A low-risk ZnT-8 allele (W325) for post-transplantation diabetes mellitus is protective against cyclosporin A-induced impairment of insulin secretion

Kim, I.; Kang, Eun Seok; Yim, Ye Seal; Ko, Sung Jea; Jeong, Seok Hoon; Rim, John Hoon; Kim, Y. S.; Ahn, Chul Woo; Soo, Bong; Lee, H. C.; Kim, C. H.

doi:10.1038/tpj.2010.22

Cited by 43 publications

(43 citation statements)

References 40 publications

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“…Thus, the risk variant R325 is less active in transporting zinc in β cells than the protective variant W325 [77]. Similar data were also obtained by Kim et al using isolated secretory granules and radiotracers ( 65 Zn) [78]. …”

supporting

confidence: 79%

Zinc and diabetes

Chabosseau

Rutter

2016

Archives of Biochemistry and Biophysics

148

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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supporting

confidence: 79%

Zinc and diabetes

Chabosseau

Rutter

2016

Archives of Biochemistry and Biophysics

148

104

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“…It is also possible that introducing positive charges at the 'tip' of the protein may impair Zn 2+ transport through the protein. These possibilities have so far been assessed by overexpression of either variant in beta cells and imaging [15] or radioisotope-based studies on isolated granules [22]. In both cases, it was inferred that the W325 form was several-fold more active than the R325 form as a zinc transporter.…”

Section: Effects Of R325-w Substitution On Znt8 Functionmentioning

confidence: 99%

“…Thus, W325-ZnT8 expressing cells displayed higher levels of fluorescence than the R325-ZnT8-expressing cells when assessed with zinc probes (FluoZin-3 and Zinquin), showing at least partial co-localisation with insulin-containing granules. However, both approaches are subject to some limitations including (1) uncertainties as to the precise subcellular localisation of the fluorescent zinc probes used [15], and (2) potential clonal effects in studies of organelles isolated from cell lines [22]. Moreover, overexpression studies lead to at least some, albeit limited, incorporation of ZnT8 into the plasma membrane [15], and it has been speculated [23] that the W variant may be leakier in these assays, and thus a less active pump into the granule lumen.…”

Section: Effects Of R325-w Substitution On Znt8 Functionmentioning

confidence: 99%

SLC30A8 mutations in type 2 diabetes

2014

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SLC30A8 encodes the secretory granule-resident and largely endocrine pancreas-restricted zinc transporter ZnT8. Interest in this gene product was sparked amongst diabetologists in 2007 when the first genome-wide association study for type 2 diabetes identified polymorphisms in SLC30A8 as affecting disease risk. Thus, the common polymorphism rs13266634 was associated with lowered beta cell function and a 14% increase in diabetes abundance per risk (C) allele. This non-synonymous variant encodes a tryptophan-to-arginine switch at position 325 in the protein's intracellular carboxy-terminal domain, resulting in reduced zinc transport activity and, consequently, decreased intragranular zinc levels. Whereas insulin secretion from isolated islets is most often increased in mice inactivated for Slc30a8, null animals usually show impaired glucose tolerance and lowered circulating insulin. Since Slc30a8 null animals display little, if any, zinc secretion from islets, the lower plasma insulin levels could be explained by increased hepatic clearance as a result of lowered local zinc levels, or less efficient insulin action on target tissues. Despite the emerging consensus on the role of ZnT8 in glucose homeostasis, a recent genetic study in humans has unexpectedly identified loss-of-function SLC30A8 mutants that are associated with protection from diabetes. Here, we attempt to reconcile these apparently contradictory findings, implicating (1) differing degrees of inhibition of ZnT8 activity in carriers of common variants vs rare loss-of-function forms, (2) effects dependent on age or hypoxic beta cell stress. We propose that these variables conspire to affect both the size and the direction of the effect of SLC30A8 risk alleles in man.

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“…Whereas, cells expressing ZnT8 R325 were suppressed by these drugs. This indicates that the structure of the ZnT8 variant W325 is important for protection against post-transplant diabetes [90]. Kang and colleagues reported that a polymorphism in the zinc transporter gene SLC30A8 confers resistance against post-transplant diabetes in renal transplant recipients [110].…”

Section: Znt7 and Znt8mentioning

confidence: 99%

“…Kang and colleagues reported that a polymorphism in the zinc transporter gene SLC30A8 confers resistance against post-transplant diabetes in renal transplant recipients [110]. In addition, Kim and colleagues reported that the ZnT8 R325 expressed in the INS-1E cell line showed reduced insulin content and secretion when treated with cyclosporine A (CsA) [90]. When ZnT8 variant W325 expression was treated with CsA, insulin content and secretion was not affected.…”

Section: Znt7 and Znt8mentioning

confidence: 99%

Zinc and Zinc Transporter Regulation in Pancreatic Islets and the Potential Role of Zinc in Islet Transplantation

Bosco¹,

Mohanasundaram²,

Drogemuller³

et al. 2010

Rev Diabet Stud

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■ AbstractThe critical trace element zinc is essential for normal insulin production, and plays a central role in cellular protection against apoptosis and oxidative stress. The regulation of zinc within the pancreas and β-cells is controlled by the zinc transporter families ZnT and ZIP. Pancreatic islets display wide variability in the occurrence of these molecules. The zinc transporter, ZnT8 is an important target for autoimmunity in type 1 diabetes. Gene polymorphisms of this transporter confer sensitivity for immunosuppressive drugs used in islet transplantation. Understanding the biology of zinc transport within pancreatic islets will provide insight into the mechanisms of β-cell death, and may well reveal new pathways for improvement of diabetes therapy, including islet transplantation. This review discusses the possible roles of zinc in β-cell physiology with a special focus on islet transplantation.

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A low-risk ZnT-8 allele (W325) for post-transplantation diabetes mellitus is protective against cyclosporin A-induced impairment of insulin secretion

Cited by 43 publications

References 40 publications

Zinc and diabetes

Zinc and diabetes

SLC30A8 mutations in type 2 diabetes

Zinc and Zinc Transporter Regulation in Pancreatic Islets and the Potential Role of Zinc in Islet Transplantation

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