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Guy A. Rutter - One of the best experts on this subject based on the ideXlab platform.
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Over-expression of SLC30A8/ZnT8 selectively in the mouse α cell impairs glucagon release and responses to hypoglycemia.
Nutrition & metabolism, 2016Co-Authors: Antonia Solomou, Erwann Philippe, Pauline Chabosseau, Julien Gaitan, Jochen Lang, Christophe Magnan, Stéphanie Migrenne-li, Guy A. RutterAbstract:Background The human SLC30A8 gene encodes the secretory granule-localised zinc transporter ZnT8 whose expression is chiefly restricted to the endocrine pancreas. Single nucleotide polymorphisms (SNPs) in the human SLC30A8 gene have been associated, through genome-wide studies, with altered type 2 diabetes risk. In addition to a role in the control of insulin release, recent studies involving targeted gene ablation from the pancreatic α cell (Solomou et al., J Biol Chem 290(35):21432-42) have also implicated ZnT8 in the control of glucagon release. Up to now, however, the possibility that increased levels of the transporter in these cells may impact glucagon secretion has not been explored.
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over expression of SLC30A8 znt8 selectively in the mouse α cell impairs glucagon release and responses to hypoglycemia
Nutrition & Metabolism, 2016Co-Authors: Antonia Solomou, Erwann Philippe, Pauline Chabosseau, Julien Gaitan, Jochen Lang, Christophe Magnan, Stephanie Migrenneli, Guy A. RutterAbstract:Background The human SLC30A8 gene encodes the secretory granule-localised zinc transporter ZnT8 whose expression is chiefly restricted to the endocrine pancreas. Single nucleotide polymorphisms (SNPs) in the human SLC30A8 gene have been associated, through genome-wide studies, with altered type 2 diabetes risk. In addition to a role in the control of insulin release, recent studies involving targeted gene ablation from the pancreatic α cell (Solomou et al., J Biol Chem 290(35):21432-42) have also implicated ZnT8 in the control of glucagon release. Up to now, however, the possibility that increased levels of the transporter in these cells may impact glucagon secretion has not been explored.
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molecular genetic regulation of SLC30A8 znt8 reveals a positive association with glucose tolerance
Molecular Endocrinology, 2016Co-Authors: Ryan K. Mitchell, Pauline Chabosseau, Elisa A Bellomo, Gargi Meur, Matthew C. Cane, Raffaella Carzaniga, Lucy M. Collinson, David J. Hodson, Guy A. RutterAbstract:Zinc transporter 8 (ZnT8), encoded by SLC30A8, is chiefly expressed within pancreatic islet cells, where it mediates zinc (Zn2+) uptake into secretory granules. Although a common nonsynonymous polymorphism (R325W), which lowers activity, is associated with increased type 2 diabetes (T2D) risk, rare inactivating mutations in SLC30A8 have been reported to protect against T2D. Here, we generate and characterize new mouse models to explore the impact on glucose homeostasis of graded changes in ZnT8 activity in the β-cell. Firstly, SLC30A8 was deleted highly selectively in these cells using the novel deleter strain, Ins1Cre. The resultant Ins1CreZnT8KO mice displayed significant (P < .05) impairments in glucose tolerance at 10 weeks of age vs littermate controls, and glucose-induced increases in circulating insulin were inhibited in vivo. Although insulin release from Ins1CreZnT8KO islets was normal, Zn2+ release was severely impaired. Conversely, transgenic ZnT8Tg mice, overexpressing the transporter inducibl...
