The common SLC30A8 Arg325Trp variant is associated with reduced first-phase insulin release in 846 non-diabetic offspring of type 2 diabetes patients—the EUGENE2 study

Boesgaard, Trine Welløv; Žilinskaitė, J.; Vänttinen, Markku; Laakso, Markku; Jansson, Per‐Anders; Hammarstedt, Ann; Smith, Ulf; Stefan, Norbert; Fritsche, Andreas; Häring, Hans‐Ulrich; Hribal, Marta Letizia; Sesti, Giorgio; Zobel, Dorit P; Pedersen, Oluf; Hansen, Torben

doi:10.1007/s00125-008-0955-6

Cited by 118 publications

(98 citation statements)

References 25 publications

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“…Larger studies have also confirmed susceptibility loci within the SLC30A8, CDKN2A/B, IGF2BP2 and KCNJ11 genes as altering beta cell function, so larger studies may refine our initial estimates [7,11,12]. In conclusion, while individual susceptibility alleles only moderately alter pancreatic beta cell function, the risk is additively increased when risk alleles are combined.…”

Section: Resultsmentioning

confidence: 88%

“…The additive effects of the three risk variants were associated with a decrease in 30 min insulin response (p=4.17×10 −7 ). This was decreased by 43% in the 3.1% of the cohort with five or more risk alleles compared with the 3.2% that carried no risk alleles ( Although the other novel genes, CDKN2A/B, IGF2BP2, SLC30A8 and KCNJ11 have been shown to be associated with indices of pancreatic beta cell function in other studies [7,11,12], they did not reach statistical significance individually in our cohort [10]. However, when we included them in our additive model the relationships between increasing number of risk alleles and decreasing 30 min insulin response and decreasing beta cell glucose sensitivity still remained significant (p<0.001 and p=0.003, respectively).…”

Section: Resultsmentioning

confidence: 94%

“…Many of the confirmed type 2 diabetes variants have since been shown in population cohorts to alter beta cell function [7][8][9][10][11][12][13]. These studies include the RISC (Relationship between Insulin Sensitivity and Cardiovascular Disease) study [14], where we previously showed that CDKAL1 (rs10946398) and HHEX/IDE (rs1111875) loci were associated with altered beta cell function as measured by the 30 min insulin response and pancreatic beta cell glucose sensitivity derived from an OGTT [10].…”

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confidence: 99%

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Beta cell glucose sensitivity is decreased by 39% in non-diabetic individuals carrying multiple diabetes-risk alleles compared with those with no risk alleles

et al. 2008

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Aims/hypothesis Novel type 2 diabetes-susceptibility loci have been identified with evidence that individually they mediate the increased diabetes risk through altered pancreatic beta cell function. The aim of this study was to test the cumulative effects of diabetes-risk alleles on measures of beta cell function in non-diabetic individuals. Methods A total of 1,211 non-diabetic individuals underwent metabolic assessment including an OGTT, from which measures of beta cell function were derived. Individuals were genotyped at each of the risk loci and then classified according to the total number of risk alleles that they carried. Initial analysis focused on CDKAL1, HHEX/IDE and TCF7L2 loci, which were individually associated with a decrease in beta cell function in our cohort. Risk alleles for CDKN2A/B, SLC30A8, IGF2BP2 and KCNJ11 loci were subsequently included into the analysis. Results The diabetes-risk alleles for CDKAL1, HHEX/IDE and TCF7L2 showed an additive model of association with measures of beta cell function. Beta cell glucose sensitivity was decreased by 39% in those individuals with five or more risk alleles compared with those individuals with no risk alleles (geometric mean [SEM]: 84 [1.07] vs 137 [1.11] pmol min −1 m −2 (mmol/l) −1 , p=1.51×10 −6 ). The same was seen for the 30 min insulin response (p=4.17×10 −7 ). The relationship remained after adding in the other four susceptibility loci (30 min insulin response and beta cell glucose sensitivity, p<0.001 and p=0.003, respectively).Conclusions/interpretation This study shows how individual type 2 diabetes-risk alleles combine in an additive manner to impact upon pancreatic beta cell function in nondiabetic individuals.

