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Sermersheim TJ, Phillips LJ, Evans PL, Kahn BB, Welc SS, Witczak CA. Regulation of injury-induced skeletal myofiber regeneration by glucose transporter 4 (GLUT4). Skelet Muscle 2024; 14:33. [PMID: 39695900 DOI: 10.1186/s13395-024-00366-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2024] [Accepted: 12/03/2024] [Indexed: 12/20/2024] Open
Abstract
BACKGROUND Insulin resistance and type 2 diabetes impair cellular regeneration in multiple tissues including skeletal muscle. The molecular basis for this impairment is largely unknown. Glucose uptake via glucose transporter GLUT4 is impaired in insulin resistance. In healthy muscle, acute injury stimulates glucose uptake. Whether decreased glucose uptake via GLUT4 impairs muscle regeneration is presently unknown. The goal of this study was to determine whether GLUT4 regulates muscle glucose uptake and/or regeneration following acute injury. METHODS Tibialis anterior and extensor digitorum longus muscles from wild-type, control, or muscle-specific GLUT4 knockout (mG4KO) mice were injected with the myotoxin barium chloride to induce muscle injury. After 3, 5, 7, 10, 14, or 21 days (in wild-type mice), or after 7 or 14 days (in control & mG4KO) mice, muscles were isolated to examine [3H]-2-deoxyglucose uptake, GLUT4 levels, extracellular fluid space, fibrosis, myofiber cross-sectional area, and myofiber centralized nuclei. RESULTS In wild-type mice, muscle glucose uptake was increased 3, 5, 7, and 10 days post-injury. There was a rapid decrease in GLUT4 protein levels that were restored to baseline at 5-7 days post-injury, followed by a super-compensation at 10-21 days. In mG4KO mice, there were no differences in muscle glucose uptake, extracellular fluid space, muscle fibrosis, myofiber cross-sectional areas, or percentage of centrally nucleated myofibers at 7 days post-injury. In contrast, at 14 days injured muscles from mG4KO mice exhibited decreased glucose uptake, muscle weight, myofiber cross sectional areas, and centrally nucleated myofibers, with no change in extracellular fluid space or fibrosis. CONCLUSIONS Collectively, these findings demonstrate that glucose uptake via GLUT4 regulates skeletal myofiber regeneration following acute injury.
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Affiliation(s)
- Tyler J Sermersheim
- Department of Anatomy, Cell Biology & Physiology, Indiana University School of Medicine, Indianapolis, IN, USA
- Indiana Center for Diabetes & Metabolic Diseases, Indianapolis, IN, USA
| | - LeAnna J Phillips
- Department of Anatomy, Cell Biology & Physiology, Indiana University School of Medicine, Indianapolis, IN, USA
- Indiana Center for Diabetes & Metabolic Diseases, Indianapolis, IN, USA
| | - Parker L Evans
- Department of Anatomy, Cell Biology & Physiology, Indiana University School of Medicine, Indianapolis, IN, USA
- Indiana Center for Diabetes & Metabolic Diseases, Indianapolis, IN, USA
| | - Barbara B Kahn
- Division of Endocrinology, Diabetes & Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA
| | - Steven S Welc
- Department of Anatomy, Cell Biology & Physiology, Indiana University School of Medicine, Indianapolis, IN, USA
- Indiana Center for Musculoskeletal Health, Indianapolis, IN, USA
| | - Carol A Witczak
- Department of Anatomy, Cell Biology & Physiology, Indiana University School of Medicine, Indianapolis, IN, USA.
- Indiana Center for Diabetes & Metabolic Diseases, Indianapolis, IN, USA.
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Bhatt IS, Garay JAR, Torkamani A, Dias R. DNA Methylation Patterns Associated with Tinnitus in Young Adults-A Pilot Study. J Assoc Res Otolaryngol 2024; 25:507-523. [PMID: 39147981 PMCID: PMC11528087 DOI: 10.1007/s10162-024-00961-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2023] [Accepted: 07/31/2024] [Indexed: 08/17/2024] Open
Abstract
PURPOSE Tinnitus, the perception of sound without any external sound source, is a prevalent hearing health concern. Mounting evidence suggests that a confluence of genetic, environmental, and lifestyle factors can influence the pathogenesis of tinnitus. We hypothesized that alteration in DNA methylation, an epigenetic modification that occurs at cytosines of cytosine-phosphate-guanine (CpG) dinucleotide sites, where a methyl group from S-adenyl methionine gets transferred to the fifth carbon of the cytosine, could contribute to tinnitus. DNA methylation patterns are tissue-specific, but the tissues involved in tinnitus are not easily accessible in humans. This pilot study used saliva as a surrogate tissue to identify differentially methylated CpG regions (DMRs) associated with tinnitus. The study was conducted on healthy young adults reporting bilateral continuous chronic tinnitus to limit the influence of age-related confounding factors and health-related comorbidities. METHODS The present study evaluated the genome-wide methylation levels from saliva-derived DNA samples from 24 healthy young adults with bilateral continuous chronic tinnitus (> 1 year) and 24 age, sex, and ethnicity-matched controls with no tinnitus. Genome-wide DNA methylation was evaluated for > 850,000 CpG sites using the Infinium Human Methylation EPIC BeadChip. The association analysis used the Bumphunter algorithm on 23 cases and 20 controls meeting the quality control standards. The methylation level was expressed as the area under the curve of CpG sites within DMRs.The FDR-adjusted p-value threshold of 0.05 was used to identify statistically significant DMRs associated with tinnitus. RESULTS We obtained 25 differentially methylated regions (DMRs) associated with tinnitus. Genes within or in the proximity of the hypermethylated DMRs related to tinnitus included LCLAT1, RUNX1, RUFY1, NUDT12, TTC23, SLC43A2, C4orf27 (STPG2), and EFCAB4B. Genes within or in the proximity of hypomethylated DMRs associated with tinnitus included HLA-DPB2, PM20D1, TMEM18, SNTG2, MUC4, MIR886, MIR596, TXNRD1, EID3, SDHAP3, HLA-DPB2, LASS3 (CERS3), C10orf11 (LRMDA), HLA-DQB1, NADK, SZRD1, MFAP2, NUP210L, TPM3, INTS9, and SLC2A14. The burden of genetic variation could explain the differences in the methylation levels for DMRs involving HLA-DPB2, HLA-DQB1, and MUC4, indicating the need for replication in large independent cohorts. CONCLUSION Consistent with the literature on comorbidities associated with tinnitus, we identified genes within or close to DMRs involved in auditory functions, chemical dependency, cardiovascular diseases, psychiatric conditions, immune disorders, and metabolic syndromes. These results indicate that epigenetic mechanisms could influence tinnitus, and saliva can be a good surrogate for identifying the epigenetic underpinnings of tinnitus in humans. Further research with a larger sample size is needed to identify epigenetic biomarkers and investigate their influence on the phenotypic expression of tinnitus.