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the zinc transporter SLC30A8 znt8 is required in a subpopulation of pancreatic α cells for hypoglycemia induced glucagon secretion
Journal of Biological Chemistry, 2015Co-Authors: Antonia Solomou, Erwann Philippe, Christophe Magnan, Elisa A Bellomo, Gargi Meur, David J. Hodson, Alejandra Tomas, Pedro Luis Herrera, Guy A. RutterAbstract:SLC30A8 encodes a zinc transporter ZnT8 largely restricted to pancreatic islet β- and α-cells, and responsible for zinc accumulation into secretory granules. Although common SLC30A8 variants, believed to reduce ZnT8 activity, increase type 2 diabetes risk in humans, rare inactivating mutations are protective. To investigate the role of SLC30A8 in the control of glucagon secretion, SLC30A8 was inactivated selectively in α-cells by crossing mice with alleles floxed at exon 1 to animals expressing Cre recombinase under the pre-proglucagon promoter. Further crossing to Rosa26:tdRFP mice, and sorting of RFP(+): glucagon(+) cells from KO mice, revealed recombination in ∼ 30% of α-cells, of which ∼ 50% were ZnT8-negative (14 ± 1.8% of all α-cells). Although glucose and insulin tolerance were normal, female αZnT8KO mice required lower glucose infusion rates during hypoglycemic clamps and displayed enhanced glucagon release (p < 0.001) versus WT mice. Correspondingly, islets isolated from αZnT8KO mice secreted more glucagon at 1 mm glucose, but not 17 mm glucose, than WT controls (n = 5; p = 0.008). Although the expression of other ZnT family members was unchanged, cytoplasmic (n = 4 mice per genotype; p < 0.0001) and granular (n = 3, p < 0.01) free Zn(2+) levels were significantly lower in KO α-cells versus control cells. In response to low glucose, the amplitude and frequency of intracellular Ca(2+) increases were unchanged in α-cells of αZnT8KO KO mice. ZnT8 is thus important in a subset of α-cells for normal responses to hypoglycemia and acts via Ca(2+)-independent mechanisms.
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The zinc transporter SLC30A8/ZnT8 is required in a subpopulation of pancreatic α cells for hypoglycemia-induced glucagon secretion
The Journal of biological chemistry, 2015Co-Authors: Antonia Solomou, Erwann Philippe, Christophe Magnan, Elisa A Bellomo, Gargi Meur, David J. Hodson, Alejandra Tomas, Pedro Luis Herrera, Guy A. RutterAbstract:SLC30A8 encodes a zinc transporter ZnT8 largely restricted to pancreatic islet β- and α-cells, and responsible for zinc accumulation into secretory granules. Although common SLC30A8 variants, believed to reduce ZnT8 activity, increase type 2 diabetes risk in humans, rare inactivating mutations are protective. To investigate the role of SLC30A8 in the control of glucagon secretion, SLC30A8 was inactivated selectively in α-cells by crossing mice with alleles floxed at exon 1 to animals expressing Cre recombinase under the pre-proglucagon promoter. Further crossing to Rosa26:tdRFP mice, and sorting of RFP(+): glucagon(+) cells from KO mice, revealed recombination in ∼ 30% of α-cells, of which ∼ 50% were ZnT8-negative (14 ± 1.8% of all α-cells). Although glucose and insulin tolerance were normal, female αZnT8KO mice required lower glucose infusion rates during hypoglycemic clamps and displayed enhanced glucagon release (p < 0.001) versus WT mice. Correspondingly, islets isolated from αZnT8KO mice secreted more glucagon at 1 mm glucose, but not 17 mm glucose, than WT controls (n = 5; p = 0.008). Although the expression of other ZnT family members was unchanged, cytoplasmic (n = 4 mice per genotype; p < 0.0001) and granular (n = 3, p < 0.01) free Zn(2+) levels were significantly lower in KO α-cells versus control cells. In response to low glucose, the amplitude and frequency of intracellular Ca(2+) increases were unchanged in α-cells of αZnT8KO KO mice. ZnT8 is thus important in a subset of α-cells for normal responses to hypoglycemia and acts via Ca(2+)-independent mechanisms.
James K. Oeser - One of the best experts on this subject based on the ideXlab platform.
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Potential positive and negative consequences of ZnT8 inhibition.
