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Zhang L, Wu M, Zhang J, Liu T, Fu S, Wang Y, Xu Z. The pivotal role of glucose transporter 1 in diabetic kidney disease. Life Sci 2024; 353:122932. [PMID: 39067659 DOI: 10.1016/j.lfs.2024.122932] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2024] [Revised: 07/12/2024] [Accepted: 07/20/2024] [Indexed: 07/30/2024]
Abstract
Diabetes mellitus (DM) is a significant public health problem. Diabetic kidney disease (DKD) is the most common complication of DM, and its incidence has been increasing with the increasing prevalence of DM. Given the association between DKD and mortality in patients with DM, DKD is a significant burden on public health resources. Despite its significance in DM progression, the pathogenesis of DKD remains unclear. Aberrant glucose uptake by cells is an important pathophysiological mechanism underlying DKD renal injury. Glucose is transported across the bilayer cell membrane by a glucose transporter (GLUT) located on the cell membrane. Multiple GLUT proteins have been identified in the kidney, and GLUT1 is one of the most abundantly expressed isoforms. GLUT1 is a crucial regulator of intracellular glucose metabolism and plays a key pathological role in the phenotypic changes in DKD mesangial cells. In an attempt to understand the pathogenesis of DKD better, we here present a review of studies on the role of GLUT1 in the development and progression of DKD.
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Affiliation(s)
- Li Zhang
- Department of Nephrology, The First Hospital of Jilin University, Changchun, 130021, China
| | - Meiyan Wu
- Department of Nephrology, The First Hospital of Jilin University, Changchun, 130021, China
| | - Jizhou Zhang
- Department of Biochemistry, College of Basic Medical Sciences, Jilin University, Changchun 130021, China
| | - Tingting Liu
- Department of Nephrology, The First Hospital of Jilin University, Changchun, 130021, China
| | - Shaojie Fu
- Department of Nephrology, The First Hospital of Jilin University, Changchun, 130021, China
| | - Yue Wang
- Department of Nephrology, The First Hospital of Jilin University, Changchun, 130021, China
| | - Zhonggao Xu
- Department of Nephrology, The First Hospital of Jilin University, Changchun, 130021, China.
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Stefanidis I, Tziastoudi M, Tsironi EE, Dardiotis E, Tachmitzi SV, Fotiadou A, Pissas G, Kytoudis K, Sounidaki M, Ampatzis G, Mertens PR, Liakopoulos V, Eleftheriadis T, Hadjigeorgiou GM, Santos M, Zintzaras E. The contribution of genetic variants of SLC2A1 gene in T2DM and T2DM-nephropathy: association study and meta-analysis. Ren Fail 2018; 40:561-576. [PMID: 30353771 PMCID: PMC6201811 DOI: 10.1080/0886022x.2018.1496931] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2017] [Revised: 06/15/2018] [Accepted: 06/28/2018] [Indexed: 12/22/2022] Open
Abstract
An association study was conducted to investigate the relation between 14 variants of glucose transporter 1 gene (SLC2A1) and the risk of type 2 diabetes (T2DM) leading to nephropathy. We also performed a meta-analysis of 11 studies investigating association between diabetic nephropathy (DN) and SLC2A1 variants. The cohort included 197 cases (T2DM with nephropathy), 155 diseased controls (T2DM without nephropathy) and 246 healthy controls. The association of variants with disease progression was tested using generalized odds ratio (ORG). The risk of type 2 diabetes leading to nephropathy was estimated by the OR of additive and co-dominant models. The mode of inheritance was assessed using the degree of dominance index (h-index). We synthesized results of 11 studies examining association between 5 SLC2A1 variants and DN. ORG was used to assess the association between variants and DN using random effects models. Significant results were derived for co-dominant model of rs12407920 [OR = 2.01 (1.17-3.45)], rs841847 [OR = 1.73 (1.17-2.56)] and rs841853 [OR = 1.74 (1.18-2.55)] and for additive model of rs3729548 [OR = 0.52 (0.29-0.90)]. The mode of inheritance for rs12407920, rs841847 and rs841853 was 'dominance of each minor allele' and for rs3729548 'non-dominance'. Frequency of one haplotype (C-G-G-A-T-C-C-T-G-T-C-C-A-G) differed significantly between cases and healthy controls [p = .014]. Regarding meta-analysis, rs841853 contributed to an increased risk of DN [(ORG = 1.43 (1.09-1.88); ORG = 1.58 (1.01-2.48)] between diseased controls versus cases and healthy controls versus cases, respectively. Further studies confirm the association of rs12407920, rs841847, rs841853, as well as rs3729548 and the risk of T2DM leading to nephropathy.
