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)