Total Zinc Intake May Modify the Glucose-Raising Effect of a Zinc Transporter (<i>SLC30A8</i>) Variant

Kanoni, Stavroula; Nettleton, Jennifer A.; Hivert, Marie‐France; Zheng, Yi; Rooij, Frank J.A. van; Shungin, Dmitry; Sonestedt, Emily; Ngwa, Julius S.; Wojczynski, Mary K.; Lemaître, Rozenn N.; Gustafsson, Stefan; Anderson, Jennifer; Tanaka, Toshiko; Hindy, George; Saylor, Georgia; Renström, Frida; Bennett, Amanda J.; Duijn, Cornelia M. van; Florez, José C.; Fox, Caroline S.; Hofman, Albert; Hoogeveen, Ron C.; Houston, Denise K.; Hu, Frank B.; Jacques, Paul F.; Johansson, Ingegerd; Lind, Lars; Liu, Yongmei; McKeown, Nicola M.; Ordovas, José M.; Pankow, James S.; Sijbrands, Eric J.G.; Syvänen, Ann‐Christine; Uitterlinden, André G.; Yannakoulia, Mary; Zillikens, M. Carola; Wareham, Nick; Prokopenko, Inga; Bandinelli, Stefania; Forouhi, Nita G.; Cupples, L. Adrienne; Loos, Ruth J.F.; Hallmans, Göran; Dupuis, Josée; Langenberg, Claudia; Ferrucci, Luigi; Kritchevsky, Stephen B.; McCarthy, Mark I.; Ingelsson, Erik; Borecki, Ingrid B.; Witteman, Jacqueline C. M.; Orho‐Melander, Marju; Siscovick, David S.; Meigs, James B.; Franks, Paul W.; Dedoussis, George

doi:10.2337/db11-0176

Cited by 89 publications

(64 citation statements)

References 48 publications

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“…The effects on the diabetic phenotype vary but globally, scientists observed beneficial effects especially in decreasing HbA1c levels and cholesterol. However, it is still unclear if dietary zinc supplementation would have an effect in preventing the disease in adults with insulino-resistance [17], and it has been shown recently that supplementation may affect the insulin response differentially, depending on the patient genotype for the SLC30A8 gene encoding the zinc transporter ZnT8 [18,19] (see below).…”

Section: Zinc and The Diabetic Patientmentioning

confidence: 99%

Zinc and diabetes

Chabosseau

Rutter

2016

Archives of Biochemistry and Biophysics

152

104

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Zn 2+ ions are essential for the normal processing and storage of insulin and altered pancreatic insulin content is associated with all forms of diabetes mellitus. Work of the past decade has identified variants in the human SLC30A8 gene, encoding the zinc transporter ZnT8 which is expressed highly selectively on the secretory granule of pancreatic islet β and α cells, as affecting the risk of Type 2 Diabetes. Here, we review the regulation and roles of Zn 2+ ions in islet cells, the mechanisms through which SLC30A8 variants might affect glucose homeostasis and diabetes risk, and the novel technologies including recombinant targeted zinc probes and knockout mice which have been developed to explore these questions. Abbreviation ISG: Insulin Secreting Granules; T2D: Type 2 Diabetes; T1D: Type 1 Diabetes; 2 Diabetes mellitus is a common metabolic disease, affecting approximately 9% of the adult population worldwide. It is characterized by high circulating glucose levels over a prolonged period of time which leads to long-term health complications [1]. Type 1 Diabetes (T1D) involves the autoimmune destruction of insulin-secreting β cells while Type 2 Diabetes (T2D) is linked to both a decrease of insulin release and deficient hormone action on targeted organs [2].The links among Zn 2+ , diabetes and insulin were established in the 1930s, a decade after the discovery of the hormone, when a study showed crystallized insulin contains Zn 2+ and that Zn 2+ , along with other metal ions, could reversibly trigger insulin crystallization [3]. Zinc was later demonstrated to prolong insulin action when co-injected with the hormone [4].These early studies, as well as much more recent findings showing association between T2D risk and the inheritance of gene variants encoding a critical β cell Zn 2+ transporter, ZnT8[5] have generated considerable interest in the role of Zn 2+ in diabetes aetiology and as a possible therapeutic target [6]. Zinc and the diabetic patientScott and Fisher were the first to report a direct link between zinc and diabetes in patients.While assessing the insulin content in the pancreas of diabetic patients compared to nondiabetic cadavers, they showed that in the former group zinc content was reduced by 75 % [7].Epidemiological studies also demonstrated that diabetes and whole body zinc status are associated [8][9][10][11]. In T1D and T2D patients, serum zinc levels are significantly decreased [9][10][11], this being associated with an increased zinc urinary loss [8].Zinc may have important anti-oxidant properties, as it acts as a cofactor of the superoxide dismutase enzyme which regulates the detoxification of reactive oxygen species, regulating the expression and protecting against the oxidative stress induced by chronic hyperglycaemia (for review, [12]). Furthermore, zinc inhibits alpha-ketoglutarate-dependent mitochondrial respiration suggesting that Zn 2+ can interfere with mitochondrial antioxidant production and may also stimulate production of reactive oxygen [13].Zinc supplementation h...