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Affiliation(s)
- I. Stefanidis
- Department of Nephrology, University of Thessaly School of Medicine, Larissa, Greece
| | - M. Tziastoudi
- Department of Biomathematics, University of Thessaly School of Medicine, Larissa, Greece
| | - E. E. Tsironi
- Department of Ophthalmology, University of Thessaly School of Medicine, Larissa, Greece
| | - E. Dardiotis
- Department of Neurology, University of Thessaly School of Medicine, Larissa, Greece
| | - S. V. Tachmitzi
- Department of Ophthalmology, University of Thessaly School of Medicine, Larissa, Greece
| | - A. Fotiadou
- Department of Ophthalmology, University of Thessaly School of Medicine, Larissa, Greece
| | - G. Pissas
- Department of Nephrology, University of Thessaly School of Medicine, Larissa, Greece
| | - K. Kytoudis
- Department of Nephrology, University of Thessaly School of Medicine, Larissa, Greece
| | - M. Sounidaki
- Department of Nephrology, University of Thessaly School of Medicine, Larissa, Greece
| | - G. Ampatzis
- Department of Nephrology, University of Thessaly School of Medicine, Larissa, Greece
| | - P. R. Mertens
- Department of Nephrology, Hypertension, Diabetes and Endocrinology, School of Medicine, University of Magdeburg, Magdeburg, Germany
| | - V. Liakopoulos
- Department of Nephrology, University of Thessaly School of Medicine, Larissa, Greece
| | - T. Eleftheriadis
- Department of Nephrology, University of Thessaly School of Medicine, Larissa, Greece
| | - G. M Hadjigeorgiou
- Department of Neurology, University of Thessaly School of Medicine, Larissa, Greece
| | - M. Santos
- Departament de Genètica i de Microbiologia, Universitat Autònoma de Barcelona, Bellaterra, Spain
| | - E. Zintzaras
- Department of Biomathematics, University of Thessaly School of Medicine, Larissa, Greece
- The Institute for Clinical Research and Health Policy Studies, Tufts Medical Center, Tufts University School of Medicine, Boston, MA, USA
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Glucose transporter 1( GLUT1 ) gene frequency distribution of Xba IG > T and Hae IIIT > C polymorphisms among different West Indian patients with type 2 diabetes mellitus. GENE REPORTS 2017. [DOI: 10.1016/j.genrep.2016.11.006] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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Rizvi S, Raza ST, Mahdi F. Association of genetic variants with diabetic nephropathy. World J Diabetes 2014; 5:809-816. [PMID: 25512783 PMCID: PMC4265867 DOI: 10.4239/wjd.v5.i6.809] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2014] [Revised: 07/09/2014] [Accepted: 09/10/2014] [Indexed: 02/05/2023] Open
Abstract
Diabetic nephropathy accounts for the most serious microvascular complication of diabetes mellitus. It is suggested that the prevalence of diabetic nephropathy will continue to increase in future posing a major challenge to the healthcare system resulting in increased morbidity and mortality. It occurs as a result of interaction between both genetic and environmental factors in individuals with both type 1 and type 2 diabetes. Genetic susceptibility has been proposed as an important factor for the development and progression of diabetic nephropathy, and various research efforts are being executed worldwide to identify the susceptibility gene for diabetic nephropathy. Numerous single nucleotide polymorphisms have been found in various genes giving rise to various gene variants which have been found to play a major role in genetic susceptibility to diabetic nephropathy. The risk of developing diabetic nephropathy is increased several times by inheriting risk alleles at susceptibility loci of various genes like ACE, IL, TNF-α, COL4A1, eNOS, SOD2, APOE, GLUT, etc. The identification of these genetic variants at a biomarker level could thus, allow the detection of those individuals at high risk for diabetic nephropathy which could thus help in the treatment, diagnosis and early prevention of the disease. The present review discusses about the various gene variants found till date to be associated with diabetic nephropathy.