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Affiliation(s)
- Ishan Sunilkumar Bhatt
- Department of Communication Sciences & Disorders, University of Iowa, Iowa City, IA, 52242, USA.
| | - Juan Antonio Raygoza Garay
- Department of Communication Sciences & Disorders, University of Iowa, Iowa City, IA, 52242, USA
- Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA, 52242, USA
| | - Ali Torkamani
- Department of Integrative Structural and Computational Biology, Scripps Science Institute, La Jolla, CA, 92037, USA
| | - Raquel Dias
- Department of Microbiology and Cell Science, University of Florida, Gainesville, FL, 32608, USA
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Bolat E, Eker F, Yılmaz S, Karav S, Oz E, Brennan C, Proestos C, Zeng M, Oz F. BCM-7: Opioid-like Peptide with Potential Role in Disease Mechanisms. Molecules 2024; 29:2161. [PMID: 38731652 PMCID: PMC11085506 DOI: 10.3390/molecules29092161] [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: 04/11/2024] [Revised: 04/25/2024] [Accepted: 04/29/2024] [Indexed: 05/13/2024] Open
Abstract
Bovine milk is an essential supplement due to its rich energy- and nutrient-rich qualities. Caseins constitute the vast majority of the proteins in milk. Among these, β-casein comprises around 37% of all caseins, and it is an important type of casein with several different variants. The A1 and A2 variants of β-casein are the most researched genotypes due to the changes in their composition. It is accepted that the A2 variant is ancestral, while a point mutation in the 67th amino acid created the A1 variant. The digestion derived of both A1 and A2 milk is BCM-7. Digestion of A2 milk in the human intestine also forms BCM-9 peptide molecule. The opioid-like characteristics of BCM-7 are highlighted for their potential triggering effect on several diseases. Most research has been focused on gastrointestinal-related diseases; however other metabolic and nervous system-based diseases are also potentially triggered. By manipulating the mechanisms of these diseases, BCM-7 can induce certain situations, such as conformational changes, reduction in protein activity, and the creation of undesired activity in the biological system. Furthermore, the genotype of casein can also play a role in bone health, such as altering fracture rates, and calcium contents can change the characteristics of dietary products. The context between opioid molecules and BCM-7 points to a potential triggering mechanism for the central nervous system and other metabolic diseases discussed.
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Affiliation(s)
- Ecem Bolat
- Department of Molecular Biology and Genetics, Çanakkale Onsekiz Mart University, Çanakkale 17100, Türkiye; (E.B.); (F.E.); (S.Y.)
| | - Furkan Eker
- Department of Molecular Biology and Genetics, Çanakkale Onsekiz Mart University, Çanakkale 17100, Türkiye; (E.B.); (F.E.); (S.Y.)
| | - Selin Yılmaz
- Department of Molecular Biology and Genetics, Çanakkale Onsekiz Mart University, Çanakkale 17100, Türkiye; (E.B.); (F.E.); (S.Y.)
| | - Sercan Karav
- Department of Molecular Biology and Genetics, Çanakkale Onsekiz Mart University, Çanakkale 17100, Türkiye; (E.B.); (F.E.); (S.Y.)
| | - Emel Oz
- Department of Food Engineering, Faculty of Agriculture, Atatürk University, Erzurum 25030, Türkiye; (E.O.); (F.O.)
| | - Charles Brennan
- School of Science, RMIT University, Melbourne, VIC 3001, Australia;
| | - Charalampos Proestos
- Laboratory of Food Chemistry, Department of Chemistry, School of Sciences, National and Kapodistrian University of Athens Zografou, 157 84 Athens, Greece;
| | - Maomao Zeng
- State Key Laboratory of Food Science and Resources, Jiangnan University, Wuxi 214122, China;
| | - Fatih Oz
- Department of Food Engineering, Faculty of Agriculture, Atatürk University, Erzurum 25030, Türkiye; (E.O.); (F.O.)
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Mondal S, Bandyopadhyay A. Glucose transporters (GLUTs): Underreported yet crucial molecules in unraveling testicular toxicity. Biochimie 2024; 219:55-62. [PMID: 37967737 DOI: 10.1016/j.biochi.2023.11.004] [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: 09/07/2023] [Revised: 11/06/2023] [Accepted: 11/09/2023] [Indexed: 11/17/2023]
Abstract
Glucose transporters (GLUTs) are crucial in maintaining glucose homeostasis and supporting energy production in various tissues, including the testes. This review article delves into the distribution and function of GLUTs in distinct testicular cell types, namely Leydig cells, Sertoli cells, germ cells, and spermatozoa, shedding light on their significance in the context of male reproductive health-an issue of mounting global concern. Furthermore, this article examines the implications of GLUT dysregulation in testicular dysfunction. Altered GLUT expression has been associated with impaired steroidogenesis, spermatogenesis, sperm count, and motility in various animal models. Lastly, the article underscores the potential therapeutic implications of targeting GLUTs concerning testicular toxicity. Insights gleaned from studies in diabetes and cancer suggest that modulating GLUT expression and translocation could present novel strategies for mitigating testicular dysfunction and safeguarding male fertility. In summary, the intricate interplay between GLUTs, glucose metabolism, and testicular health underscores the significance of sustaining testicular glucose homeostasis for male reproductive health. Manipulating GLUTs presents an innovative avenue to address testicular dysfunction, potentially revolutionizing therapeutic strategies to restore male fertility and overall reproductive well-being. Future research in this field holds great promise for advancing male fertility treatments and reproductive health interventions.
