Insulin crystallization depends on zinc transporter ZnT8 expression, but is not required for normal glucose homeostasis in mice
Open accessAbstract
Zinc co-crystallizes with insulin in dense core secretory granules, but its role in insulin biosynthesis, storage and secretion is unknown. In this study we assessed the role of the zinc transporter ZnT8 using ZnT8-knockout ( ZnT8 −/− ) mice. Absence of ZnT8 expression caused loss of zinc release upon stimulation of exocytosis, but normal rates of insulin biosynthesis, normal insulin content and preserved glucose-induced insulin release. Ultrastructurally, mature dense core insulin granules were rare in ZnT8 −/− beta cells and were replaced by immature, pale insulin “progranules,” which were larger than in ZnT8 +/+ islets. When mice were fed a control diet, glucose tolerance and insulin sensitivity were normal. However, after high-fat diet feeding, the ZnT8 −/− mice became glucose intolerant or diabetic, and islets became less responsive to glucose. Our data show that the ZnT8 transporter is essential for the formation of insulin crystals in beta cells, contributing to the packaging efficiency of stored insulin. Interaction between the ZnT8 −/− genotype and diet to induce diabetes is a model for further studies of the mechanism of disease of human ZNT8 gene mutations.
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A common polymorphism in SLC30A8 (rs13266634) affects T2DM risk.
“A common polymorphism in SLC30A8 (rs13266634) affects T2DM risk (384, 627).”
From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [384]
The introduction reports an association between a SNP marker in SLC30A8 and genetic susceptibility to type 2 diabetes. Our copy does not identify that marker as rs13266634 or state that it is common, so it supports the risk association but not those specifics. (LLM, conf=0.85)
Experimental — accuracy not yet measuredIn mice lacking ZnT8, the insulin granule core is less condensed but this is not associated with gross changes in insulin secretion at the isolated islet or animal level.
“In mice lacking ZnT8, the insulin granule core is less condensed but this is not associated with any gross changes in insulin secretion, either at the level of the isolated islet or the animal (384).”
From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [384]
The Results report that ZnT8-knockout granules lost their condensed cores and that isolated islets showed no difference in insulin release after glucose or KCl stimulation. Under a regular diet, the mice also had similar plasma insulin levels and normal glucose tolerance. The claim omits the condition: after prolonged high-fat feeding, the paper reports that knockout islets became less responsive to glucose and the mice developed glucose intolerance or diabetes. (LLM, conf=0.86)
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References 37 · Cited by 330
Research works printed but not linked: 1
- [29]Nicolson TJ, et al. (In press) The type 2 diabetes-associated vesicular zinc transporter SLC30A8 /ZnT8 is critical for beta-cell Zn 2 + handling and normal glucose homeostasis. Diabetes , in press.
- Authors
- Lemaire, K., Ravier, M. A., Schraenen, A., Creemers, J. W. M., Van de Plas, R., Granvik, M., Van Lommel, L., Waelkens, E., Chimienti, F., Rutter, G. A., Gilon, P., Veld, P. A. I., & Schuit, F. C.
- Affiliations
- KU Leuven (BE)
- Centre National de la Recherche Scientifique (FR)
- UCLouvain (BE)
- Department of Electrical Engineering, Katholieke Universiteit Leuven, Kasteelpark Arenberg 10, 3001 Leuven, Belgium;
- Gene Expression Unit, Department Molecular Cell Biology, Katholieke Universiteit Leuven, Herestraat 49, 3000 Leuven, Belgium;
- Mellitech (France) (FR)
- Imperial College London (GB)
- Department of Pathology, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Brussels, Belgium
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2009-09
- Volume
- 106
- Issue
- 35
- Pages
- 14872-14877
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2736467
- OpenAlex
- W2130595746
- Cited by
- 330
- References
- 37
- Citations by year
- 2026: 8 · 2025: 11 · 2024: 11 · 2023: 12 · 2022: 13 · 2021: 12 · 2020: 21 · 2019: 21 · 2018: 10 · 2017: 29 · 2016: 24 · 2015: 32 · 2014: 35 · 2013: 21 · 2012: 30
- FWCI
- 23.26
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Digital Access to Libraries (Université catholique de Louvain (UCL), l'Université de Namur (UNamur) and the Université Saint-Louis (USL-B)) (submittedVersion, other-oa)
- Lirias (KU Leuven) (submittedVersion)
- Funders
- Fonds Wetenschappelijk Onderzoek
- Vlaamse regering
- Topics
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Health Sciences › Nursing › Nutrition and Dietetics › Trace Elements in Health
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
- Keywords
- zinc transporter 8, zinc transporters, insulin crystallization, insulin storage, pancreatic beta cells, insulin secretion, glucose tolerance, high-fat diet, diabetes mellitus, insulin biosynthesis
- MeSH terms
- Zinc Transporter 8, Animals, Calcium, Crystallization, Glucose, Insulin, Islets of Langerhans, Mice, Inbred C57BL, Zinc, Glucose Intolerance, Mice, Knockout, Cation Transport Proteins, Microscopy, Electron, Transmission, Mice
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