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Section: Zinc and The Diabetic Patientmentioning

confidence: 99%

Zinc and diabetes

Chabosseau

Rutter

2016

Archives of Biochemistry and Biophysics

152

104

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“…(64)(65)(66)(67)(68) . Interestingly, the effects of dietary zinc supplementation to lower T2D risk are dependent on SLC30A8 genotype (69) . More recent studies in human populations have reported twelve rare loss-of-function SNP, resulting in the production of a truncated protein that is associated with a 65 % decrease in T2D risk (70) .…”

Section: +mentioning

confidence: 99%

Intracellular zinc in insulin secretion and action: a determinant of diabetes risk?

et al. 2015

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Zinc is an important micronutrient, essential in the diet to avoid a variety of conditions associated with malnutrition such as diarrhoea and alopecia. Lowered circulating levels of zinc are also found in diabetes mellitus, a condition which affects one in twelve of the adult population and whose treatments consume approximately 10 % of healthcare budgets. Zn 2+ ions are essential for a huge range of cellular functions and, in the specialised pancreatic β-cell, for the storage of insulin within the secretory granule. Correspondingly, genetic variants in the SLC30A8 gene, which encodes the diabetes-associated granule-resident Zn 2+ transporter ZnT8, are associated with an altered risk of type 2 diabetes. Here, we focus on (i) recent advances in measuring free zinc concentrations dynamically in subcellular compartments, and (ii) studies dissecting the role of intracellular zinc in the control of glucose homeostasis in vitro and in vivo. We discuss the effects on insulin secretion and action of deleting or overexpressing Slc30a8 highly selectively in the pancreatic β-cell, and the role of zinc in insulin signalling. While modulated by genetic variability, healthy levels of dietary zinc, and hence normal cellular zinc homeostasis, are likely to play an important role in the proper release and action of insulin to maintain glucose homeostasis and lower diabetes risk.

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“…SLC30A8 (the zinc transporter-8 gene) has been suggested as an interesting candidate for studying the interaction with total zinc intake and fasting glucose levels in individuals without T2D (15). SLC30A8 is almost exclusively expressed in pancreatic b-cells and encodes a protein that transports zinc from the cytoplasm into insulin secretory vesicles, an important step in insulin synthesis and secretion (16).…”

Section: Interactions Between Zinc Transporter-8 Gene (Slc30a8) and Pmentioning

confidence: 99%

Interactions Between Zinc Transporter-8 Gene (SLC30A8) and Plasma Zinc Concentrations for Impaired Glucose Regulation and Type 2 Diabetes

et al. 2014

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Although both SLC30A8 rs13266634 single nucleotide polymorphism and plasma zinc concentrations have been associated with impaired glucose regulation (IGR) and type 2 diabetes ( T2D), their interactions for IGR and T2D remain unclear. Therefore, to assess zinc-SLC30A8 interactions, we performed a case-control study in 1,796 participants: 218 newly diagnosed IGR patients, 785 newly diagnosed T2D patients, and 793 individuals with normal glucose tolerance. After adjustment for age, sex, BMI, family history of diabetes, and hypertension, the multivariable odds ratio (OR) of T2D associated with a 10 mg/dL higher plasma zinc level was 0.87 (95% CI 0.85-0.90). Meanwhile, the OR of SLC30A8 rs13266634 homozygous genotypes CC compared with T T was 1.53 (1.11-2.09) for T2D. Similar associations were found in IGR and IGR&T2D groups. Each 10 mg/dL increment of plasma zinc was associated with 22% Our study suggested that the C allele of rs13266634 was associated with higher odds of T2D, and higher plasma zinc was associated with lower odds. The inverse association of plasma zinc concentrations with T2D was modified by SLC30A8 rs13266634. Further studies are warranted to confirm our findings and clarify the mechanisms underlying the interaction between plasma zinc and the SLC30A8 gene in relation to T2D.

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Total Zinc Intake May Modify the Glucose-Raising Effect of a Zinc Transporter (SLC30A8) Variant

Cited by 89 publications

References 48 publications

Zinc and diabetes

Zinc and diabetes

Intracellular zinc in insulin secretion and action: a determinant of diabetes risk?

Interactions Between Zinc Transporter-8 Gene (SLC30A8) and Plasma Zinc Concentrations for Impaired Glucose Regulation and Type 2 Diabetes

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