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da Silva AS, Dias LD, Borges JF, Markoski MM, de Souza MS, Irigoyen MC, Machado UF, Schaan BD. Renal GLUT1 reduction depends on angiotensin-converting enzyme inhibition in diabetic hypertensive rats. Life Sci 2013; 92:1174-9. [DOI: 10.1016/j.lfs.2013.05.001] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2013] [Revised: 04/15/2013] [Accepted: 05/01/2013] [Indexed: 10/26/2022]
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Suazo J, Pardo R, Castillo S, Martin LM, Rojas F, Santos JL, Rotter K, Solar M, Tapia E. Family-based association study between SLC2A1, HK1, and LEPR polymorphisms with myelomeningocele in Chile. Reprod Sci 2013; 20:1207-14. [PMID: 23427181 DOI: 10.1177/1933719113477489] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Obese/diabetic mothers present a higher risk to develop offspring with myelomeningocele (MM), evidence supporting the role of energy homeostasis-related genes in neural tube defects. Using polymerase chain reaction-restriction fragment length polymorphism, we have genotyped SLC2A1, HK1, and LEPR single-nucleotide polymorphisms in 105 Chilean patients with MM and their parents in order to evaluate allele-phenotype associations by means of allele/haplotype transmission test (TDT) and parent-of-origin effects. We detected an undertransmission for the SLC2A1 haplotype T-A (rs710218-rs2229682; P = .040), which was not significant when only lower MM (90% of the cases) was analyzed. In addition, the leptin receptor rs1137100 G allele showed a significant increase in the risk of MM for maternal-derived alleles in the whole sample (2.43-fold; P = .038) and in lower MM (3.20-fold; P = .014). Our results support the role of genes involved in energy homeostasis in the risk of developing MM, thus sustaining the hypothesis of diverse pathways and genetic mechanisms acting in the expression of such birth defect.
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Affiliation(s)
- José Suazo
- 1Departmento de Nutrición, Diabetes y Metabolismo, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
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Cui W, Du B, Zhou W, Jia Y, Sun G, Sun J, Zhang D, Yuan H, Xu F, Lu X, Luo P, Miao L. Relationship between five GLUT1 gene single nucleotide polymorphisms and diabetic nephropathy: a systematic review and meta-analysis. Mol Biol Rep 2012; 39:8551-8558. [PMID: 22707195 DOI: 10.1007/s11033-012-1711-z] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2012] [Accepted: 06/06/2012] [Indexed: 12/20/2022]
Abstract
So far, case-control studies on the association between glucose transporter 1 (GLUT1) gene single nucleotide polymorphisms (SNPs) and diabetic nephropathy (DN) have generated considerable controversy. To clarify the linkage of GLUT1 SNPs on the risk of DN, a systematic review and meta-analysis was performed. A comprehensive literature search of electronic databases was conducted to obtain relative studies. Nine case-control studies were included. Significant differences were found between XbaI SNP (rs841853) and increased risk of DN in all genetic models. Subgroup analyses for Caucasians population and DN from both type 1 and type 2 diabetes also revealed positive results. For Enh2-1 SNP (rs841847), Enh2-2 SNP (rs841848) and HaeIII SNP (rs1385129), obvious linkages were demonstrated in recessive model. However, analysis for the association between HpyCH4V SNP (rs710218) and the susceptibility of DN showed no significance. Likewise, negative outcome was also found in the assessment for the influence of XbaI or Enh2-2 SNP on the pathogenesis progress of DN. The evidence currently available shows that XbaI, Enh2 and HaeIII SNPs, but not HpyCH4V SNP, in GLUT1 gene may be genetic susceptibility to DN. However, data does not support the association between either XbaI or Enh2-2 SNP and the severity of DN.
