Impact of an SLC30A8 loss-of-function variant on the pancreatic distribution of zinc and manganese: laser ablation-ICP-MS and positron emission tomography studies in mice
IntroductionCommon variants in the SLC30A8 gene, encoding the secretory granule zinc transporter ZnT8 (expressed largely in pancreatic islet alpha and beta cells), are associated with altered risk of type 2 diabetes. Unexpectedly, rare loss-of-function (LoF) variants in the gene, described in hetero...
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Frontiers Media S.A.
2023-06-01
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| Series: | Frontiers in Endocrinology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fendo.2023.1171933/full |
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| author | George Firth Eleni Georgiadou Alexander Griffiths Maral Amrahli Jana Kim Zilin Yu Ming Hu Theodora J. Stewart Isabelle Leclerc Isabelle Leclerc Haruka Okamoto Daniel Gomez Philip J. Blower Guy A. Rutter Guy A. Rutter Guy A. Rutter |
| author_facet | George Firth Eleni Georgiadou Alexander Griffiths Maral Amrahli Jana Kim Zilin Yu Ming Hu Theodora J. Stewart Isabelle Leclerc Isabelle Leclerc Haruka Okamoto Daniel Gomez Philip J. Blower Guy A. Rutter Guy A. Rutter Guy A. Rutter |
| author_sort | George Firth |
| collection | DOAJ |
| description | IntroductionCommon variants in the SLC30A8 gene, encoding the secretory granule zinc transporter ZnT8 (expressed largely in pancreatic islet alpha and beta cells), are associated with altered risk of type 2 diabetes. Unexpectedly, rare loss-of-function (LoF) variants in the gene, described in heterozygous individuals only, are protective against the disease, even though knockout of the homologous SLC30A8 gene in mice leads to unchanged or impaired glucose tolerance. Here, we aimed to determine how one or two copies of the mutant R138X allele in the mouse SLC30A8 gene impacts the homeostasis of zinc at a whole-body (using non-invasive 62Zn PET imaging to assess the acute dynamics of zinc handling) and tissue/cell level [using laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) to map the long-term distribution of zinc and manganese in the pancreas].MethodsFollowing intravenous administration of [62Zn]Zn-citrate (~7 MBq, 150 μl) in wild-type (WT), heterozygous (R138X+/−), and homozygous (R138X+/+) mutant mice (14–15 weeks old, n = 4 per genotype), zinc dynamics were measured over 60 min using PET. Histological, islet hormone immunohistochemistry, and elemental analysis with LA-ICP-MS (Zn, Mn, P) were performed on sequential pancreas sections. Bulk Zn and Mn concentration in the pancreas was determined by solution ICP-MS.ResultsOur findings reveal that whereas uptake into organs, assessed using PET imaging of 62Zn, is largely unaffected by the R138X variant, mice homozygous of the mutant allele show a substantial lowering (to 40% of WT) of total islet zinc, as anticipated. In contrast, mice heterozygous for this allele, thus mimicking human carriers of LoF alleles, show markedly increased endocrine and exocrine zinc content (1.6-fold increase for both compared to WT), as measured by LA-ICP-MS. Both endocrine and exocrine manganese contents were also sharply increased in R138X+/− mice, with smaller increases observed in R138X+/+ mice.DiscussionThese data challenge the view that zinc depletion from the beta cell is the likely underlying driver for protection from type 2 diabetes development in carriers of LoF alleles. Instead, they suggest that heterozygous LoF may paradoxically increase pancreatic β-cell zinc and manganese content and impact the levels of these metals in the exocrine pancreas to improve insulin secretion. |
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| spelling | doaj.art-75ed93d9f1f64c898d27e6bd1f975e332023-06-16T07:47:46ZengFrontiers Media S.A.Frontiers in Endocrinology1664-23922023-06-011410.3389/fendo.2023.11719331171933Impact of an SLC30A8 loss-of-function variant on the pancreatic distribution of zinc and manganese: laser ablation-ICP-MS and positron emission tomography studies in miceGeorge Firth0Eleni Georgiadou1Alexander Griffiths2Maral Amrahli3Jana Kim4Zilin Yu5Ming Hu6Theodora J. Stewart7Isabelle Leclerc8Isabelle Leclerc9Haruka Okamoto10Daniel Gomez11Philip J. Blower12Guy A. Rutter13Guy A. Rutter14Guy A. Rutter15School of Biomedical Engineering and Imaging Sciences, King’s College London, St Thomas’ Hospital, London, United KingdomSection of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Imperial Centre for Translational and Experimental Medicine, Imperial College London, London, United KingdomLondon Metallomics Facility, King’s College London, London, United KingdomLondon Metallomics Facility, King’s College London, London, United KingdomSchool of Biomedical Engineering and Imaging Sciences, King’s College London, St Thomas’ Hospital, London, United KingdomSchool of Biomedical Engineering and Imaging Sciences, King’s College London, St Thomas’ Hospital, London, United KingdomSection of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Imperial Centre for Translational and Experimental Medicine, Imperial College London, London, United KingdomLondon Metallomics Facility, King’s College London, London, United