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Affiliation(s)
- Shirsha Mondal
- Department of Zoology, Govt. College Dhimarkheda (Rani Durgavati Vishwavidyalaya), Katni, 483 332, Madhya Pradesh, India.
| | - Arindam Bandyopadhyay
- Department of Zoology, University of Allahabad, Prayagraj, 211 002, Uttar Pradesh, India.
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Geiser A, Foylan S, Tinning PW, Bryant NJ, Gould GW. GLUT4 dispersal at the plasma membrane of adipocytes: a super-resolved journey. Biosci Rep 2023; 43:BSR20230946. [PMID: 37791639 PMCID: PMC10600063 DOI: 10.1042/bsr20230946] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2023] [Revised: 10/03/2023] [Accepted: 10/04/2023] [Indexed: 10/05/2023] Open
Abstract
In adipose tissue, insulin stimulates glucose uptake by mediating the translocation of GLUT4 from intracellular vesicles to the plasma membrane. In 2010, insulin was revealed to also have a fundamental impact on the spatial distribution of GLUT4 within the plasma membrane, with the existence of two GLUT4 populations at the plasma membrane being defined: (1) as stationary clusters and (2) as diffusible monomers. In this model, in the absence of insulin, plasma membrane-fused GLUT4 are found to behave as clusters. These clusters are thought to arise from exocytic events that retain GLUT4 at their fusion sites; this has been proposed to function as an intermediate hub between GLUT4 exocytosis and re-internalisation. By contrast, insulin stimulation induces the dispersal of GLUT4 clusters into monomers and favours a distinct type of GLUT4-vesicle fusion event, known as fusion-with-release exocytosis. Here, we review how super-resolution microscopy approaches have allowed investigation of the characteristics of plasma membrane-fused GLUT4 and further discuss regulatory step(s) involved in the GLUT4 dispersal machinery, introducing the scaffold protein EFR3 which facilitates localisation of phosphatidylinositol 4-kinase type IIIα (PI4KIIIα) to the cell surface. We consider how dispersal may be linked to the control of transporter activity, consider whether macro-organisation may be a widely used phenomenon to control proteins within the plasma membrane, and speculate on the origin of different forms of GLUT4-vesicle exocytosis.
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Affiliation(s)
- Angéline Geiser
- Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, U.K
| | - Shannan Foylan
- Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, U.K
| | - Peter W Tinning
- Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, U.K
| | - Nia J Bryant
- Department of Biology, University of York, Heslington, York, U.K
| | - Gwyn W Gould
- Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, U.K
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Wang C, Lin R, Qi X, Xu Q, Sun X, Zhao Y, Jiang T, Jiang J, Sun Y, Deng Y, Wen J. Alternative glucose uptake mediated by β-catenin/RSK1 axis under stress stimuli in mammalian cells. Biochem Pharmacol 2023:115645. [PMID: 37321415 DOI: 10.1016/j.bcp.2023.115645] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2023] [Revised: 06/04/2023] [Accepted: 06/07/2023] [Indexed: 06/17/2023]
Abstract
Cells adapt to stress conditions by increasing glucose uptake as cytoprotective strategy. The efficiency of glucose uptake is determined by the translocation of glucose transporters (GLUTs) from cytosolic vesicles to cellular membranes in many tissues and cells. GLUT translocation is tightly controlled by the activation of Tre-2/BUB2/CDC16 1 domain family 4 (TBC1D4) via its phosphorylation. The mechanisms of glucose uptake under stress conditions remain to be clarified. In this study, we surprisingly found that glucose uptake is apparently increased for the early response to three stress stimuli, glucose starvation and the exposure to lipopolysaccharide (LPS) or deoxynivalenol (DON). The stress-induced glucose uptake was mainly controlled by the increment of β-catenin level and the activation of RSK1. Mechanistically, β-catenin directly interacted with RSK1 and TBC1D4, acting as the scaffold protein to recruit activated RSK1 to promote the phosphorylation of TBC1D4. In addition, β-catenin was further stabilized due to the inhibition of GSK3β kinase activity which is caused by activated RSK1 phosphorylating GSK3β at Ser9. In general, this triple protein complex consisting of β-catenin, phosphorylated RSK1, and TBC1D4 were increased in the early response to these stress signals, and consequently, further promoted the phosphorylation of TBC1D4 to facilitate the translocation of GLUT4 to the cell membrane. Our study revealed that the β-catenin/RSK1 axis contributed to the increment of glucose uptake for cellular adaption to these stress conditions, shedding new insights into cellular energy utilization under stress.
