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

Shan, Zhilei; Bao, Wei; Zhang, Yan; Rong, Yuluo; Wang, Xia; Jin, Yilin; Song, Yadong; Yao, Ping; Sun, Changhao; Hu, Frank B.; Liu, Liegang

doi:10.2337/db13-0606

Cited by 85 publications

(66 citation statements)

References 41 publications

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“…insulin AUC and proinsulin:insulin at 5 and 10 min), suggesting that our findings are in fact true for our study population. Also, a recent cross-sectional study in Chinese participants demonstrated that the inverse association between plasma zinc and diabetes was attenuated in those with the RR genotype [35]; these results are consistent with our finding that zinc may be most beneficial in those with the W allele. Our WW genotype group was too small to make conclusions regarding its response.…”

Section: Discussionsupporting

confidence: 92%

“…While our findings for the RR genotype group were unexpected, consistency in the direction of effect of changes in acute insulin release and proinsulin:insulin as well as recent studies of rs13266634 [25, 35] lend support to our overall findings. Moreover, the complexity of SLC30A8 variation is highlighted by a recent study demonstrating that some rare loss-of-function mutations in SLC30A8 actually decrease diabetes risk [48] and that nutrient interactions with rs13266634 may be sensitive to baseline nutrition status [39].…”

Section: Discussionsupporting

confidence: 86%

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Effect of zinc supplementation on insulin secretion: interaction between zinc and SLC30A8 genotype in Old Order Amish

Maruthur

Clark

et al. 2014

Diabetologia

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Aims/hypothesis SLC30A8 encodes a zinc transporter in the beta cell; individuals with a common missense variant (rs13266634; R325W) in SLC30A8 demonstrate a lower early insulin response to glucose and an increased risk of type 2 diabetes. We hypothesised that zinc supplementation may improve insulin secretion in a genotype-dependent manner. Methods We evaluated the early insulin response to glucose (using frequently sampled intravenous glucose tolerance testing) by R325W genotype before and after 14 days of supplementation with oral zinc acetate (50 mg elemental zinc) twice daily in healthy non-diabetic Amish individuals (N=55). Results Individuals with RW/WW genotypes (n=32) had the lowest insulin response to glucose at 5 and 10 min at baseline (vs RR homozygotes [n=23]). After zinc supplementation, the RW/WW group experienced 15% and 14% increases in the insulin response to glucose at 5 and 10 min, respectively (p≤0.04), and, compared with RR homozygotes, experienced a 26% (p=0.04) increase in insulin at 5 min. We observed reciprocal decreases in proinsulin:insulin in the RW/WW (p=0.002) vs RR group (p=0.048), suggesting a genotype-specific improvement in insulin processing. Conclusions/interpretation Zinc supplementation appears to affect the early insulin response to glucose differentially by rs13266634 genotype and could be beneficial for diabetes prevention and/or treatment for some individuals based on SLC30A8 variation.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 86%

Effect of zinc supplementation on insulin secretion: interaction between zinc and SLC30A8 genotype in Old Order Amish

Maruthur

Clark

et al. 2014

Diabetologia

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“…This single nucleotide polymorphism (SNP) rs1326663 causes the replacement of an arginine residue with a tryptophan (R325W) in the cytosolic Cterminus of the transporter. Possession of the risk variant of rs13266634 is associated with a 17% increase in disease risk per allele [65]. R325 allele carriers also present an increased proinsulin:insulin ratio during an oral glucose tolerance test [66], an impaired insulin secretion during an intravenous glucose tolerance test [67] and lower β cell function (HOMA-B assessment) [68].…”

Section: Znt8 and T2d: Gwas Studiesmentioning

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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“…The cases were consecutively recruited from patients diagnosed as having new-onset type 2 diabetes at the outpatient clinics of the Department of Endocrinology at the Tongji Medical College Hospital during the period of January 2012-December 2014. Concomitantly, we recruited healthy individuals who were frequency matched by age (65 y) and sex to cases from an unselected population undergoing a routine health checkup in the same hospital, as described elsewhere (20,21). We excluded participants who had any of the following conditions: age ,30 y, BMI (in kg/m 2 ) $40, a history of diagnosed diabetes, a history of pharmacologic treatment of hyperlipidemia, any clinically systemic disease, any acute illness, or chronic inflammatory or any infective disease.…”

Section: Study Populationmentioning

confidence: 99%

Association between microbiota-dependent metabolite trimethylamine-N-oxide and type 2 diabetes

Shan

Sun

Huang

et al. 2017

The American Journal of Clinical Nutrition

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166

121

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Background: The association of trimethylamine-N-oxide (TMAO), a microbiota-dependent metabolite from dietary choline and carnitine, with type 2 diabetes was inconsistent. Objective: We evaluated the association of plasma TMAO with newly diagnosed type 2 diabetes and the potential modification of TMAO-generating enzyme flavin monooxygenase 3 (FMO3) polymorphisms. Design: This was an age-and sex-matched case-control study of 2694 participants: 1346 newly diagnosed cases of type 2 diabetes and 1348 controls. Concentrations of plasma TMAO were measured, and FMO3 E158K polymorphisms (rs2266782) were genotyped. Results: Medians (IQRs) of plasma TMAO concentration were 1.47 mmol/L (0.81-2.20 mmol/L) for controls and 1.77 mmol/L (1.09-2.80 mmol/L) for type 2 diabetes cases. From the lowest to the highest quartiles of plasma TMAO, the multivariable adjusted ORs of type 2 diabetes were 1.00 (reference), 1.38 (95% CI: 1.08, 1.77), 1.64 (95% CI: 1.28, 2.09), and 2.55 (95% CI: 1.99, 3.28) (Ptrend , 0.001); each SD of ln-transformed plasma TMAO was associated with a 38% (95% CI: 26%, 51%) increment in ORs of type 2 diabetes. The FMO3 rs2266782 polymorphism was not associated with type 2 diabetes. The positive association between plasma TMAO and type 2 diabetes was consistent in each rs2266782 genotype group, and no significant interaction was observed (P = 0.093). Conclusions: Our results suggested that higher plasma TMAO was associated with increased odds of newly diagnosed type 2 diabetes and that this association was not modified by the FMO3 rs2266782 polymorphism. This study was registered at clinicaltrials.gov as NCT03130894.Am J Clin Nutr 2017;106:888-94.

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

Cited by 85 publications

References 41 publications

Effect of zinc supplementation on insulin secretion: interaction between zinc and SLC30A8 genotype in Old Order Amish

Effect of zinc supplementation on insulin secretion: interaction between zinc and SLC30A8 genotype in Old Order Amish

Zinc and diabetes

Association between microbiota-dependent metabolite trimethylamine-N-oxide and type 2 diabetes

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