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Affiliation(s)
- Wenpeng Cui
- Department of Nephrology, Second Hospital, Jilin University, 218 Ziqiang Street, Changchun 130041, Jilin, China
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Amann T, Kirovski G, Bosserhoff AK, Hellerbrand C. Analysis of a promoter polymorphism of the GLUT1 gene in patients with hepatocellular carcinoma. Mol Membr Biol 2011; 28:182-6. [PMID: 21332301 DOI: 10.3109/09687688.2011.554447] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
The glucose transporter isoform 1 (GLUT1) is a key rate-limiting factor in the transport and metabolism of glucose in cancer cells. Recently, we found that GLUT1 expression is increased in hepatocellular carcinoma (HCC) and promotes tumorigenicity of HCC cells. Hypoxia further increased GLUT1 expression in HCC cells, and this induction was dependent on the activation of the transcription factor hypoxia-inducible factor (HIF)-1alpha. The promoter region of the GLUT1 gene harbors a single nucleotide polymorphism (SNP; Rs710218; A to T at -2841) closely positioned to a putative HIF-1alpha binding site, and recently, this SNP was found to be more frequent in patients with renal cell carcinoma. In the present study, the A-2841T genotype distribution did not differ significantly between HCC patients (n = 95; AA: 60%; AT 36% and TT: 4%) and healthy controls (n = 127; AA: 50%; AT 41% and TT: 9%). However and noteworthy, non-carriers of the T allele had higher GLUT1 expression levels in cancerous hepatic tissue, and tended to reveal a more aggressive tumour growth. These data indicate that the SNP Rs710218 is not associated with a higher risk for HCC but rather for HCC progression, potentially via HIF-1alpha mediated increased GLUT1 expression.
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Affiliation(s)
- Thomas Amann
- Department of Internal Medicine I, University Hospital Regensburg, Regensburg
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Hsu CC, Kao WL, Steffes MW, Gambir T, Brancati FL, Heilig CW, Shuldiner AR, Boerwinkle EA, Coresh J. Genetic variation of glucose transporter-1 (GLUT1) and albuminuria in 10,278 European Americans and African Americans: a case-control study in the Atherosclerosis Risk in Communities (ARIC) study. BMC MEDICAL GENETICS 2011; 12:16. [PMID: 21247498 PMCID: PMC3034664 DOI: 10.1186/1471-2350-12-16] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/29/2009] [Accepted: 01/19/2011] [Indexed: 11/10/2022]
Abstract
Background Evidence suggests glucose transporter-1(GLUT1) genetic variation affects diabetic nephropathy and albuminuria. Our aim was to evaluate associations with albuminuria of six GLUT1 single nucleotide polymorphisms(SNPs), particularly XbaI and the previously associated Enhancer-2(Enh2) SNP. Methods A two-stage case-control study was nested in a prospective cohort study of 2156 African Americans and 8122 European Americans with urinary albumin-to-creatinine ratio(ACR). Cases comprised albuminuria(N = 825; ≥ 30 μg/mg) and macroalbuminuria(N = 173; ≥ 300 μg/mg). ACR < 30 μg/mg classified controls(n = 9453). Logistic regression and odds ratios(OR) assessed associations. The evaluation phase(stage 1, n = 2938) tested associations of albuminuria(n = 305) with six GLUT1 SNPs: rs841839, rs3768043, rs2297977, Enh2(rs841847) XbaI(rs841853), and rs841858. Enh2 was examined separately in the replication phase(stage 2, n = 7340) and the total combined sample (n = 10,278), with all analyses stratified by race and type 2 diabetes. Results In European Americans, after adjusting for diabetes and other GLUT1 SNPs in stage 1, Enh2 risk genotype(TT) was more common in albuminuric cases(OR = 3.37, P = 0.090) whereas XbaI (OR = 0.94, p = 0.931) and remaining SNPs were not. In stage 1, the Enh2 association with albuminuria was significant among diabetic European Americans(OR = 2.36, P = 0.025). In African Americans, Enh2 homozygosity was rare(0.3%); XbaI was common(18.0% AA) and not associated with albuminuria. In stage 2(n = 7,340), Enh2 risk genotype had