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Affiliation(s)
- Caizhu Wang
- Guangdong Provincial Key Laboratory of Protein Function and Regulation in Agricultural Organisms, College of Life Sciences, South China Agricultural University, Guangzhou, 510642, Guangdong, PR China; Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou, 510642, Guangdong, PR China; Key Laboratory of Zoonosis of Ministry of Agriculture and Rural Affairs, South China Agricultural University, Guangzhou, 510642, Guangdong, PR China
| | - Ruqin Lin
- Guangdong Provincial Key Laboratory of Protein Function and Regulation in Agricultural Organisms, College of Life Sciences, South China Agricultural University, Guangzhou, 510642, Guangdong, PR China; Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou, 510642, Guangdong, PR China; Key Laboratory of Zoonosis of Ministry of Agriculture and Rural Affairs, South China Agricultural University, Guangzhou, 510642, Guangdong, PR China
| | - Xueying Qi
- Guangdong Provincial Key Laboratory of Protein Function and Regulation in Agricultural Organisms, College of Life Sciences, South China Agricultural University, Guangzhou, 510642, Guangdong, PR China; Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou, 510642, Guangdong, PR China; Key Laboratory of Zoonosis of Ministry of Agriculture and Rural Affairs, South China Agricultural University, Guangzhou, 510642, Guangdong, PR China
| | - Qiang Xu
- Guangdong Provincial Key Laboratory of Protein Function and Regulation in Agricultural Organisms, College of Life Sciences, South China Agricultural University, Guangzhou, 510642, Guangdong, PR China; Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou, 510642, Guangdong, PR China; Key Laboratory of Zoonosis of Ministry of Agriculture and Rural Affairs, South China Agricultural University, Guangzhou, 510642, Guangdong, PR China
| | - Xingsheng Sun
- Guangdong Provincial Key Laboratory of Protein Function and Regulation in Agricultural Organisms, College of Life Sciences, South China Agricultural University, Guangzhou, 510642, Guangdong, PR China; Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou, 510642, Guangdong, PR China; Key Laboratory of Zoonosis of Ministry of Agriculture and Rural Affairs, South China Agricultural University, Guangzhou, 510642, Guangdong, PR China
| | - Yurong Zhao
- Guangdong Provincial Key Laboratory of Protein Function and Regulation in Agricultural Organisms, College of Life Sciences, South China Agricultural University, Guangzhou, 510642, Guangdong, PR China; Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou, 510642, Guangdong, PR China; Key Laboratory of Zoonosis of Ministry of Agriculture and Rural Affairs, South China Agricultural University, Guangzhou, 510642, Guangdong, PR China
| | - Tianqing Jiang
- Guangdong Provincial Key Laboratory of Protein Function and Regulation in Agricultural Organisms, College of Life Sciences, South China Agricultural University, Guangzhou, 510642, Guangdong, PR China; Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou, 510642, Guangdong, PR China; Key Laboratory of Zoonosis of Ministry of Agriculture and Rural Affairs, South China Agricultural University, Guangzhou, 510642, Guangdong, PR China
| | - Jun Jiang
- Guangdong Provincial Key Laboratory of Protein Function and Regulation in Agricultural Organisms, College of Life Sciences, South China Agricultural University, Guangzhou, 510642, Guangdong, PR China; Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou, 510642, Guangdong, PR China; Key Laboratory of Zoonosis of Ministry of Agriculture and Rural Affairs, South China Agricultural University, Guangzhou, 510642, Guangdong, PR China
| | - Yu Sun
- Guangdong Provincial Key Laboratory of Protein Function and Regulation in Agricultural Organisms, College of Life Sciences, South China Agricultural University, Guangzhou, 510642, Guangdong, PR China; Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou, 510642, Guangdong, PR China; Key Laboratory of Zoonosis of Ministry of Agriculture and Rural Affairs, South China Agricultural University, Guangzhou, 510642, Guangdong, PR China
| | - Yiqun Deng
- Guangdong Provincial Key Laboratory of Protein Function and Regulation in Agricultural Organisms, College of Life Sciences, South China Agricultural University, Guangzhou, 510642, Guangdong, PR China; Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou, 510642, Guangdong, PR China; Key Laboratory of Zoonosis of Ministry of Agriculture and Rural Affairs, South China Agricultural University, Guangzhou, 510642, Guangdong, PR China.
| | - Jikai Wen
- Guangdong Provincial Key Laboratory of Protein Function and Regulation in Agricultural Organisms, College of Life Sciences, South China Agricultural University, Guangzhou, 510642, Guangdong, PR China; Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou, 510642, Guangdong, PR China; Key Laboratory of Zoonosis of Ministry of Agriculture and Rural Affairs, South China Agricultural University, Guangzhou, 510642, Guangdong, PR China.
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Aragoneses-Cazorla G, Vallet-Regí M, Gómez-Gómez MM, González B, Luque-Garcia JL. Integrated transcriptomics and metabolomics analysis reveals the biomolecular mechanisms associated to the antitumoral potential of a novel silver-based core@shell nanosystem. Mikrochim Acta 2023; 190:132. [PMID: 36914921 PMCID: PMC10011303 DOI: 10.1007/s00604-023-05712-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2022] [Accepted: 02/28/2023] [Indexed: 03/14/2023]
Abstract
A combination of omics techniques (transcriptomics and metabolomics) has been used to elucidate the mechanisms responsible for the antitumor action of a nanosystem based on a Ag core coated with mesoporous silica on which transferrin has been anchored as a targeting ligand against tumor cells (Ag@MSNs-Tf). Transcriptomics analysis has been carried out by gene microarrays and RT-qPCR, while high-resolution mass spectrometry has been used for metabolomics. This multi-omics strategy has enabled the discovery of the effect of this nanosystem on different key molecular pathways including the glycolysis, the pentose phosphate pathway, the oxidative phosphorylation and the synthesis of fatty acids, among others.
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Affiliation(s)
- Guillermo Aragoneses-Cazorla
- Department of Analytical Chemistry, Faculty of Chemical Sciences, Complutense University of Madrid, 28040, Madrid, Spain
| | - María Vallet-Regí
- Department of Chemistry in Pharmaceutical Sciences, Faculty of Pharmacy, Complutense University of Madrid, Instituto de Investigación Sanitaria Hospital, 12 de Octubre (I+12), 28040, Madrid, Spain
- Centro de Investigación Biomédica en Red de Bioingeniería, Biomateriales Y Nanomedicina (CIBER-BBN), Saragossa, Spain
| | - Ma Milagros Gómez-Gómez
- Department of Analytical Chemistry, Faculty of Chemical Sciences, Complutense University of Madrid, 28040, Madrid, Spain
| | - Blanca González
- Department of Chemistry in Pharmaceutical Sciences, Faculty of Pharmacy, Complutense University of Madrid, Instituto de Investigación Sanitaria Hospital, 12 de Octubre (I+12), 28040, Madrid, Spain
- Centro de Investigación Biomédica en Red de Bioingeniería, Biomateriales Y Nanomedicina (CIBER-BBN), Saragossa, Spain
| | - Jose L Luque-Garcia
- Department of Analytical Chemistry, Faculty of Chemical Sciences, Complutense University of Madrid, 28040, Madrid, Spain.
