TNF-α gene expression is increased following zinc supplementation in type 2 diabetes mellitus

Genes & Nutrition, Nov 2014

Chronic low-grade inflammation in type 2 diabetes mellitus (DM) can elicit changes in whole-body zinc metabolism. The interaction among the expression of inflammatory cytokines, zinc transporter and metallothionein (MT) genes in peripheral blood mononuclear cells in type 2 DM remains unclear. In a 12-week randomized controlled trial, the effects of zinc (40 mg/day) supplementation on the gene expression of cytokines, zinc transporters and MT in women with type 2 DM were examined. In the zinc-supplemented group, gene expression of tumour necrosis factor (TNF)-α tended to be upregulated by 27 ± 10 % at week 12 compared to baseline (P = 0.053). TNF-α fold change in the zinc-treated group was higher than in those without zinc supplementation (P < 0.05). No significant changes were observed in the expression or fold change of interleukin (IL)-1β or IL-6. Numerous bivariate relationships were observed between the fold changes of cytokines and zinc transporters, including ZnT7 with IL-1β (P < 0.01), IL-6 (P < 0.01) and TNF-α (P < 0.01). In multiple regression analysis, IL-1β expression was predicted by the expression of all zinc transporters and MT measured at baseline (r 2 = 0.495, P < 0.05) and at week 12 (r 2 = 0.532, P < 0.03). The current study presents preliminary evidence that zinc supplementation increases cytokine gene expression in type 2 DM. The relationships found among zinc transporters, MT and cytokines suggest close  interactions between zinc homeostasis and inflammation.

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TNF-α gene expression is increased following zinc supplementation in type 2 diabetes mellitus

Genes Nutr TNF-a gene expression is increased following zinc supplementation in type 2 diabetes mellitus Anna Chu 0 1 2 3 Meika Foster 0 1 2 3 Dale Hancock 0 1 2 3 Kim Bell-Anderson 0 1 2 3 Peter Petocz 0 1 2 3 Samir Samman 0 1 2 3 0 P. Petocz Department of Statistics, Macquarie University , Sydney, NSW 2109 , Australia 1 D. Hancock Discipline of Molecular Biology, School of Molecular Bioscience, University of Sydney , Sydney, NSW 2006 , Australia 2 A. Chu M. Foster K. Bell-Anderson S. Samman Discipline of Nutrition and Metabolism, School of Molecular Bioscience, University of Sydney , Sydney, NSW 2006 , Australia 3 S. Samman (&) Department of Human Nutrition, University of Otago , PO Box 56, Dunedin 9054 , New Zealand Chronic low-grade inflammation in type 2 diabetes mellitus (DM) can elicit changes in whole-body zinc metabolism. The interaction among the expression of inflammatory cytokines, zinc transporter and metallothionein (MT) genes in peripheral blood mononuclear cells in type 2 DM remains unclear. In a 12-week randomized controlled trial, the effects of zinc (40 mg/day) supplementation on the gene expression of cytokines, zinc transporters and MT in women with type 2 DM were examined. In the zinc-supplemented group, gene expression of tumour necrosis factor (TNF)-a tended to be upregulated by 27 ± 10 % at week 12 compared to baseline (P = 0.053). TNF-a fold change in the zinc-treated group was higher than in those without zinc supplementation (P \ 0.05). No significant changes were observed in the expression or fold change of interleukin (IL)-1b or IL-6. Numerous bivariate relationships were observed between the fold changes of cytokines and zinc transporters, including ZnT7 with IL-1b (P \ 0.01), IL-6 (P \ 0.01) and TNF-a (P \ 0.01). In multiple regression analysis, IL-1b expression was predicted by the expression of all zinc transporters and MT measured at baseline (r2 = 0.495, P 0.05) and at week 12 (r2 = 0.532, P 0.03). The current study presents preliminary evidence that zinc supplementation increases cytokine gene expression in type 2 DM. The relationships found among zinc transporters, MT and cytokines suggest close interactions between zinc homeostasis and inflammation. Inflammation; Cytokines; Zinc transporters; Metallothionein; Gene expression; Type 2 diabetes mellitus Introduction Zinc is involved in the biosynthesis, storage and secretion of insulin within the pancreatic b-cells (Huang 2014) . Furthermore, intracellular zinc can act directly on the insulin signalling pathway to improve glucose uptake and insulin sensitivity in peripheral tissues (Haase and Maret 2005; Foster and Samman 2010) . Individuals with type 2 diabetes mellitus (DM) are suggested to be of poor zinc status due to the presentation of higher urinary zinc excretion and lower serum zinc concentrations (Jansen et al. 2009) . Suboptimal zinc status can affect glycaemic control by compromising the production and secretion of insulin in the pancreas (Huber and Gershoff 1973) and impacting insulin sensitivity in peripheral tissues (Jansen et al. 2009; Kelleher et al. 2011) . Hence, the persistent elevation of blood glucose concentration featured in type 2 DM may be attributed partly to perturbed zinc homeostasis. Cellular zinc homeostasis is regulated primarily by two families of zinc transporters and metallothionein (MT) (Lichten and Cousins 2009) . The Zrt- and Irt-like protein (Zip) (SLC39) family of transporters is responsible for increasing cytoplasmic zinc concentration by transporting zinc from intracellular organelles or the extracellular space. Conversely, the ZnT (SLC30) family of transporters functions to decrease the cytoplasmic zinc concentration by transporting zinc from the cytosol into the extracellular space or internal organelles, such as those involved in secretory pathways. MT acts as a target for zinc ion binding in the cytoplasm and is believed to assist in the trafficking of zinc ions through the cell (Babula et al. 2012) . The regulatory control of cellular zinc transporters and MT is complex and has been shown to be influenced by zinc status, systemic glucose and inflammatory cytokines (Lichten and Cousins 2009; Hennigar and Kelleher 2012) . Cellular zinc transporters in different cell types have been shown to be both up- and downregulated to meet the changing demand for zinc in inflammatory conditions (Foster and Samman 2012) . The redistribution of zinc from the systemic circulation into cellular compartments is thought to be crucial for immune function. During acute infection, an increase in systemic interleukin (IL)-6 can induce hepatic accumulation of zinc, which contributes to the rapid decrease in the plasma zinc concentration often seen in the acute phase response (Liuzzi et al. 2005) . The chronically activated innate immune system in type 2 DM (Pickup 2004) also can elicit changes to whole-body zinc metabolism. Exposure to systemic cytokines, such as IL1b, (...truncated)


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Anna Chu, Meika Foster, Dale Hancock, Kim Bell-Anderson, Peter Petocz, Samir Samman. TNF-α gene expression is increased following zinc supplementation in type 2 diabetes mellitus, Genes & Nutrition, 2015, pp. 440, Volume 10, Issue 1, DOI: 10.1007/s12263-014-0440-4