increased but non-significant OR among diabetic European Americans(OR = 1.66, P = 0.192) and not non-diabetics(OR = 0.99, p = 0.953), not replicating stage 1. Combining stages 1 and 2, Enh2 was associated with albuminuria(OR 2.14 [1.20-3.80], P = 0.009) and macroalbuminuria(OR 2.69, [1.02-7.09], P = 0.045) in diabetic European Americans. The Enh2 association with macroalbuminuria among non-diabetic European Americans with fasting insulin(OR = 1.84, P = 0.210) was stronger at the highest insulin quartile(OR = 4.08, P = 0.040). Conclusions As demonstrated with type 1 diabetic nephropathy, the GLUT1 Enh2 risk genotype, instead of XbaI, may be associated with type 2 diabetic albuminuria among European Americans, though an association is not conclusive. The association among diabetic European Americans found in stage 1 was not replicated in stage 2; however, this risk association was evident after combining all diabetic European Americans from both stages. Additionally, our results suggest this association may extend to non-diabetics with high insulin concentrations. Rarity of the Enh2 risk genotype among African Americans precludes any definitive conclusions, although data suggest a risk-enhancing role.
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Affiliation(s)
- Charles C Hsu
- Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA
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Kim SJ, Hwang SH, Kim IJ, Lee MK, Lee CH, Lee SY, Lee EY. The association of 18F-deoxyglucose (FDG) uptake of PET with polymorphisms in the glucose transporter gene (SLC2A1) and hypoxia-related genes (HIF1A, VEGFA, APEX1) in non-small cell lung cancer. SLC2A1 polymorphisms and FDG-PET in NSCLC patients. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2010; 29:69. [PMID: 20540786 PMCID: PMC2898683 DOI: 10.1186/1756-9966-29-69] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 03/31/2010] [Accepted: 06/12/2010] [Indexed: 11/10/2022]
Abstract
BACKGROUND Positron emission tomography imaging of lung cancers with 2-[fluorine-18]-fluoro-2-deoxy-D-glucose is a non-invasive diagnostic, and prognostic tool that measures tumor metabolism. We have analyzed the effect of solute carrier family 2 (facilitated glucose transporter), member 1 polymorphisms on 2-[fluorine-18]-fluoro-2-deoxy-D-glucose-uptake with a combination of polymorphisms of hypoxia-inducible factor 1 alpha, apurinic/apyimidinic endonuclease, and vascular endothelial growth factor A in a hypoxia-related pathway. METHODS We investigated the association between solute carrier family 2 (facilitated glucose transporter), member 1 -2841A>T, hypoxia-inducible factor 1 alpha Pro582Ser, Ala588Thr, apurinic/apyimidinic endonuclease Asp148Glu, or vascular endothelial growth factor A +936C>T and 2-[fluorine-18]-fluoro-2-deoxy-D-glucose-uptake among 154 patients with non-small-cell lung cancer. RESULTS The solute carrier family 2 (facilitated glucose transporter), member 1 -2841A>T polymorphism was significantly associated with 2-[fluorine-18]-fluoro-2-deoxy-D-glucose-uptake in combination with the apurinic/apyimidinic endonuclease Asp148Glu (T>G) polymorphism in the squamous cell type of non-small-cell lung cancer. The solute carrier family 2 (facilitated glucose transporter), member 1 TT genotype had a higher maximum standardized uptake values than the AA + AT genotype when the apurinic/apyimidinic endonuclease genotype was TT (mean maximum standardized uptake values, 12.47 +/- 1.33 versus 8.46 +/- 2.90, respectively; P = 0.028). The mean maximum standardized uptake values were not statistically different with respect to vascular endothelial growth factor A and hypoxia-inducible factor 1 alpha polymorphisms. CONCLUSION A glucose transporter gene polymorphism was shown to be statistically associated with glucose-uptake when the apurinic/apyimidinic endonuclease genotype is TT in patients with the squamous cell type of non-small-cell lung cancer. Our findings suggest that a newly developed tracer for positron emission tomography could be affected by genetic polymorphisms.