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Aedh AI, Alshahrani MS, Huneif MA, Pryme IF, Oruch R. A Glimpse into Milestones of Insulin Resistance and an Updated Review of Its Management. Nutrients 2023; 15:nu15040921. [PMID: 36839279 PMCID: PMC9960458 DOI: 10.3390/nu15040921] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2023] [Revised: 02/03/2023] [Accepted: 02/08/2023] [Indexed: 02/15/2023] Open
Abstract
Insulin is the main metabolic regulator of fuel molecules in the diet, such as carbohydrates, lipids, and proteins. It does so by facilitating glucose influx from the circulation into the liver, adipose tissue, and skeletal myocytes. The outcome of which is subjected to glycogenesis in skeletal muscle and lipogenesis in adipose tissue, as well as in the liver. Therefore, insulin has an anabolic action while, on the contrary, hypoinsulinemia promotes the reverse process. Protein breakdown in myocytes is also encountered during the late stages of diabetes mellitus. The balance of the blood glucose level in physiological conditions is maintained by virtue of the interactive functions of insulin and glucagon. In insulin resistance (IR), the balance is disturbed because glucose transporters (GLUTs) of cell membranes fail to respond to this peptide hormone, meaning that glucose molecules cannot be internalized into the cells, the consequence of which is hyperglycemia. To develop the full state of diabetes mellitus, IR should be associated with the impairment of insulin release from beta-cells of the pancreas. Periodic screening of individuals of high risk, such as those with obesity, hypercholesterolemia, and pregnant nulliparous women in antenatal control, is vital, as these are important checkpoints to detect cases of insulin resistance. This is pivotal as IR can be reversed, provided it is detected in its early stages, through healthy dietary habits, regular exercise, and the use of hypoglycemic agents. In this review, we discuss the pathophysiology, etiology, diagnosis, preventive methods, and management of IR in brief.
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Affiliation(s)
- Abdullah I. Aedh
- Department of Internal Medicine, School of Medicine, Najran University, Najran 66324, Saudi Arabia
| | - Majed S. Alshahrani
- Department of Obstetrics & Gynecology, School of Medicine, Najran University, Najran 66324, Saudi Arabia
| | - Mohammed A. Huneif
- Department of Pediatrics, School of Medicine, Najran University, Najran 66324, Saudi Arabia
| | - Ian F. Pryme
- Department of Biomedicine, School of Medicine, University of Bergen, 5020 Bergen, Norway
| | - Ramadhan Oruch
- Department of Biochemistry and Molecular Biology, School of Medicine, Najran University, Najran 66324, Saudi Arabia
- Correspondence: ; Tel.: +966-562144606
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Baines DL, Vasiljevs S, Kalsi KK. Getting sweeter: new evidence for glucose transporters in specific cell types of the airway? Am J Physiol Cell Physiol 2023; 324:C153-C166. [PMID: 36409177 PMCID: PMC9829484 DOI: 10.1152/ajpcell.00140.2022] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
New technologies such as single-cell RNA sequencing (scRNAseq) has enabled identification of the mRNA transcripts expressed by individual cells. This review provides insight from recent scRNAseq studies on the expression of glucose transporters in the epithelial cells of the airway epithelium from trachea to alveolus. The number of studies analyzed was limited, not all reported the full range of glucose transporters and there were differences between cells freshly isolated from the airways and those grown in vitro. Furthermore, glucose transporter mRNA transcripts were expressed at lower levels than other epithelial marker genes. Nevertheless, these studies highlighted that there were differences in cellular expression of glucose transporters. GLUT1 was the most abundant of the broadly expressed transporters that included GLUT8, 10, and 13. GLUT9 transcripts were more common in basal cells and GLUT12 in ionocytes/ciliated cells. In addition to alveolar cells, SGLT1 transcripts were present in secretory cells. GLUT3 mRNA transcripts were expressed in a cell cluster that expressed monocarboxylate (MCT2) transporters. Such distributions likely underlie cell-specific metabolic requirements to support proliferation, ion transport, mucous secretion, environment sensing, and airway glucose homeostasis. These studies have also highlighted the role of glucose transporters in the movement of dehydroascorbic acid/vitamin C/myoinositol/urate, which are factors important to the innate immune properties of the airways. Discrepancies remain between detection of mRNAs, protein, and function of glucose transporters in the lungs. However, collation of the data from further scRNAseq studies may provide a better consensus and understanding, supported by qPCR, immunohistochemistry, and functional experiments.
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Affiliation(s)
- Deborah L. Baines
- Institute for Infection and Immunity, St George’s, University of London, London, United Kingdom
| | - Stanislavs Vasiljevs
- Institute for Infection and Immunity, St George’s, University of London, London, United Kingdom
| | - Kameljit K. Kalsi
- Institute for Infection and Immunity, St George’s, University of London, London, United Kingdom
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10
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Nishizawa D, Terui T, Ishitani K, Kasai S, Hasegawa J, Nakayama K, Ebata Y, Ikeda K. Genome-Wide Association Study Identifies Candidate Loci Associated with Opioid Analgesic Requirements in the Treatment of Cancer Pain. Cancers (Basel) 2022; 14:cancers14194692. [PMID: 36230616 PMCID: PMC9564079 DOI: 10.3390/cancers14194692] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Revised: 09/20/2022] [Accepted: 09/21/2022] [Indexed: 11/29/2022] Open
Abstract
Considerable individual differences have been widely observed in the sensitivity to opioids. We conducted a genome-wide association study (GWAS) in patients with cancer pain to identify potential candidate single-nucleotide polymorphisms (SNPs) that contribute to individual differences in opioid analgesic requirements in pain treatment by utilizing whole-genome genotyping arrays with more than 650,000 markers. The subjects in the GWAS were 428 patients who provided written informed consent and underwent treatment for pain with opioid analgesics in a palliative care unit at Higashi-Sapporo Hospital. The GWAS showed two intronic SNPs, rs1283671 and rs1283720, in the ANGPT1 gene that encodes a secreted glycoprotein that belongs to the angiopoietin family. These two SNPs were strongly associated with average daily opioid requirements for the treatment of pain in both the additive and recessive models (p < 5.0000 × 10−8). Several other SNPs were also significantly associated with the phenotype. In the gene-based analysis, the association was significant for the SLC2A14 gene in the additive model. These results indicate that these SNPs could serve as markers that predict the efficacy of opioid analgesics in cancer pain treatment. Our findings may provide valuable information for achieving satisfactory pain control and open new avenues for personalized pain treatment.