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Section: Resultsmentioning

confidence: 88%

Section: Resultsmentioning

confidence: 94%

mentioning

confidence: 99%

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Beta cell glucose sensitivity is decreased by 39% in non-diabetic individuals carrying multiple diabetes-risk alleles compared with those with no risk alleles

et al. 2008

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“…A polymorphism in SLC30A8 the gene encoding the ZnT8 transporter that mediates sequestration of zinc in secretory vesicles of pancreatic b-cells, is associated with both DM type 2 (DM2) (Boesgaard et al 2008;Jing et al 2011) and DM type 1 (DM1) (Gohlke et al 2008). It is unclear how the Znt8 polymorphism contributes to DM2 risk (Boesgaard et al 2008), but autoimmune dysfunction involving antibodies against Znt8 could contribute to DM1 (Wenzlau et al 2011).…”

Section: Zinc and Insulin Signaling In Diabetes Mellitus And Dementiamentioning

confidence: 99%

“…It is unclear how the Znt8 polymorphism contributes to DM2 risk (Boesgaard et al 2008), but autoimmune dysfunction involving antibodies against Znt8 could contribute to DM1 (Wenzlau et al 2011). Considering that zinc supplementation has clinical benefits in DM patients; research is needed to investigate if this polymorphism affects optimal zinc requirements.…”

Section: Zinc and Insulin Signaling In Diabetes Mellitus And Dementiamentioning

confidence: 99%

Zinc and the aging brain

Nuttall

Oteiza

2013

Genes Nutr

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Alterations in trace element homeostasis could be involved in the pathology of dementia, and in particular of Alzheimer's disease (AD). Zinc is a structural or functional component of many proteins, being involved in numerous and relevant physiological functions. Zinc homeostasis is affected in the elderly, and current evidence points to alterations in the cellular and systemic distribution of zinc in AD. Although the association of zinc and other metals with AD pathology remains unclear, therapeutic approaches designed to restore trace element homeostasis are being tested in clinical trials. Not only could zinc supplementation potentially benefit individuals with AD, but zinc supplementation also improves glycemic control in the elderly suffering from diabetes mellitus. However, the findings that select genetic polymorphisms may alter an individual's zinc intake requirements should be taken into consideration when planning zinc supplementation. This review will focus on current knowledge regarding pathological and protective mechanisms involving brain zinc in AD to highlight areas where future research may enable development of new and improved therapies.

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Zn²⁺‐transporter‐8: A dual role in diabetes

Chistiakov

Voronova

2009

BioFactors

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Diabetes mellitus arises from defects in insulin secretion or action, or both. In pancreatic islets, insulin production is linked with zinc transport mediated by zinc transporter ZnT-8, a product of the SLC30A8 gene. Therefore, altered activity of ZnT-8 is expected to be associated with impaired glucose-induced insulin response and promote progression from glucose intolerance to diabetes. Recent findings do emerge with a role of SLC30A8 in diabetes. Genome-wide association scans for type 2 diabetes (T2D) susceptibility loci revealed and then replicated a highly significant association between the R allele of the R325W variant of SLC30A8 (marker rs13266634) and susceptibility to T2D in Caucasians. A role of ZnT-8 as a new major self-antigenic determinant in type 1 diabetes (T1D) was found. Marker rs13266634 was also shown to modulate anti-ZnT-8 self-antibody specificity in islet autoimmunity. Hence, these findings suggest for a dual role of SLC30A8 in diabetes, which is consisted in conferring genetic susceptibility to T2D and being a major islet self-antigen in T1D as well. Here we characterize an emerging role of ZnT-8 in diabetes and discuss potential mechanisms of its involvement in the etiology of both forms of diabetes.

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The common SLC30A8 Arg325Trp variant is associated with reduced first-phase insulin release in 846 non-diabetic offspring of type 2 diabetes patients—the EUGENE2 study

Cited by 118 publications

References 25 publications

Beta cell glucose sensitivity is decreased by 39% in non-diabetic individuals carrying multiple diabetes-risk alleles compared with those with no risk alleles

Beta cell glucose sensitivity is decreased by 39% in non-diabetic individuals carrying multiple diabetes-risk alleles compared with those with no risk alleles

Zinc and the aging brain

Zn²⁺‐transporter‐8: A dual role in diabetes

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The common SLC30A8 Arg325Trp variant is associated with reduced first-phase insulin release in 846 non-diabetic offspring of type 2 diabetes patients—the EUGENE2 study

Cited by 118 publications

References 25 publications

Beta cell glucose sensitivity is decreased by 39% in non-diabetic individuals carrying multiple diabetes-risk alleles compared with those with no risk alleles

Beta cell glucose sensitivity is decreased by 39% in non-diabetic individuals carrying multiple diabetes-risk alleles compared with those with no risk alleles

Zinc and the aging brain

Zn2+‐transporter‐8: A dual role in diabetes

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Zn²⁺‐transporter‐8: A dual role in diabetes