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Affiliation(s)
- Seong-Jang Kim
- Departments of Laboratory Medicine, Pusan National University Hospital, School of Medicine Pusan National University, Busan, Korea.
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Frequency distribution of XbaIG > T and HaeIIIT > C GLUT1 polymorphisms among different Brazilian ethnic groups. Mol Biol Rep 2009; 37:75-9. [PMID: 19347605 DOI: 10.1007/s11033-009-9528-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2008] [Accepted: 03/20/2009] [Indexed: 01/25/2023]
Abstract
GLUT is the major glucose transporter in mammalian cells. Single nucleotide polymorphisms (SNP) at GLUT1 promoter and regulatory regions have been associated to the risk of developing nephropathy in different type 1 and type 2 diabetic populations. It has been demonstrated that differences in allelic and genotypic frequencies of GLUT1 gene (SLC2A1) polymorphisms occur among different populations. Therefore, ethnic differences in distribution of GLUT1 gene polymorphisms may be an important factor in determining gene-disease association. In this study, we investigated the XbaIG > T and HaeIIIT > C polymorphisms in six different Brazilian populations: 102 individuals from Salvador population (Northern Brazil), 56 European descendants from Joinville (South Brazil), 85 Indians from Tiryió tribe (North Brazil) and 127 samples from Southern Brazil: 44 from European descendants, 42 from African descendants and 41 from Japanese descendants. Genotype frequencies from both sites did not differ significantly from those expected under the Hardy-Weinberg equilibrium. We verified that the allele frequencies of both polymorphisms were heterogeneous in these six Brazilian ethnic groups.
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Costa GCS, Azevedo R, Gadelha SR, Kashima SH, Muricy G, Olavarria VN, Covas DT, Takayanagui OM, Galvão-Castro B, Alcantara LCJ. Polymorphisms at GLUT1 gene are not associated with the development of TSP/HAM in Brazilian HTLV-1 infected individuals and the discovery of a new polymorphism at GLUT1 gene. J Med Virol 2009; 81:552-7. [PMID: 19152396 DOI: 10.1002/jmv.21421] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Abstract
The development of HTLV-1 associated clinical manifestations, such as TSP/HAM and ATLL, occur in 2-4% of the infected population and it is still unclear why this infection remains asymptomatic in most infected carriers. Recently, it has been demonstrated that HTLV uses the Glucose transporter type 1 (GLUT1) to infect T-CD4(+) lymphocytes and that single nucleotide polymorphisms (SNP) in the GLUT1 gene are associated with diabetic nephropathy in patients with diabetes mellitus in different populations. These polymorphisms could contribute to a higher GLUT1 protein expression on cellular membrane, facilitating the entry of HTLV and its transmission cell by cell. This could result in a higher provirus load and consequently in the development of TSP/HAM. To evaluate the role of GLUT1 gene polymorphisms in the development of TSP/HAM in HTLV-1 infected individuals, the g.22999G > T, g.15339T > C and c.-2841A > T sites were analyzed by PCR/RFLP or sequencing in 244 infected individuals and 102 normal controls. The proviral load of the HTLV-1 infected patients was also analyzed using Real Time Quantitative PCR. Genotypic and allelic frequencies of the three sites did not differ significantly between controls and HTLV-1 infected individuals. There was no difference in genotypic and allelic distributions among patients as to the presence or absence of HTLV-1 associated clinic manifestations. As regards the quantification of the provirus load, we observed a significant reduction in the asymptomatic individuals compared with the oligosymptomatic and TSP/HAM individuals. These results suggest that g.22999G > T, g.15339T > C, and c.-2841A > T SNP do not contribute to HTLV-1 infection nor to the genetic susceptibility of TSP/HAM in Brazilian HTLV-1 infected individuals.
