siRNA‐mediated knock‐down of ZnT3 and ZnT8 affects production and secretion of insulin and apoptosis in INS‐1E cells

Petersen, Andreas Brønden; Smidt, Kamille; Magnusson, Nils E.; Moore, Fabrice; Egefjord, Lærke; Rungby, Jørgen

doi:10.1111/j.1600-0463.2010.02698.x

Cited by 32 publications

(33 citation statements)

References 35 publications

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“…These results are somewhat different from the previous studies performed on b-cell lines. In particular, Znt8 knockdown in INS-1E cells increased apoptosis, and Znt8 overexpression protected cells from zinc depletion-induced apoptosis while knockdown increased cell death (Chimienti et al 2006, Petersen et al 2011. The reason for these discrepancies remains unclear but may be related to differences in the physiology of primary islets and INS cells.…”

Section: Discussionmentioning

confidence: 88%

Regulation and functional effects of ZNT8 in human pancreatic islets

Lefebvre

Vandewalle²,

Balavoine³

et al. 2012

Journal of Endocrinology

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Zinc ions are essential for the formation of insulin crystals in pancreatic b cells, thereby contributing to packaging efficiency of stored insulin. Zinc fluxes are regulated through the SLC30A (zinc transporter, ZNT) family. Here, we investigated the effect of metabolic stress associated with the prediabetic state (zinc depletion, glucotoxicity, and lipotoxicity) on ZNT expression and human pancreatic islet function. Both zinc depletion and lipotoxicity (but not glucotoxicity) downregulated ZNT8 (SLC30A8) expression and altered the glucose-stimulated insulin secretion index (GSIS). ZNT8 overexpression in human islets protected them from the decrease in GSIS induced by tetrakis-(2-pyridylmethyl) ethylenediamine and palmitate but not from cell death. In addition, zinc supplementation decreased palmitate-induced human islet cell death without restoring GSIS. Altogether, we showed that ZNT8 expression responds to variation in zinc and lipid levels in human b cells, with repercussions on insulin secretion. Prospects for increasing ZNT8 expression and/or activity may prove beneficial in type 2 diabetes in humans.

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Section: Discussionmentioning

confidence: 88%

Regulation and functional effects of ZNT8 in human pancreatic islets

Lefebvre

Vandewalle²,

Balavoine³

et al. 2012

Journal of Endocrinology

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“…ZnT3 was shown to be up-regulated by glucose in a concentration-dependent manner, and glucose metabolism is affected in vivo in ZnT3 knock-out mice (44) . The same group showed more recently that silencing of ZnT3 in INS-1E cells significantly increased cell death, while both insulin content and secretion were decreased (45) . Contrasting with the ubiquitous expression of some other ZnT, the Zn transporter ZnT8 has a unique expression profile, being almost exclusively restricted to pancreatic islets (46) .…”

Section: Zinc and The Pancreatic B-cellmentioning

confidence: 92%

“…The transition T-C in the coding region of SLC30A8 induces in the protein a change in amino acid, from a tryptophan to arginine at position 325, which impairs the Zn transport activity of the protein (51) . The link between impaired b-cell function and decreased Zn transport activity by ZnT8 has also been reported in vitro and in clinical studies (45,52) . For example, ZnT8 has been shown to affect insulin secretion in a Danish population, where homozygous carriers of the risk allele had an estimated 22 % lower insulin response than carriers of the protective allele (53) .…”

Section: Zinc and The Pancreatic B-cellmentioning

confidence: 99%

Zinc, pancreatic islet cell function and diabetes: new insights into an old story

Chimienti

2013

Nutr. Res. Rev.

106

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Zn is an essential trace element, involved in many different cellular processes. A relationship between Zn, pancreatic function and diabetes was suggested almost 70 years ago. To emphasise the importance of Zn in biology, the history of Zn research in the field of diabetes along with a general description of Zn transporter families will be reviewed. The paper will then focus on the effects of Zn on pancreatic b-cell function, including insulin synthesis and secretion, Zn signalling in the pancreatic islet, the redox functions of Zn and its target genes. The recent association of two 'Zn genes', i.e. metallothionein (MT) and Zn transporter 8 (SLC 30A8 ), with type 2 diabetes at the genetic level and with insulin secretion in clinical studies offers a potential new way to identify new drug targets to modulate Zn homeostasis directly in b-cells. The action of Zn for insulin action in its target organs, as Zn signalling in other pancreatic islet cells, will be addressed. Therapeutic Zn-insulin preparations and the influence of Zn and Zn transporters in type 1 diabetes will also be discussed. An extensive review of the literature on the clinical studies using Zn supplementation in the prevention and treatment of both types of diabetes, including complications of the disease, will evaluate the overall beneficial effects of Zn supplementation on blood glucose control, suggesting that Zn might be a candidate ion for diabetes prevention and therapy. Clearly, the story of the links between Zn, pancreatic islet cells and diabetes is only now unfolding, and we are presently only at the first chapter.

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“…Another connection seems to exist between Znt3 and Znt8 gene expression in INS-1E cells since conditions leading to an up-regulation of Znt3 expression (high glucose concentration or DEDTC treatment) cause a down-regulation of Znt8 expression (Smidt et al 2009). Specifically, knockdown of ZnT3 leads to an up-regulation of ZnT8 expression and vice versa (Petersen et al 2011). …”

Section: Interaction With Other Proteinsmentioning

confidence: 98%

ZnT3: a zinc transporter active in several organs

Smidt

Rungby

2011

Biometals

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The review collects the emerging information about zinc transporter 3 (ZnT3). ZnT3 has been associated with Alzheimer's disease, airway diseases and diabetes. ZnT3 was discovered and cloned in 1996. Since then, the major interest in the protein has been in its ability to transport zinc into pre-synaptic vesicles of glutamatergic neurones and its role during the development of amyloid β plaques in Alzheimer's disease. Increasing evidence suggests that ZnT3 is present in various cell types like different cell types in the brain, cells from adipose tissue, beta-cells from pancreatic islets, epithelial cells, cells from testis, prostate cancer cells and cells from retina. The expression of ZnT3 is regulated by age, hormones, fatty acids, zinc chelation, and glucose.

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siRNA‐mediated knock‐down of ZnT3 and ZnT8 affects production and secretion of insulin and apoptosis in INS‐1E cells

Cited by 32 publications

References 35 publications

Regulation and functional effects of ZNT8 in human pancreatic islets

Regulation and functional effects of ZNT8 in human pancreatic islets

Zinc, pancreatic islet cell function and diabetes: new insights into an old story

ZnT3: a zinc transporter active in several organs

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