chronic diseases.