ArticleThe Journal of clinical investigation2013
The diabetes-susceptible gene SLC30A8/ZnT8 regulates hepatic insulin clearance.
Article in The Journal of clinical investigation, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 140 papers, 4 of them syntheses that pooled it.
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Who cites it
140 citing papers in PubMed, 4 syntheses or guidelines pooled it, 241 citations in OpenAlex.
- Zinc Intake and Status and Risk of Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis.Nutrients · 2019Pooled it
- Association of type 2 diabetes susceptible genes GCKR, SLC30A8, and FTO polymorphisms with gestational diabetes mellitus risk: a meta-analysis.Endocrine · 2018Pooled it
- Expression of the ZIP/SLC39A transporters in β-cells: a systematic review and integration of multiple datasets.BMC genomics · 2017Pooled it
- Association between SLC30A8 rs13266634 Polymorphism and Type 2 Diabetes Risk: A Meta-Analysis.Medical science monitor : international medical journal of experimental and clinical research · 2015Pooled it
- Dipeptidyl peptidase-4 inhibitor, anagliptin, alters hepatic insulin clearance in relation to the glycemic status in Japanese individuals with type 2 diabetes.Journal of diabetes investigation · 2021Trial
- Ingestion of an exogenous ketone monoester improves the glycemic response during oral glucose tolerance test in individuals with impaired glucose tolerance: A cross-over randomized trial.Journal of diabetes investigation · 2021Trial
- Association of increased hepatic insulin clearance and change in serum triglycerides or β-hydroxybutyrate concentration via the sodium/glucose-cotransporter 2 inhibitor tofogliflozin.Diabetes, obesity & metabolism · 2020Trial
- Article
- Technology-enabled insights into SLC transporters in MAFLD: redefining the multi-hit pathogenesis and therapeutic landscape.Acta pharmacologica Sinica · 2026Review
- Rethinking Zinc Requirements in Diabetes Mellitus: Comprehensive Review of Experimental and Clinical Studies Evidence.Biological trace element research · 2026Review
- Zinc Homeostasis and the Risk of Type 2 Diabetes: Complex Role of ZnT8 in Insulin and Glucagon Secretion.Current nutrition reports · 2026Review
- Functional genomics reveals mediators of beta cell survival in ER stress and type 2 diabetes risk.bioRxiv : the preprint server for biology · 2026Article
- Zinc Coordination by Thymosin β4: Structural Determinants and Functional Implications.International journal of molecular sciences · 2026Article
- Correlative imaging reveals metal dyshomeostasis and altered zinc coordination environments in a pre-clinical Type 2 diabetes model.Metallomics : integrated biometal science · 2026Article
- SLC30A8 Promoter Hypomethylation is Associated with Impaired Renal Function in Type 2 Diabetes: A Cross-Sectional Study.Diabetes, metabolic syndrome and obesity : targets and therapy · 2026Article
- Complete loss of SLC30A8 in humans improves glucose metabolism and beta cell function.Diabetologia · 2025Article
- Sex-Specific Association Between Serum Zinc Concentration and Risk of Developing Type 2 Diabetes in Individuals with Isolated Impaired Fasting Glucose: A Prospective Cohort.Biological trace element research · 2025Article
- Association of serum zinc concentration with multiple surrogates of insulin resistance in a population-based study.Scientific reports · 2025Article
- High Serum Zinc Concentration Accelerates Progression of Isolated Impaired Glucose Tolerance to Type 2 Diabetes: A Cohort Study.Biological trace element research · 2025Article
- Type 2 diabetes mellitus and zinc dysregulation: From basic and epidemiological evidence to interventions.Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements (GMS) · 2025Review
80 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
23 authors at 6 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Recent genome-wide association studies demonstrated that common variants of solute carrier family 30 member 8 gene (SLC30A8) increase susceptibility to type 2 diabetes. SLC30A8 encodes zinc transporter-8 (ZnT8), which delivers zinc ion from the cytoplasm into insulin granules. Although it is well known that insulin granules contain high amounts of zinc, the physiological role of secreted zinc remains elusive. In this study, we generated mice with β cell-specific Slc30a8 deficiency (ZnT8KO mice) and demonstrated an unexpected functional linkage between Slc30a8 deletion and hepatic insulin clearance. The ZnT8KO mice had low peripheral blood insulin levels, despite insulin hypersecretion from pancreatic β cells. We also demonstrated that a substantial amount of the hypersecreted insulin was degraded during its first passage through the liver. Consistent with these findings, ZnT8KO mice and human individuals carrying rs13266634, a major risk allele of SLC30A8, exhibited increased insulin clearance, as assessed by c-peptide/insulin ratio. Furthermore, we demonstrated that zinc secreted in concert with insulin suppressed hepatic insulin clearance by inhibiting clathrin-dependent insulin endocytosis. Our results indicate that SLC30A8 regulates hepatic insulin clearance and that genetic dysregulation of this system may play a role in the pathogenesis of type 2 diabetes.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.