SLC30A3 Responds to Glucose- and Zinc Variations in ß-Cells and Is Critical for Insulin Production and In Vivo Glucose-Metabolism During ß-Cell Stress

Smidt, Kamille; Jessen, Niels; Petersen, Andreas Brønden; Larsen, Agnete; Magnusson, Nils E.; Jeppesen, Johanne Bruun; Stoltenberg, Meredin; Culvenor, Janetta G.; Tsatsanis, Andrew; Brock, Birgitte; Schmitz, Ole; Wogensen, Lise; Bush, Ashley I.; Rungby, Jørgen

doi:10.1371/journal.pone.0005684

Cited by 83 publications

(90 citation statements)

References 40 publications

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“…ZnT3 (SLC30A3) protein has been reported in the islets, and in the pancreatic β cell line INS-1E but not in a corresponding pancreatic α-cell line, α-TC6 [40][41][42]. While ZnT3 mRNA was reported in purified human β cells in one study [38], levels were zero, or at the limit of detection, in samples from several subjects in another [37].…”

Section: Znt Familymentioning

confidence: 95%

Zinc and diabetes

Chabosseau

Rutter

2016

Archives of Biochemistry and Biophysics

149

104

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Zn 2+ ions are essential for the normal processing and storage of insulin and altered pancreatic insulin content is associated with all forms of diabetes mellitus. Work of the past decade has identified variants in the human SLC30A8 gene, encoding the zinc transporter ZnT8 which is expressed highly selectively on the secretory granule of pancreatic islet β and α cells, as affecting the risk of Type 2 Diabetes. Here, we review the regulation and roles of Zn 2+ ions in islet cells, the mechanisms through which SLC30A8 variants might affect glucose homeostasis and diabetes risk, and the novel technologies including recombinant targeted zinc probes and knockout mice which have been developed to explore these questions. Abbreviation ISG: Insulin Secreting Granules; T2D: Type 2 Diabetes; T1D: Type 1 Diabetes; 2 Diabetes mellitus is a common metabolic disease, affecting approximately 9% of the adult population worldwide. It is characterized by high circulating glucose levels over a prolonged period of time which leads to long-term health complications [1]. Type 1 Diabetes (T1D) involves the autoimmune destruction of insulin-secreting β cells while Type 2 Diabetes (T2D) is linked to both a decrease of insulin release and deficient hormone action on targeted organs [2].The links among Zn 2+ , diabetes and insulin were established in the 1930s, a decade after the discovery of the hormone, when a study showed crystallized insulin contains Zn 2+ and that Zn 2+ , along with other metal ions, could reversibly trigger insulin crystallization [3]. Zinc was later demonstrated to prolong insulin action when co-injected with the hormone [4].These early studies, as well as much more recent findings showing association between T2D risk and the inheritance of gene variants encoding a critical β cell Zn 2+ transporter, ZnT8[5] have generated considerable interest in the role of Zn 2+ in diabetes aetiology and as a possible therapeutic target [6]. Zinc and the diabetic patientScott and Fisher were the first to report a direct link between zinc and diabetes in patients.While assessing the insulin content in the pancreas of diabetic patients compared to nondiabetic cadavers, they showed that in the former group zinc content was reduced by 75 % [7].Epidemiological studies also demonstrated that diabetes and whole body zinc status are associated [8][9][10][11]. In T1D and T2D patients, serum zinc levels are significantly decreased [9][10][11], this being associated with an increased zinc urinary loss [8].Zinc may have important anti-oxidant properties, as it acts as a cofactor of the superoxide dismutase enzyme which regulates the detoxification of reactive oxygen species, regulating the expression and protecting against the oxidative stress induced by chronic hyperglycaemia (for review, [12]). Furthermore, zinc inhibits alpha-ketoglutarate-dependent mitochondrial respiration suggesting that Zn 2+ can interfere with mitochondrial antioxidant production and may also stimulate production of reactive oxygen [13].Zinc supplementation h...

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Section: Znt Familymentioning

confidence: 95%

Zinc and diabetes

Chabosseau

Rutter

2016

Archives of Biochemistry and Biophysics

149

104

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“…In addition to the brain, ZnT3 expression is detected in pancreatic ␤ cells where it is involved in the regulation of insulin production (379). ZnT3 mRNA is also abundantly expressed in the testis; however, the ZnT3 protein is not expressed (308).…”

Section: Znt3mentioning

confidence: 99%

The Physiological, Biochemical, and Molecular Roles of Zinc Transporters in Zinc Homeostasis and Metabolism

Kambe

Tsuji

Hashimoto

et al. 2015

Physiological Reviews

848

797

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Zinc is involved in a variety of biological processes, as a structural, catalytic, and intracellular and intercellular signaling component. Thus zinc homeostasis is tightly controlled at the whole body, tissue, cellular, and subcellular levels by a number of proteins, with zinc transporters being particularly important. In metazoan, two zinc transporter families, Zn transporters (ZnT) and Zrt-, Irt-related proteins (ZIP) function in zinc mobilization of influx, efflux, and compartmentalization/ sequestration across biological membranes. During the last two decades, significant progress has been made in understanding the molecular properties, expression, regulation, and cellular and physiological roles of ZnT and ZIP transporters, which underpin the multifarious functions of zinc. Moreover, growing evidence indicates that malfunctioning zinc homeostasis due to zinc transporter dysfunction results in the onset and progression of a variety of diseases. This review summarizes current progress in our understanding of each ZnT and ZIP transporter from the perspective of zinc physiology and pathogenesis, discussing challenging issues in their structure and zinc transport mechanisms.

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“…Apparently so: ZNT3, also downregulated by interleukin 1-beta [18], may be important for adequate beta cell function as knockout causes accelerated glucose intolerance in streptozotocin-treated animals [29].…”

Section: Perspectivesmentioning

confidence: 99%

Zinc, zinc transporters and diabetes

Rungby

2010

Diabetologia

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The role of zinc in islet function has recently achieved new attention as a consequence of the identification of zinc transporter 8 (ZNT8) in islets, and the association of mutations in the gene for this zinc transporter with glucose intolerance and type 2 diabetes. ZNT8 is also an autoantigen associated with the appearance of type 1 diabetes. A number of experimental models have been employed to suggest how ZNT8 and other zinc transporters regulate beta cell insulin processing and possibly secretion. An additional role for the zinc transporters in regulating alpha cell function has been suggested. In this issue of Diabetologia, Wijesekara and colleagues, using a cell-specific Znt8 (also known as Slc30a8) knockout model, demonstrate that beta cell insulin processing and glucose tolerance is negatively affected after beta cell knock out of Znt8, whereas Znt8 knockout in alpha cells seems to have little effect on glucagon secretion or glucose tolerance. Although we are yet to see the therapeutic potential of these new findings, the area represents a field through which manipulation of islet function may eventually be possible.

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SLC30A3 Responds to Glucose- and Zinc Variations in ß-Cells and Is Critical for Insulin Production and In Vivo Glucose-Metabolism During ß-Cell Stress

Cited by 83 publications

References 40 publications

Zinc and diabetes

Zinc and diabetes

The Physiological, Biochemical, and Molecular Roles of Zinc Transporters in Zinc Homeostasis and Metabolism

Zinc, zinc transporters and diabetes

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