The Journal of endocrinology, 2020Co-Authors: Kristen E. Syring, James K. Oeser, Owen P. Mcguinness, Karin J. Bosma, Slavina B Goleva, Kritika Singh, Christopher A. Lopez, Eric P. Skaar, Lea K. Davis, David R. PowellAbstract:SLC30A8 encodes the zinc transporter ZnT8. SLC30A8 haploinsufficiency protects against type 2 diabetes (T2D), suggesting that ZnT8 inhibitors may prevent T2D. We show here that, while adult chow fed SLC30A8 haploinsufficient and knockout (KO) mice have normal glucose tolerance, they are protected against diet-induced obesity (DIO), resulting in improved glucose tolerance. We hypothesize that this protection against DIO may represent one mechanism whereby SLC30A8 haploinsufficiency protects against T2D in humans and that, while SLC30A8 is predominantly expressed in pancreatic islet beta cells, this may involve a role for ZnT8 in extra-pancreatic tissues. Consistent with this latter concept we show in humans, using electronic health record-derived phenotype analyses, that the 'C' allele of the non-synonymous rs13266634 SNP, which confers a gain of ZnT8 function, is associated not only with increased T2D risk and blood glucose, but also with increased risk for hemolytic anemia and decreased mean corpuscular hemoglobin (MCH). In SLC30A8 KO mice, MCH was unchanged but reticulocytes, platelets and lymphocytes were elevated. Both young and adult SLC30A8 KO mice exhibit a delayed rise in insulin after glucose injection, but only the former exhibit increased basal insulin clearance and impaired glucose tolerance. Young SLC30A8 KO mice also exhibit elevated pancreatic G6pc2 gene expression, potentially mediated by decreased islet zinc levels. These data indicate that the absence of ZnT8 results in a transient impairment in some aspects of metabolism during development. These observations in humans and mice suggest the potential for negative effects associated with T2D prevention using ZnT8 inhibitors.
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Evidence that Evolution of the Diabetes Susceptibility Gene SLC30A8 that Encodes the Zinc Transporter ZnT8 Drives Variations in Pancreatic Islet Zinc Content in Multiple Species
Journal of Molecular Evolution, 2019Co-Authors: Karin J. Bosma, Kristen E. Syring, James K. Oeser, Jason D. Lee, Richard K. P. Benninger, Matthew E. Pamenter, Richard M. O’brienAbstract:Pancreatic islet zinc levels vary widely between species. Very low islet zinc levels in Guinea pigs were thought to be driven by evolution of the INS gene that resulted in the generation of an isoform lacking a histidine at amino acid 10 in the B chain of insulin that is unable to bind zinc. However, we recently showed that the SLC30A8 gene, that encodes the zinc transporter ZnT8, is a pseudogene in Guinea pigs, providing an alternate mechanism to potentially explain the low zinc levels. We show here that the SLC30A8 gene is also inactivated in sheep, cows, chinchillas and naked mole rats but in all four species a histidine is retained at amino acid 10 in the B chain of insulin. Zinc levels are known to be very low in sheep and cow islets. These data suggest that evolution of SLC30A8 rather than INS drives variation in pancreatic islet zinc content in multiple species.
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The Diabetes Susceptibility Gene SLC30A8 that Encodes the Zinc Transporter ZnT8 is a Pseudogene in Guinea Pigs Potentially Contributing to Low Guinea Pig Islet Zinc Content
Journal of molecular evolution, 2018Co-Authors: Kristen E. Syring, James K. Oeser, Karin J. Bosma, Masakazu Shiota, Richard M. O'brienAbstract:In most mammals pancreatic islet beta cells have very high zinc levels that promote the crystallization and storage of insulin. Guinea pigs are unusual amongst mammals in that their islets have very low zinc content. The selectionist theory of insulin evolution proposes that low environmental zinc led to the selection of a mutation in Guinea pig insulin that negated the requirement for zinc binding. In mice deletion of the SLC30A8 gene, that encodes the zinc transporter ZnT8, markedly reduces islet zinc content. We show here that SLC30A8 is a pseudogene in Guinea pigs. We hypothesize that inactivation of the SLC30A8 gene led to low islet zinc content that allowed for the evolution of insulin that no longer bound zinc.