KingdomSection of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Imperial Centre for Translational and Experimental Medicine, Imperial College London, London, United KingdomCentre hospitalier de l’Université de Montréal (CHUM) Research Center and Faculty of Medicine, University of Montreal, Montreal, QC, CanadaRegeneron Pharmaceuticals, Inc., Tarrytown, NY, United StatesRegeneron Pharmaceuticals, Inc., Tarrytown, NY, United StatesSchool of Biomedical Engineering and Imaging Sciences, King’s College London, St Thomas’ Hospital, London, United KingdomSection of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Imperial Centre for Translational and Experimental Medicine, Imperial College London, London, United KingdomCentre hospitalier de l’Université de Montréal (CHUM) Research Center and Faculty of Medicine, University of Montreal, Montreal, QC, CanadaLee Kong Chian School of Medicine, Nanyang Technological, University, Singapore, SingaporeIntroductionCommon variants in the SLC30A8 gene, encoding the secretory granule zinc transporter ZnT8 (expressed largely in pancreatic islet alpha and beta cells), are associated with altered risk of type 2 diabetes. Unexpectedly, rare loss-of-function (LoF) variants in the gene, described in heterozygous individuals only, are protective against the disease, even though knockout of the homologous SLC30A8 gene in mice leads to unchanged or impaired glucose tolerance. Here, we aimed to determine how one or two copies of the mutant R138X allele in the mouse SLC30A8 gene impacts the homeostasis of zinc at a whole-body (using non-invasive 62Zn PET imaging to assess the acute dynamics of zinc handling) and tissue/cell level [using laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) to map the long-term distribution of zinc and manganese in the pancreas].MethodsFollowing intravenous administration of [62Zn]Zn-citrate (~7 MBq, 150 μl) in wild-type (WT), heterozygous (R138X+/−), and homozygous (R138X+/+) mutant mice (14–15 weeks old, n = 4 per genotype), zinc dynamics were measured over 60 min using PET. Histological, islet hormone immunohistochemistry, and elemental analysis with LA-ICP-MS (Zn, Mn, P) were performed on sequential pancreas sections. Bulk Zn and Mn concentration in the pancreas was determined by solution ICP-MS.ResultsOur findings reveal that whereas uptake into organs, assessed using PET imaging of 62Zn, is largely unaffected by the R138X variant, mice homozygous of the mutant allele show a substantial lowering (to 40% of WT) of total islet zinc, as anticipated. In contrast, mice heterozygous for this allele, thus mimicking human carriers of LoF alleles, show markedly increased endocrine and exocrine zinc content (1.6-fold increase for both compared to WT), as measured by LA-ICP-MS. Both endocrine and exocrine manganese contents were also sharply increased in R138X+/− mice, with smaller increases observed in R138X+/+ mice.DiscussionThese data challenge the view that zinc depletion from the beta cell is the likely underlying driver for protection from type 2 diabetes development in carriers of LoF alleles. Instead, they suggest that heterozygous LoF may paradoxically increase pancreatic β-cell zinc and manganese content and impact the levels of these metals in the exocrine pancreas to improve insulin secretion.https://www.frontiersin.org/articles/10.3389/fendo.2023.1171933/fullSLC30A8diabetespancreaszincmanganeseLA-ICP-MS |
| spellingShingle | George Firth Eleni Georgiadou Alexander Griffiths Maral Amrahli Jana Kim Zilin Yu Ming Hu Theodora J. Stewart Isabelle Leclerc Isabelle Leclerc Haruka Okamoto Daniel Gomez Philip J. Blower Guy A. Rutter Guy A. Rutter Guy A. Rutter Impact of an SLC30A8 loss-of-function variant on the pancreatic distribution of zinc and manganese: laser ablation-ICP-MS and positron emission tomography studies in mice Frontiers in Endocrinology SLC30A8 diabetes pancreas zinc manganese LA-ICP-MS |
| title | Impact of an SLC30A8 loss-of-function variant on the pancreatic distribution of zinc and manganese: laser ablation-ICP-MS and positron emission tomography studies in mice |
| title_full | Impact of an SLC30A8 loss-of-function variant on the pancreatic distribution of zinc and manganese: laser ablation-ICP-MS and positron emission tomography studies in mice |
| title_fullStr | Impact of an SLC30A8 loss-of-function variant on the pancreatic distribution of zinc and manganese: laser ablation-ICP-MS and positron emission tomography studies in mice |
| title_full_unstemmed | Impact of an SLC30A8 loss-of-function variant on the pancreatic distribution of zinc and manganese: laser ablation-ICP-MS and positron emission tomography studies in mice |
| title_short | Impact of an SLC30A8 loss-of-function variant on the pancreatic distribution of zinc and manganese: laser ablation-ICP-MS and positron emission tomography studies in mice |
| title_sort | impact of an slc30a8 loss of function variant on the pancreatic distribution of zinc and manganese laser ablation icp ms and positron emission tomography studies in mice |
| topic | SLC30A8 diabetes pancreas zinc manganese LA-ICP-MS |
| url | https://www.frontiersin.org/articles/10.3389/fendo.2023.1171933/full |
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