Regulation and functional effects of ZNT8 in human pancreatic islets

Lefebvre, Bruno; Vandewalle, B.; Balavoine, Anne-Sophie; Quéniat, Gurvan; Moerman, Ericka; Vantyghem, Marie-Christine; Bacquer, Olivier Le; Gmyr, Valéry; Pawlowski, Valérie; Kerr–Conte, Julie; Pattou, François

doi:10.1530/joe-12-0071

Cited by 30 publications

(25 citation statements)

References 42 publications

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“…The expression of Slc30a8 /ZnT8 has previously been shown to be regulated by changes in intracellular free Zn 2+ [36], which in turn are expected to be influenced by alterations in metallothionein expression. We therefore determined whether the regulation of Slc30a8 expression by hypoxia might be diminished in islets from mice null for Mt1 and Mt2 [20].…”

Section: Resultsmentioning

confidence: 99%

Hypoxia lowers SLC30A8/ZnT8 expression and free cytosolic Zn2+ in pancreatic beta cells

et al. 2014

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Aims/hypothesisHypoxic damage complicates islet isolation for transplantation and may contribute to beta cell failure in type 2 diabetes. Polymorphisms in the SLC30A8 gene, encoding the secretory granule zinc transporter 8 (ZnT8), influence type 2 diabetes risk, conceivably by modulating cytosolic Zn2+ levels. We have therefore explored the role of ZnT8 and cytosolic Zn2+ in the response to hypoxia of pancreatic islet cells.MethodsHuman, mouse or rat islets were isolated and exposed to varying O2 tensions. Cytosolic free zinc was measured using the adenovirally expressed recombinant targeted zinc probe eCALWY4. Gene expression was measured using quantitative (q)RT-PCR, western (immuno-) blotting or immunocytochemistry. Beta cells were identified by insulin immunoreactivity.ResultsDeprivation of O2 (1% vs 5% or 21%) for 24 h lowered free cytosolic Zn2+ concentrations by ~40% (p < 0.05) and ~30% (p < 0.05) in mouse and human islet cells, respectively. Hypoxia similarly decreased SLC30A8 mRNA expression in islets, and immunoreactivity in beta cells. Implicating lowered ZnT8 levels in the hypoxia-induced fall in cytosolic Zn2+, genetic ablation of Slc30a8 from mouse islets lowered cytosolic Zn2+ by ~40% (p < 0.05) and decreased the induction of metallothionein (Mt1, Mt2) genes. Cell survival in the face of hypoxia was enhanced in small islets of older (>12 weeks) Slc30a8 null mice vs controls, but not younger animals.Conclusions/interpretationThe response of pancreatic beta cells to hypoxia is characterised by decreased SLC30A8 expression and lowered cytosolic Zn2+ concentrations. The dependence on ZnT8 of hypoxia-induced changes in cell survival may contribute to the actions of SLC30A8 variants on diabetes risk in humans.Electronic supplementary materialThe online version of this article (doi:10.1007/s00125-014-3266-0) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

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Section: Resultsmentioning

confidence: 99%

Hypoxia lowers SLC30A8/ZnT8 expression and free cytosolic Zn2+ in pancreatic beta cells

et al. 2014

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“…altered expression of ZnTs/ZIPs and antioxidant proteins) which result in lowered [Zn 2+ ] i and ROS production, allowing the cells to avoid possible damage by Zn 2+ -induced ROS production. Despite the beneficial effect on cell survival, low [Zn 2+ ] i may also have caused mitochondrial dysfunction in ATP13A2 −/− cells due to its adverse effect on mitochondrial function as shown in TPEN-mediated impairment of Δ Ψ m and ATP production (45, 46). …”

Section: Discussionmentioning

confidence: 99%

Parkinson's disease-associated human ATP13A2 (PARK9) deficiency causes zinc dyshomeostasis and mitochondrial dysfunction

Park

Koentjoro

Veivers

et al. 2014

Human Molecular Genetics

129

142

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Human ATP13A2 (PARK9), a lysosomal type 5 P-type ATPase, has been associated with autosomal recessive early-onset Parkinson's disease (PD). ATP13A2 encodes a protein that is highly expressed in neurons and is predicted to function as a cation pump, although the substrate specificity remains unclear. Accumulation of zinc and mitochondrial dysfunction are established aetiological factors that contribute to PD; however, their underlying molecular mechanisms are largely unknown. Using patient-derived human olfactory neurosphere cultures, which harbour loss-of-function mutations in both alleles of ATP13A2, we identified a low intracellular free zinc ion concentration ([Zn2+]i), altered expression of zinc transporters and impaired sequestration of Zn2+ into autophagy-lysosomal pathway-associated vesicles, indicating that zinc dyshomeostasis occurs in the setting of ATP13A2 deficiency. Pharmacological treatments that increased [Zn2+]i also induced the production of reactive oxygen species and aggravation of mitochondrial abnormalities that gave rise to mitochondrial depolarization, fragmentation and cell death due to ATP depletion. The toxic effect of Zn2+ was blocked by ATP13A2 overexpression, Zn2+ chelation, antioxidant treatment and promotion of mitochondrial fusion. Taken together, these results indicate that human ATP13A2 deficiency results in zinc dyshomeostasis and mitochondrial dysfunction. Our data provide insights into the molecular mechanisms of zinc dyshomeostasis in PD and its contribution to mitochondrial dysfunction with ATP13A2 as a molecular link between the two distinctive aetiological factors of PD.

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“…This gene encodes for a protein that is involved in the storage and secretion of insulin granules and that is expressed at a high level only in the pancreas, particularly in the islets of Langerhans [59] . This provides an obvious mechanism by which it may be involved in conferring T2D risk and this association has been replicated in multiple studies in different populations [60][61][62] .…”

Section: Slc30a8mentioning

confidence: 99%

Genetics of type 2 diabetes

Ali¹

2013

WJD

275

197

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Type 2 diabetes (T2D) is the result of interaction between environmental factors and a strong hereditary component. We review the heritability of T2D as well as the history of genetic and genomic research in this area. Very few T2D risk genes were identified using candidate gene and linkage-based studies, but the advent of genome-wide association studies has led to the identification of multiple genes, including several that were not previously known to play any role in T2D. Highly replicated genes, for example TCF7L2, KCNQ1 and KCNJ11, are discussed in greater detail. Taken together, the genetic loci discovered to date explain only a small proportion of the observed heritability. We discuss possible explanations for this "missing heritability", including the role of rare variants, gene-environment interactions and epigenetics. The clinical utility of current findings and avenues of future research are also discussed.© 2013 Baishideng. All rights reserved.Key words: Type 2 diabetes; Genetics; TCF7L2; Genome-wide association studies; Heritability Core tip: We review the history and the current state of knowledge regarding the genetic component of type 2 diabetes risk. Genes like TCF7L2 that have been replicated in multiple studies are discussed in detail. The significance of these findings is discussed and gaps in our knowledge are identified, as are avenues for future research.

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Regulation and functional effects of ZNT8 in human pancreatic islets

Cited by 30 publications

References 42 publications

Hypoxia lowers SLC30A8/ZnT8 expression and free cytosolic Zn2+ in pancreatic beta cells

Hypoxia lowers SLC30A8/ZnT8 expression and free cytosolic Zn2+ in pancreatic beta cells

Parkinson's disease-associated human ATP13A2 (PARK9) deficiency causes zinc dyshomeostasis and mitochondrial dysfunction

Genetics of type 2 diabetes

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