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Combined Deletion of Slc30a7 and SLC30A8 Unmasks a Critical Role for ZnT8 in Glucose-Stimulated Insulin Secretion.
Endocrinology, 2016Co-Authors: Kristen E. Syring, Kayla A. Boortz, James K. Oeser, Alessandro Ustione, Kenneth A. Platt, Melanie K. Shadoan, Owen P. Mcguinness, David W. Piston, David R. Powell, Richard M. O'brienAbstract:Polymorphisms in the SLC30A8 gene, which encodes the ZnT8 zinc transporter, are associated with altered susceptibility to type 2 diabetes (T2D), and SLC30A8 haploinsufficiency is protective against the development of T2D in obese humans. SLC30A8 is predominantly expressed in pancreatic islet β-cells, but surprisingly, multiple knockout mouse studies have shown little effect of SLC30A8 deletion on glucose tolerance or glucose-stimulated insulin secretion (GSIS). Multiple other Slc30a isoforms are expressed at low levels in pancreatic islets. We hypothesized that functional compensation by the Slc30a7 isoform, which encodes ZnT7, limits the impact of SLC30A8 deletion on islet function. We therefore analyzed the effect of Slc30a7 deletion alone or in combination with SLC30A8 on in vivo glucose metabolism and GSIS in isolated islets. Deletion of Slc30a7 alone had complex effects in vivo, impairing glucose tolerance and reducing the glucose-stimulated increase in plasma insulin levels, hepatic glycogen levels, and pancreatic insulin content. Slc30a7 deletion also affected islet morphology and increased the ratio of islet α- to β-cells. However, deletion of Slc30a7 alone had no effect on GSIS in isolated islets, whereas combined deletion of Slc30a7 and SLC30A8 abolished GSIS. These data demonstrate that the function of ZnT8 in islets can be unmasked by removal of ZnT7 and imply that ZnT8 may affect T2D susceptibility through actions in other tissues where it is expressed at low levels rather than through effects on pancreatic islet function.
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Characterization of the human SLC30A8 promoter and intronic enhancer.
Journal of molecular endocrinology, 2011Co-Authors: Lynley D. Pound, James K. Oeser, Suparna A. Sarkar, Stéphane Cauchi, Yingda Wang, Catherine E. Lee, Philippe Froguel, John C. Hutton, Richard M. O'brienAbstract:Genome-wide association studies have shown that a polymorphic variant in SLC30A8, which encodes zinc transporter-8, is associated with altered susceptibility to type 2 diabetes (T2D). This association is consistent with the observation that glucose-stimulated insulin secretion is decreased in islets isolated from SLC30A8 knockout mice. In this study, immunohistochemical staining was first used to show that SLC30A8 is expressed specifically in pancreatic islets. Fusion gene studies were then used to examine the molecular basis for the islet-specific expression of SLC30A8. The analysis of SLC30A8-luciferase expression in bTC-3 cells revealed that the proximal promoter region, located between K6154 and K1, relative to the translation start site, was only active in stable but not transient transfections. VISTA analyses identified three regions in the SLC30A8 promoter and a region in SLC30A8 intron 2 that are conserved in the mouse SLC30A8 gene. Additional fusion gene experiments demonstrated that none of these SLC30A8 promoter regions exhibited enhancer activity when ligated to a heterologous promoter whereas the conserved region in SLC30A8 intron 2 conferred elevated reporter gene expression selectively in bTC-3 but not in aTC-6 cells. Finally, the functional effects of a single nucleotide polymorphism (SNP), rs62510556, in this conserved intron 2 enhancer were investigated. Gel retardation studies showed that rs62510556 affects the binding of an unknown transcription factor and fusion gene analyses showed that it modulates enhancer activity. However, genetic analyses suggest that this SNP is not a causal variant that contributes to the association between SLC30A8 and T2D, at least in Europeans.