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Affiliation(s)
- Daisuke Nishizawa
- Addictive Substance Project, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan
| | - Takeshi Terui
- Division of Internal Medicine, Department of Medicine, Higashi-Sapporo Hospital, Sapporo 003-8585, Japan
| | - Kunihiko Ishitani
- Division of Internal Medicine, Department of Medicine, Higashi-Sapporo Hospital, Sapporo 003-8585, Japan
| | - Shinya Kasai
- Addictive Substance Project, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan
| | - Junko Hasegawa
- Addictive Substance Project, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan
| | - Kyoko Nakayama
- Addictive Substance Project, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan
| | - Yuko Ebata
- Addictive Substance Project, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan
| | - Kazutaka Ikeda
- Addictive Substance Project, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan
- Correspondence: ; Tel.: +81-3-6834-2379
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11
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Ismail A, Tanasova M. Importance of GLUT Transporters in Disease Diagnosis and Treatment. Int J Mol Sci 2022; 23:8698. [PMID: 35955833 PMCID: PMC9368955 DOI: 10.3390/ijms23158698] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2022] [Revised: 07/29/2022] [Accepted: 07/30/2022] [Indexed: 12/04/2022] Open
Abstract
Facilitative sugar transporters (GLUTs) are the primary method of sugar uptake in all mammalian cells. There are 14 different types of those transmembrane proteins, but they transport only a handful of substrates, mainly glucose and fructose. This overlap and redundancy contradict the natural tendency of cells to conserve energy and resources, and has led researchers to hypothesize that different GLUTs partake in more metabolic roles than just sugar transport into cells. Understanding those roles will lead to better therapeutics for a wide variety of diseases and disorders. In this review we highlight recent discoveries of the role GLUTs play in different diseases and disease treatments.
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Affiliation(s)
- Abdelrahman Ismail
- Department of Chemistry, Michigan Technological University, 1400 Townsend Drive, Houghton, MI 49931, USA
| | - Marina Tanasova
- Department of Chemistry, Michigan Technological University, 1400 Townsend Drive, Houghton, MI 49931, USA
- Health Research Institute, Michigan Technological University, Houghton, MI 49931, USA
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12
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Li DD, Jawale CV, Zhou C, Lin L, Trevejo-Nunez GJ, Rahman SA, Mullet SJ, Das J, Wendell SG, Delgoffe GM, Lionakis MS, Gaffen SL, Biswas PS. Fungal sensing enhances neutrophil metabolic fitness by regulating antifungal Glut1 activity. Cell Host Microbe 2022; 30:530-544.e6. [PMID: 35316647 PMCID: PMC9026661 DOI: 10.1016/j.chom.2022.02.017] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2021] [Revised: 12/10/2021] [Accepted: 02/16/2022] [Indexed: 12/30/2022]
Abstract
Combating fungal pathogens poses metabolic challenges for neutrophils, key innate cells in anti-Candida albicans immunity, yet how host-pathogen interactions cause remodeling of the neutrophil metabolism is unclear. We show that neutrophils mediate renal immunity to disseminated candidiasis by upregulating glucose uptake via selective expression of glucose transporter 1 (Glut1). Mechanistically, dectin-1-mediated recognition of β-glucan leads to activation of PKCδ, which triggers phosphorylation, localization, and early glucose transport by a pool of pre-formed Glut1 in neutrophils. These events are followed by increased Glut1 gene transcription, leading to more sustained Glut1 accumulation, which is also dependent on the β-glucan/dectin-1/CARD9 axis. Card9-deficient neutrophils show diminished glucose incorporation in candidiasis. Neutrophil-specific Glut1-ablated mice exhibit increased mortality in candidiasis caused by compromised neutrophil phagocytosis, reactive oxygen species (ROS), and neutrophil extracellular trap (NET) formation. In human neutrophils, β-glucan triggers metabolic remodeling and enhances candidacidal function. Our data show that the host-pathogen interface increases glycolytic activity in neutrophils by regulating Glut1 expression, localization, and function.
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Affiliation(s)
- De-Dong Li
- Division of Rheumatology & Clinical Immunology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
| | - Chetan V Jawale
- Division of Rheumatology & Clinical Immunology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
| | - Chunsheng Zhou
- Division of Rheumatology & Clinical Immunology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
| | - Li Lin
- Division of Rheumatology & Clinical Immunology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
| | - Giraldina J Trevejo-Nunez
- Division of Infectious Diseases, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
| | - Syed A Rahman
- Center for Systems Immunology, Departments of Immunology and Computational & Systems Biology, University of Pittsburgh, Pittsburgh, PA, USA
| | - Steven J Mullet
- Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA
| | - Jishnu Das
- Center for Systems Immunology, Departments of Immunology and Computational & Systems Biology, University of Pittsburgh, Pittsburgh, PA, USA
| | - Stacy G Wendell
- Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA
| | - Greg M Delgoffe
- Department of Pharmacology & Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA
| | - Michail S Lionakis
- Fungal Pathogenesis Section, National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA
| | - Sarah L Gaffen
- Division of Rheumatology & Clinical Immunology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
| | - Partha S Biswas
- Division of Rheumatology & Clinical Immunology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
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13
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Ryniawec JM, Coope MR, Loertscher E, Bageerathan V, de Oliveira Pessoa D, Warfel NA, Cress AE, Padi M, Rogers GC. GLUT3/SLC2A3 Is an Endogenous Marker of Hypoxia in Prostate Cancer Cell Lines and Patient-Derived Xenograft Tumors. Diagnostics (Basel) 2022; 12:diagnostics12030676. [PMID: 35328229 PMCID: PMC8946944 DOI: 10.3390/diagnostics12030676] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2022] [Revised: 03/06/2022] [Accepted: 03/07/2022] [Indexed: 01/17/2023] Open
Abstract
The microenvironment of solid tumors is dynamic and frequently contains pockets of low oxygen levels (hypoxia) surrounded by oxygenated tissue. Indeed, a compromised vasculature is a hallmark of the tumor microenvironment, creating both spatial gradients and temporal variability in oxygen availability. Notably, hypoxia associates with increased metastasis and poor survival in patients. Therefore, to aid therapeutic decisions and better understand hypoxia’s role in cancer progression, it is critical to identify endogenous biomarkers of hypoxia to spatially phenotype oncogenic lesions in human tissue, whether precancerous, benign, or malignant. Here, we characterize the glucose transporter GLUT3/SLC2A3 as a biomarker of hypoxic prostate epithelial cells and prostate tumors. Transcriptomic analyses of non-tumorigenic, immortalized prostate epithelial cells revealed a highly significant increase in GLUT3 expression under hypoxia. Additionally, GLUT3 protein increased 2.4-fold in cultured hypoxic prostate cell lines and was upregulated within hypoxic regions of xenograft tumors, including two patient-derived xenografts (PDX). Finally, GLUT3 out-performs other established hypoxia markers; GLUT3 staining in PDX specimens detects 2.6–8.3 times more tumor area compared to a mixture of GLUT1 and CA9 antibodies. Therefore, given the heterogeneous nature of tumors, we propose adding GLUT3 to immunostaining panels when trying to detect hypoxic regions in prostate samples.