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Affiliation(s)
- Giselle Calasans Souza Costa
- Laboratório Avançado de Saúde Pública, Centro de Pesquisa Gonçalo Moniz, Fundação Oswaldo Cruz, Salvador, Bahia, Brazil
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Makni K, Jarraya F, Rebaï M, Mnif F, Boudawara M, Hamza N, Rekik N, Abid M, Hachicha J, Granier C, Rebaï A, Ayadi H. Risk genotypes and haplotypes of the GLUT1 gene for type 2 diabetic nephropathy in the Tunisian population. Ann Hum Biol 2008; 35:490-8. [PMID: 18821326 DOI: 10.1080/03014460802247142] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
OBJECTIVE Diabetic nephropathy (DN) is a long-term complication of both type 1 and type 2 diabetes. Genetic studies on DN have been of little help so far, since several genetic association studies have shown conflicting results. Here we report the findings of a case-control study on five SNPs in the glucose transporter 1 (GLUT1) gene. The study investigated the association of five GLUT1 genotypes and haplotypes with DN. RESEARCH DESIGN AND METHODS All subjects, 126 DN (cases) and 273 type 2 diabetes (controls), were genotyped using the polymerase chain reaction restriction fragment length polymorphism. RESULTS The TT and the AA genotypes of the Haell and Enh2 SNP1, increased the risk of DN. The study also identified CGT as the highest risk haplotype (4.4-fold) followed by CAT with an increased risk of DN of 2.6-fold. CONCLUSIONS The GLUT1 gene confers susceptibility to DN in type 2 diabetes patients in the Tunisian population.
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Affiliation(s)
- K Makni
- Research Unit Target for Diagnosis and Therapeutic in the Human Pathology, Center of Biotechnology of Sfax, Tunisia.
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Makni K, Mnif F, Boudawara M, Hamza N, Rekik N, Abid M, Rebaï A, Jarraya F, Granier C, Ayadi H. Association of glucose transporter 1 polymorphisms with type 2 diabetes in the Tunisian population. Diabetes Metab Res Rev 2008; 24:544-8. [PMID: 18613291 DOI: 10.1002/dmrr.866] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
BACKGROUND T2DM is a complex metabolic disease. Genetic studies on T2DM have been of little help so far because several genetic association studies have shown conflicting results. In this study, we report the findings of a case-control study on three SNPs in the GLUT1 gene. For this, we investigated the association of GLUT1 genotypes and haplotypes with T2DM. RESEARCH DESIGN AND METHODS All 273 T2DM subjects (cases) and 343 healthy subjects (controls) were genotyped using the polymerase chain reaction restriction fragment length polymorphism. RESULTS Results showed that the GT genotype of XbaI SNP could increase the risk of susceptibility to T2DM to 2.4 and that TAT is a 'risk haplotype' conferring a risk of 3.4 to T2DM. CONCLUSION The TAT haplotype of the GLUT1 gene confers susceptibility to T2DM in the Tunisian population.
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Affiliation(s)
- K Makni
- Research Unit 'Targets for Diagnostic and Therapy of Human Diseases', Centre of Biotechnology of Sfax, and Laboratoire International Associé No 135, Sfax, Tunisia.
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Abstract
Perspectives on the News commentaries are part of a free monthly CME activity. The Mount Sinai School of Medicine, New York, New York, designates this activity for 2.0 AMA PRA Category 1 credits. If you wish to participate, review this article and visit www.diabetes.procampus.net to complete a posttest and receive a certificate. The Mount Sinai School of Medicine is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.