Marju Orho-melander - One of the best experts on this subject based on the ideXlab platform.
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A prospective study of dietary and supplemental zinc intake and risk of type 2 diabetes depending on genetic variation in SLC30A8.
Genes & nutrition, 2017Co-Authors: Isabel Drake, George Hindy, Ulrika Ericson, Marju Orho-melanderAbstract:The solute carrier family 30 member 8 gene (SLC30A8) encodes a zinc transporter in the pancreatic beta cells and the major C-allele of a missense variant (rs13266634; C/T; R325W) in SLC30A8 is associated with an increased risk of type 2 diabetes (T2D). We hypothesized that the association between zinc intake and T2D may be modified by the SLC30A8 genotype. We carried out a prospective study among subjects with no history cardio-metabolic diseases in the Malmo Diet and Cancer Study cohort (N = 26,132, 38% men; 86% with genotype data). Zinc intake was assessed using a diet questionnaire and food record. During a median follow-up of 19 years, 3676 T2D cases occurred. A BMI-stratified Cox proportional hazards regression model with attained age as the time scale was used to model the association between total and dietary zinc intake, zinc supplement use, zinc to iron ratio, and risk of T2D adjusting for putative confounding factors. The median total zinc intake was 11.4 mg/day, and the median dietary zinc intake was 10.7 mg/day. Zinc supplement users (17%) had a median total zinc intake of 22.4 mg/day. Dietary zinc intake was associated with increased risk of T2D (P trend
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A non-synonymous variant in SLC30A8 is not associated with type 1 diabetes in the Danish population
Molecular genetics and metabolism, 2008Co-Authors: Caroline Brorsson, Regine Bergholdt, Marketa Sjögren, Stefanie Eising, Karina Meden Sørensen, David M. Hougaard, Marju Orho-melander, Leif Groop, Flemming PociotAbstract:Genome-wide association scans in type 2 diabetes (T2D) have identified a risk variant, rs13266634 (Arg325Trp), in SLC30A8 on chromosome 8. SLC30A8 encodes a β-cell specific zinc-ion transporter and rs13266634 has been shown to affect insulin secretion. Recently, autoantibodies for SLC30A8 with high predictive value were demonstrated in individuals with type 1 diabetes (T1D), making this gene an interesting T1D candidate gene. We genotyped rs13266634 in 3008 cases and controls and 246 families from Denmark. Association to T1D could not be demonstrated.
Isabel Drake - One of the best experts on this subject based on the ideXlab platform.
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a prospective study of dietary and supplemental zinc intake and risk of type 2 diabetes depending on genetic variation in SLC30A8
Genes and Nutrition, 2017Co-Authors: Isabel Drake, George Hindy, Ulrika Ericson, Marju OrhomelanderAbstract:The solute carrier family 30 member 8 gene (SLC30A8) encodes a zinc transporter in the pancreatic beta cells and the major C-allele of a missense variant (rs13266634; C/T; R325W) in SLC30A8 is associated with an increased risk of type 2 diabetes (T2D). We hypothesized that the association between zinc intake and T2D may be modified by the SLC30A8 genotype. We carried out a prospective study among subjects with no history cardio-metabolic diseases in the Malmo Diet and Cancer Study cohort (N = 26,132, 38% men; 86% with genotype data). Zinc intake was assessed using a diet questionnaire and food record. During a median follow-up of 19 years, 3676 T2D cases occurred. A BMI-stratified Cox proportional hazards regression model with attained age as the time scale was used to model the association between total and dietary zinc intake, zinc supplement use, zinc to iron ratio, and risk of T2D adjusting for putative confounding factors. The median total zinc intake was 11.4 mg/day, and the median dietary zinc intake was 10.7 mg/day. Zinc supplement users (17%) had a median total zinc intake of 22.4 mg/day. Dietary zinc intake was associated with increased risk of T2D (P trend < 0.0001). In contrast, we observed a lower risk of T2D among zinc supplement users (HR = 0.79, 95% CI 0.70–0.89). The SLC30A8 CC genotype was associated with a higher risk of T2D (HR = 1.16, 95% CI 1.07–1.24), and the effect was stronger among subjects with higher BMI (P interaction = 0.007). We observed no significant modification of the zinc-T2D associations by SLC30A8 genotype. However, a three-way interaction between SLC30A8 genotype, BMI, and zinc to iron ratio was observed (P interaction = 0.007). A high zinc to iron ratio conferred a protective associated effect on T2D risk among obese subjects, and the effect was significantly more pronounced among T-allele carriers. Zinc supplementation and a high zinc to iron intake ratio may lower the risk of T2D, but these associations could be modified by obesity and the SLC30A8 genotype. The findings implicate that when considering zinc supplementation for T2D prevention, both obesity status and SLC30A8 genotype may need to be accounted for.