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Affiliation(s)
- John M. Ryniawec
- Department of Cellular and Molecular Medicine, University of Arizona Cancer Center, University of Arizona, Tucson, AZ 85719, USA; (J.M.R.); (M.R.C.); (E.L.); (N.A.W.)
| | - Matthew R. Coope
- Department of Cellular and Molecular Medicine, University of Arizona Cancer Center, University of Arizona, Tucson, AZ 85719, USA; (J.M.R.); (M.R.C.); (E.L.); (N.A.W.)
| | - Emily Loertscher
- Department of Cellular and Molecular Medicine, University of Arizona Cancer Center, University of Arizona, Tucson, AZ 85719, USA; (J.M.R.); (M.R.C.); (E.L.); (N.A.W.)
| | - Vignesh Bageerathan
- Biostatistics and Bioinformatics Shared Resource, University of Arizona Cancer Center, University of Arizona, Tucson, AZ 85724, USA; (V.B.); (D.d.O.P.)
| | - Diogo de Oliveira Pessoa
- Biostatistics and Bioinformatics Shared Resource, University of Arizona Cancer Center, University of Arizona, Tucson, AZ 85724, USA; (V.B.); (D.d.O.P.)
| | - Noel A. Warfel
- Department of Cellular and Molecular Medicine, University of Arizona Cancer Center, University of Arizona, Tucson, AZ 85719, USA; (J.M.R.); (M.R.C.); (E.L.); (N.A.W.)
| | - Anne E. Cress
- Department of Cellular and Molecular Medicine, University of Arizona Cancer Center, University of Arizona, Tucson, AZ 85719, USA; (J.M.R.); (M.R.C.); (E.L.); (N.A.W.)
- Correspondence: (A.E.C.); (M.P.); (G.C.R.)
| | - Megha Padi
- Department of Molecular and Cellular Biology, University of Arizona Cancer Center, University of Arizona, Tucson, AZ 85721, USA
- Correspondence: (A.E.C.); (M.P.); (G.C.R.)
| | - Gregory C. Rogers
- Department of Cellular and Molecular Medicine, University of Arizona Cancer Center, University of Arizona, Tucson, AZ 85719, USA; (J.M.R.); (M.R.C.); (E.L.); (N.A.W.)
- Correspondence: (A.E.C.); (M.P.); (G.C.R.)
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14
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The Leloir Cycle in Glioblastoma: Galactose Scavenging and Metabolic Remodeling. Cancers (Basel) 2021; 13:cancers13081815. [PMID: 33920278 PMCID: PMC8069026 DOI: 10.3390/cancers13081815] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Revised: 03/22/2021] [Accepted: 04/07/2021] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND Glioblastoma (GBM) can use metabolic fuels other than glucose (Glc). The ability of GBM to use galactose (Gal) as a fuel via the Leloir pathway is investigated. METHODS Gene transcript data were accessed to determine the association between expression of genes of the Leloir pathway and patient outcomes. Growth studies were performed on five primary patient-derived GBM cultures using Glc-free media supplemented with Gal. The role of Glut3/Glut14 in sugar import was investigated using antibody inhibition of hexose transport. A specific inhibitor of GALK1 (Cpd36) was used to inhibit Gal catabolism. Gal metabolism was examined using proton, carbon and phosphorous NMR spectroscopy, with 13C-labeled Glc and Gal as tracers. RESULTS Data analysis from published databases revealed that elevated levels of mRNA transcripts of SLC2A3 (Glut3), SLC2A14 (Glut14) and key Leloir pathway enzymes correlate with poor patient outcomes. GBM cultures proliferated when grown solely on Gal in Glc-free media and switching Glc-grown GBM cells into Gal-enriched/Glc-free media produced elevated levels of Glut3 and/or Glut14 enzymes. The 13C NMR-based metabolic flux analysis demonstrated a fully functional Leloir pathway and elevated pentose phosphate pathway activity for efficient Gal metabolism in GBM cells. CONCLUSION Expression of Glut3 and/or Glut14 together with the enzymes of the Leloir pathway allows GBM to transport and metabolize Gal at physiological glucose concentrations, providing GBM cells with an alternate energy source. The presence of this pathway in GBM and its selective targeting may provide new treatment strategies.
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15
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Chen X, Zhao Y, Gao Y, Qi Y, Du J. Outcomes in hepatocellular carcinoma patients undergoing sorafenib treatment: toxicities, cellular oxidative stress, treatment adherence, and quality of life: Erratum. Anticancer Drugs 2021; 32:345-364. [PMID: 33417326 DOI: 10.1097/cad.0000000000001029] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Affiliation(s)
- Xiaotong Chen
- School of Life Sciences, Zhengzhou University, Zhengzhou
| | - Yunshuo Zhao
- School of Life Sciences, Zhengzhou University, Zhengzhou
| | - Yanfeng Gao
- School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Shenzhen, China
| | - Yuanming Qi
- School of Life Sciences, Zhengzhou University, Zhengzhou
| | - Jiangfeng Du
- School of Life Sciences, Zhengzhou University, Zhengzhou
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16
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Wang T, Wang J, Hu X, Huang XJ, Chen GX. Current understanding of glucose transporter 4 expression and functional mechanisms. World J Biol Chem 2020; 11:76-98. [PMID: 33274014 PMCID: PMC7672939 DOI: 10.4331/wjbc.v11.i3.76] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Revised: 08/22/2020] [Accepted: 09/22/2020] [Indexed: 02/05/2023] Open
Abstract
Glucose is used aerobically and anaerobically to generate energy for cells. Glucose transporters (GLUTs) are transmembrane proteins that transport glucose across the cell membrane. Insulin promotes glucose utilization in part through promoting glucose entry into the skeletal and adipose tissues. This has been thought to be achieved through insulin-induced GLUT4 translocation from intracellular compartments to the cell membrane, which increases the overall rate of glucose flux into a cell. The insulin-induced GLUT4 translocation has been investigated extensively. Recently, significant progress has been made in our understanding of GLUT4 expression and translocation. Here, we summarized the methods and reagents used to determine the expression levels of Slc2a4 mRNA and GLUT4 protein, and GLUT4 translocation in the skeletal muscle, adipose tissues, heart and brain. Overall, a variety of methods such real-time polymerase chain reaction, immunohistochemistry, fluorescence microscopy, fusion proteins, stable cell line and transgenic animals have been used to answer particular questions related to GLUT4 system and insulin action. It seems that insulin-induced GLUT4 translocation can be observed in the heart and brain in addition to the skeletal muscle and adipocytes. Hormones other than insulin can induce GLUT4 translocation. Clearly, more studies of GLUT4 are warranted in the future to advance of our understanding of glucose homeostasis.
