ArticleDiabetologia2014
Hypoxia lowers SLC30A8/ZnT8 expression and free cytosolic Zn2+ in pancreatic beta cells.
Article in Diabetologia, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed, 45 citations in OpenAlex.
- Trial
- A loss of function variant inmedRxiv : the preprint server for health sciences · 2026Article
- Crosstalk between the aryl hydrocarbon receptor and hypoxia-inducible factor 1α pathways in human islet models.Islets · 2025Article
- Improving cellular fitness of human stem cell-derived islets under hypoxia.Nature communications · 2025Article
- The association of islet autoantibodies with the neural retinal thickness and microcirculation in type 1 diabetes mellitus with no clinical evidence of diabetic retinopathy.Acta diabetologica · 2024Article
- Roles of β-Cell Hypoxia in the Progression of Type 2 Diabetes.International journal of molecular sciences · 2024Review
- Article
- Lack of ZnT8 protects pancreatic islets from hypoxia- and cytokine-induced cell death.The Journal of endocrinology · 2022Article
- Isoform-specific Roles of Prolyl Hydroxylases in the Regulation of Pancreatic β-Cell Function.Endocrinology · 2022Article
- Pancreatic β cell-selective zinc transporter 8 insufficiency accelerates diabetes associated with islet amyloidosis.JCI insight · 2021Article
- Emerging Roles of Metallothioneins in Beta Cell Pathophysiology: Beyond and Above Metal Homeostasis and Antioxidant Response.Biology · 2021Review
- Paracrine regulation and improvement of β-cell function by thioredoxin.Redox biology · 2020Article
- Insights into pancreatic islet cell dysfunction from type 2 diabetes mellitus genetics.Nature reviews. Endocrinology · 2020Review
- Article
- ZnT8 Haploinsufficiency Impacts MIN6 Cell Zinc Content and β-Cell Phenotype via ZIP-ZnT8 Coregulation.International journal of molecular sciences · 2019Article
- Loss of ZnT8 function protects against diabetes by enhanced insulin secretion.Nature genetics · 2019Article
- Zinc and its regulators in pancreas.Inflammopharmacology · 2019Review
- The Role of Oxidative Stress and Hypoxia in Pancreatic Beta-Cell Dysfunction in Diabetes Mellitus.Antioxidants & redox signaling · 2017Review
- Zinc in Pancreatic Islet Biology, Insulin Sensitivity, and Diabetes.Preventive nutrition and food science · 2017Review
- Aggregation of Engineered Human β-Cells Into Pseudoislets: Insulin Secretion and Gene Expression Profile in Normoxic and Hypoxic Milieu.Cell medicine · 2016Article
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Authors and funding
12 authors at 4 institutions in 3 countries.
Funding
Abstract
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 Zn(2+) levels. We have therefore explored the role of ZnT8 and cytosolic Zn(2+) 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 Zn(2+) 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 Zn(2+), genetic ablation of Slc30a8 from mouse islets lowered cytosolic Zn(2+) 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 Zn(2+) 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.
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