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A prospective study of dietary and supplemental zinc intake and risk of type 2 diabetes depending on genetic variation in SLC30A8.
Genes & nutrition, 2017Co-Authors: Isabel Drake, George Hindy, Ulrika Ericson, Marju Orho-melanderAbstract:The solute carrier family 30 member 8 gene (SLC30A8) encodes a zinc transporter in the pancreatic beta cells and the major C-allele of a missense variant (rs13266634; C/T; R325W) in SLC30A8 is associated with an increased risk of type 2 diabetes (T2D). We hypothesized that the association between zinc intake and T2D may be modified by the SLC30A8 genotype. We carried out a prospective study among subjects with no history cardio-metabolic diseases in the Malmo Diet and Cancer Study cohort (N = 26,132, 38% men; 86% with genotype data). Zinc intake was assessed using a diet questionnaire and food record. During a median follow-up of 19 years, 3676 T2D cases occurred. A BMI-stratified Cox proportional hazards regression model with attained age as the time scale was used to model the association between total and dietary zinc intake, zinc supplement use, zinc to iron ratio, and risk of T2D adjusting for putative confounding factors. The median total zinc intake was 11.4 mg/day, and the median dietary zinc intake was 10.7 mg/day. Zinc supplement users (17%) had a median total zinc intake of 22.4 mg/day. Dietary zinc intake was associated with increased risk of T2D (P trend
Ezio Bonifacio - One of the best experts on this subject based on the ideXlab platform.
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Autoantibodies to zinc transporter 8 and SLC30A8 genotype stratify type 1 diabetes risk
Diabetologia, 2009Co-Authors: Peter Achenbach, Kerstin Koczwara, Thomas Illig, Vito Lampasona, U Landherr, S Krause, Harald Grallert, Christiane Winkler, Maren Pflüger, Ezio BonifacioAbstract:Aims/hypothesis Our aim was to determine the relationships between autoantibodies to zinc transporter 8 (ZnT8), genotypes of the ZnT8-encoding gene SLC30A8 and type 1 diabetes risk.
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SLC30A8 (ZnT8) Polymorphism is Associated with Young Age at Type 1 Diabetes Onset
The review of diabetic studies : RDS, 2008Co-Authors: Henning Gohlke, Ezio Bonifacio, Uta Ferrari, Kerstin Koczwara, Thomas Illig, Anette-g. ZieglerAbstract:It was recently shown that the major allele of the SLC30A8 (zinc transporter 8, ZnT8) single nucleotide polymorphism (SNP) rs13266634 was associated with type 2 diabetes and with reduced insulin secretion in non-diabetic relatives. Because of its role in beta-cell function, we hypothesized that this candidate SNP may confer increased susceptibility for beta-cell destruction in type 1 diabetes. We analyzed SLC30A8 genotypes in 874 patients with type 1 diabetes and 1021 control subjects. No difference in allele and genotype frequencies of the SLC30A8 SNP rs13266634 was found between patients and controls. Analysis with respect to age at type 1 diabetes onset, however, showed that patients with a diabetes onset before age 5 years had an increased prevalence of the cytosine (C) allele (risk allele, 82%) and the homozygous CC genotype (65%) compared to patients who developed type 1 diabetes after age 5 years (67% and 49%; p < 0.01) and compared to controls (69% and 48%; p < 0.03). These data suggest that genetic susceptibility for beta-cell dysfunction in the presence of autoimmunity may lead to accelerated progression and early manifestation of the disease.
