The DOI matches its Crossref record; 5 of the 5 references it cites were found in a registry or an index.
Beta cell-specific Znt8 deletion in mice causes marked defects in insulin processing, crystallisation and secretion
Open accessAbstract
Aims/hypothesisZinc is highly concentrated in pancreatic beta cells, is critical for normal insulin storage and may regulate glucagon secretion from alpha cells. Zinc transport family member 8 (ZnT8) is a zinc efflux transporter that is highly abundant in beta cells. Polymorphisms of ZnT8 (also known as SLC30A8) gene in man are associated with increased risk of type 2 diabetes. While global Znt8 knockout (Znt8KO) mice have been characterised, ZnT8 is also present in other islet cell types and extra-pancreatic tissues. Therefore, it is important to find ways of understanding the role of ZnT8 in beta and alpha cells without the difficulties caused by the confounding effects of ZnT8 in these other tissues.MethodsWe generated mice with beta cell-specific (Znt8BKO) and alpha cell-specific (Znt8AKO) knockout of Znt8, and performed in vivo and in vitro characterisation of the phenotypes to determine the functional and anatomical impact of ZnT8 in these cells. Thus we assessed zinc accumulation, insulin granule morphology, insulin biosynthesis and secretion, and glucose homeostasis.ResultsZnt8BKO mice are glucose-intolerant, have reduced beta cell zinc accumulation and atypical insulin granules. They also display reduced first-phase glucose-stimulated insulin secretion, reduced insulin processing enzyme transcripts and increased proinsulin levels. In contrast, Znt8AKO mice show no evident abnormalities in plasma glucagon and glucose homeostasis.Conclusions/interpretationThis is the first report of specific beta and alpha cell deletion of Znt8. Our data indicate that while, under the conditions studied, ZnT8 is absolutely essential for proper beta cell function, it is largely dispensable for alpha cell function.
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Citations
Cites
A genome-wide association study identifies novel risk loci for type 2 diabetes
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Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels
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Replication of Genome-Wide Association Signals in UK Samples Reveals Risk Loci for Type 2 Diabetes
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A variant in CDKAL1 influences insulin response and risk of type 2 diabetes
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Loss-of-function mutations in SLC30A8 protect against type 2 diabetes
Go-T2D Consortium, Flannick, J., T2D-GENES Consortium, Thorleifsson, G., Beer, N. L., Jacobs, S. B. R., Grarup, N., Burtt, N. P., Mahajan, A., Fuchsberger, C., et al. (2014) · Nature Genetics · doi:10.1038/ng.2915 · Cited by 492
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Islet cholesterol accumulation due to loss of ABCA1 leads to impaired exocytosis of insulin granules
Kruit, J. K., Wijesekara, N., Fox, J. E. M., Dai, X.-Q., Brunham, L. R., Searle, G. J., Morgan, G. P., Costin, A. J., Tang, R., Bhattacharjee, A., et al. (2011) · Diabetes · doi:10.2337/db11-0081 · Cited by 113
Self-citationCryo-EM structures of human ZnT8 in both outward- and inward-facing conformations
Xue, J., Xie, T., Zeng, W., Jiang, Y., & Bai, X.-C. (2020) · eLife · doi:10.7554/elife.58823 · Cited by 78
Zinc and Diabetes: A Connection between Micronutrient and Metabolism
Ahmad, R., Shaju, R., Atfi, A., & Razzaque, M. S. (2024) · Cells · doi:10.3390/cells13161359 · Cited by 77
The Influence of Rare Genetic Variation in SLC30A8 on Diabetes Incidence and β-Cell Function
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Maternal micronutrient disturbance as risks of offspring metabolic syndrome
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Metadata
- Authors
- Wijesekara, N., Dai, F. F., Hardy, A. B., Giglou, P. R., Bhattacharjee, A., Koshkin, V., Chimienti, F., Gaisano, H. Y., Rutter, G. A., & Wheeler, M. B.
- Venue
- Diabetologia
- Published
- 2010-04-28
- Volume
- 53
- Issue
- 8
- Pages
- 1656-1668
- ISSN
- 0012-186X (ISSN-L)
- 1432-0428
- OpenAlex
- W2066752848
- Cited by
- 305
- References
- 5
- FWCI
- 22.67
- Type
- journal article
- Language
- en
- Open access
- bronze
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