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Gnudi L, Thomas SM, Viberti G. Mechanical forces in diabetic kidney disease: a trigger for impaired glucose metabolism. J Am Soc Nephrol 2007; 18:2226-32. [PMID: 17634438 DOI: 10.1681/asn.2006121362] [Citation(s) in RCA: 72] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022] Open
Abstract
Nephropathy is one of the major microvascular complications of diabetes, and both hemodynamic and metabolic stimuli participate in its development and progression toward ESRD. There is now a greater understanding of the molecular pathways that are activated by high glomerular capillary pressure and hyperglycemia and how they interplay to produce kidney pathology. The observation that overexpression of glucose transporter 1 (GLUT-1) in mesangial cells could induce a "diabetic cellular phenotype" has led to the postulation that the expression of GLUT-1 could be upregulated in glomeruli that are exposed to high pressure. This review suggests a mechanism by which mechanical forces may aggravate a metabolic insult by stimulating excessive cellular glucose uptake. Proposed is the existence of a self-maintaining cycle whereby a hemodynamic stimulus on glomerular cells induces GLUT-1 overexpression followed by greater glucose uptake and activation of intracellular glucose metabolic pathways, resulting in excess TGF-beta1 production. TGF-beta1 in turn, maintains overexpression of GLUT-1, perpetuating a signaling sequence that has, as its ultimate effect, increased extracellular matrix synthesis. This mechanical and metabolic coupling suggests a novel pathophysiologic mechanism of injury in the kidney in diabetes and possibly other glomerular diseases.
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Affiliation(s)
- Luigi Gnudi
- Cardiovascular Division, King's College London, Guy's Hospital, London SE1 9RT, UK.
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Yang B, Hodgkinson AD, Oates PJ, Kwon HM, Millward BA, Demaine AG. Elevated activity of transcription factor nuclear factor of activated T-cells 5 (NFAT5) and diabetic nephropathy. Diabetes 2006; 55:1450-5. [PMID: 16644704 DOI: 10.2337/db05-1260] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
The expression of aldose reductase is tightly regulated by the transcription factor tonicity response element binding protein (TonEBP/NFAT5) binding to three osmotic response elements (OREs; OREA, OREB, and OREC) in the gene. The aim was to investigate the contribution of NFAT5 to the pathogenesis of diabetic nephropathy. Peripheral blood mononuclear cells (PBMCs) were isolated from the following subjects: 44 Caucasoid patients with type 1 diabetes, of whom 26 had nephropathy and 18 had no nephropathy after a diabetes duration of 20 years, and 13 normal healthy control subjects. In addition, human mesangial cells (HMCs) were isolated from the normal lobe of 10 kidneys following radical nephrectomy for renal cell carcinoma. Nuclear and cytoplasmic proteins were extracted from PBMCs and HMCs and cultured in either normal or high-glucose (31 mmol/l D-glucose) conditions for 5 days. NFAT5 binding activity was quantitated using electrophoretic mobility shift assays for each of the OREs. Western blotting was used to measure aldose reductase and sorbitol dehydrogenase protein levels. There were significant fold increases in DNA binding activities of NFAT5 to OREB (2.06 +/- 0.03 vs. 1.33 +/- 0.18, P = 0.033) and OREC (1.94 +/- 0.21 vs. 1.39 +/- 0.11, P = 0.024) in PBMCs from patients with diabetic nephropathy compared with diabetic control subjects cultured under high glucose. Aldose reductase and sorbitol dehydrogenase protein levels in the patients with diabetic nephropathy were significantly increased in PBMCs cultured in high-glucose conditions. In HMCs cultured under high glucose, there were significant increases in NFAT5 binding activities to OREA, OREB, and OREC by 1.38 +/- 0.22-, 1.84 +/- 0.44-, and 2.38 +/- 1.15-fold, respectively. Similar results were found in HMCs exposed to high glucose (aldose reductase 1.30 +/- 0.06-fold and sorbitol dehydrogenease 1.54 +/- 0.24-fold increases). Finally, the silencing of the NFAT5 gene in vitro reduced the expression of the aldose reductase gene. In conclusion, these results show that aldose reductase is upregulated by the transcriptional factor NFAT5 under high-glucose conditions in both PBMCs and HMCs.
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Affiliation(s)
- Bingmei Yang
- Molecular Medicine Research Group, The John Bull Building, Research Way, Peninsula Medical School, Universities of Exeter and Plymouth, Plymouth PL6 8BU, U.K
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