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SLC30A8 polymorphismen sind assoziiert mit fruhem diabetesbeginn von typ 1
Diabetologie Und Stoffwechsel, 2008Co-Authors: U Ferrari, H Gohlke, Ezio Bonifacio, T Illig, A G ZieglerAbstract:Hintergrund und Fragestellung: Das SLC30A8 Gen codiert das Zinktransporter-Protein ZnT8, welches nur in pankreatischen Betainselzellen exprimiert wird. Ein Polymorphismus des Gens liegt vermehrt bei Patienten mit Typ-2-Diabetes (T2D) versus Kontrollen vor. Das Hauptallel von SLC30A8 Single Nucleotide Polymorphismus (SNP) rs13266634 ist bei nicht-diabetischen Verwandten von Patienten mit Typ-2-Diabetes mit einer reduzierten Insulinsekretion nach oraler oder intravenoser Glucosestimulation assoziiert. Aufgrund der Rolle des SLC30A8 Gens in der Betazellfunktion, stellten wir die Hypothese auf, dass dieses zu gesteigerter Sensibilitat fur autoimmune s-Zellzerstorung in Typ-1-Diabetes fuhren konnte. Dazu analysierten wir SLC30A8-Genotypen in Patienten mit Typ-1-Diabetes und Kontrollen. Methodik: Insgesamt wurden 874 Diabetespatienten (w: 586) und 1023 Kontrollen (w: 349) genotypisiert. Die genetische Bestimmung der Patienten und Kontrollen erfolgte am SLC30A8 SNP rs13266634 mit der iPLEXTM Methode. Es fand eine Altersstratifizierung in folgenden Jahresgruppen statt: 0–5, 5–15, 15–20, 20–30, 30–50. Ergebnisse: Die SLC30A8 SNP rs13266634 Genotypenverteilung stimmte mit dem Hardy-Weinberg-Equilibrium in der Gesamtkohorte und in den Alterssubpopulationen (p>0,1) uberein. Es gab keinen Unterschied zwischen Allel- und Genotypenhaufigkeiten zwischen Patienten mit Typ-1-Diabetes und Kontrollen. Eine erhohte Pravalenz des C Allels (82%) liegt vor bei: Patienten mit Diabetesbeginn vor versus nach dem 5. Lebensjahr (67%; p=0,0018) und verglichen zur Kontrollpopulation (69%; p=0,0084). Gleiches galt fur den CC Genotyp (p=0,008 versus spaterem Diabetesbeginn; p=0,027 versus Kontrollen). Dieser Unterschied verstarkte sich bei Patienten, die den Diabetes in den ersten zwei Lebensjahren entwickelt hatten (C Allelhaufigkeit 88%). Bei diesen sehr jungen Patienten lag, wie auch sonst typisch fur Patienten mit Typ-1-Diabetes, eine hohe Pravalenz des HLA DR3-DQ2/DR4-DQ8 Genotyps vor (60%). Schlussfolgerungen: Die Studie legt nahe, dass genetische Suskeptibilitat der Betazelldysfunktion (SLC30A8) bei vorliegender Autoimmunitat zu einer schnelleren Progression von Betazelldestruktion und fruheren Krankheitsmanifestation fuhrt. Das Ergebnis konnte Hinweise auf mogliche gemeinsame Pathomechanismen von Typ-11 und Typ-2-Diabetes geben.