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Affiliation(s)
- Tiannan Wang
- Department of Nutrition, The University of Tennessee, Knoxville, TN 37996, United States
| | - Jing Wang
- College of Pharmacy, South-Central University for Nationalities, Wuhan 430074, Hubei Province, China
| | - Xinge Hu
- Department of Nutrition, The University of Tennessee, Knoxville, TN 37996, United States
| | - Xian-Ju Huang
- College of Pharmacy, South-Central University for Nationalities, Wuhan 430074, Hubei Province, China
| | - Guo-Xun Chen
- Department of Nutrition, The University of Tennessee, Knoxville, TN 37996, United States
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17
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Chiba Y, Murakami R, Matsumoto K, Wakamatsu K, Nonaka W, Uemura N, Yanase K, Kamada M, Ueno M. Glucose, Fructose, and Urate Transporters in the Choroid Plexus Epithelium. Int J Mol Sci 2020; 21:E7230. [PMID: 33008107 PMCID: PMC7582461 DOI: 10.3390/ijms21197230] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2020] [Revised: 09/25/2020] [Accepted: 09/28/2020] [Indexed: 02/07/2023] Open
Abstract
The choroid plexus plays a central role in the regulation of the microenvironment of the central nervous system by secreting the majority of the cerebrospinal fluid and controlling its composition, despite that it only represents approximately 1% of the total brain weight. In addition to a variety of transporter and channel proteins for solutes and water, the choroid plexus epithelial cells are equipped with glucose, fructose, and urate transporters that are used as energy sources or antioxidative neuroprotective substrates. This review focuses on the recent advances in the understanding of the transporters of the SLC2A and SLC5A families (GLUT1, SGLT2, GLUT5, GLUT8, and GLUT9), as well as on the urate-transporting URAT1 and BCRP/ABCG2, which are expressed in choroid plexus epithelial cells. The glucose, fructose, and urate transporters repertoire in the choroid plexus epithelium share similar features with the renal proximal tubular epithelium, although some of these transporters exhibit inversely polarized submembrane localization. Since choroid plexus epithelial cells have high energy demands for proper functioning, a decline in the expression and function of these transporters can contribute to the process of age-associated brain impairment and pathophysiology of neurodegenerative diseases.
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Affiliation(s)
- Yoichi Chiba
- Department of Pathology and Host Defense, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa 761-0793, Japan; (Y.C.); (R.M.); (K.M.); (K.W.)
| | - Ryuta Murakami
- Department of Pathology and Host Defense, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa 761-0793, Japan; (Y.C.); (R.M.); (K.M.); (K.W.)
| | - Koichi Matsumoto
- Department of Pathology and Host Defense, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa 761-0793, Japan; (Y.C.); (R.M.); (K.M.); (K.W.)
| | - Keiji Wakamatsu
- Department of Pathology and Host Defense, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa 761-0793, Japan; (Y.C.); (R.M.); (K.M.); (K.W.)
| | - Wakako Nonaka
- Department of Supportive and Promotive Medicine of the Municipal Hospital, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa 761-0793, Japan;
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa 761-0793, Japan
| | - Naoya Uemura
- Department of Anesthesiology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa 761-0793, Japan; (N.U.); (K.Y.)
| | - Ken Yanase
- Department of Anesthesiology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa 761-0793, Japan; (N.U.); (K.Y.)
| | - Masaki Kamada
- Department of Neurological Intractable Disease Research, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa 761-0793, Japan;
| | - Masaki Ueno
- Department of Pathology and Host Defense, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa 761-0793, Japan; (Y.C.); (R.M.); (K.M.); (K.W.)
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18
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Holman GD. Structure, function and regulation of mammalian glucose transporters of the SLC2 family. Pflugers Arch 2020; 472:1155-1175. [PMID: 32591905 PMCID: PMC7462842 DOI: 10.1007/s00424-020-02411-3] [Citation(s) in RCA: 128] [Impact Index Per Article: 25.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2020] [Revised: 05/27/2020] [Accepted: 05/29/2020] [Indexed: 12/12/2022]
Abstract
The SLC2 genes code for a family of GLUT proteins that are part of the major facilitator superfamily (MFS) of membrane transporters. Crystal structures have recently revealed how the unique protein fold of these proteins enables the catalysis of transport. The proteins have 12 transmembrane spans built from a replicated trimer substructure. This enables 4 trimer substructures to move relative to each other, and thereby alternately opening and closing a cleft to either the internal or the external side of the membrane. The physiological substrate for the GLUTs is usually a hexose but substrates for GLUTs can include urate, dehydro-ascorbate and myo-inositol. The GLUT proteins have varied physiological functions that are related to their principal substrates, the cell type in which the GLUTs are expressed and the extent to which the proteins are associated with subcellular compartments. Some of the GLUT proteins translocate between subcellular compartments and this facilitates the control of their function over long- and short-time scales. The control of GLUT function is necessary for a regulated supply of metabolites (mainly glucose) to tissues. Pathophysiological abnormalities in GLUT proteins are responsible for, or associated with, clinical problems including type 2 diabetes and cancer and a range of tissue disorders, related to tissue-specific GLUT protein profiles. The availability of GLUT crystal structures has facilitated the search for inhibitors and substrates and that are specific for each GLUT and that can be used therapeutically. Recent studies are starting to unravel the drug targetable properties of each of the GLUT proteins.
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Affiliation(s)
- Geoffrey D Holman
- Department of Biology and Biochemistry, University of Bath, Bath, BA2 7AY, UK.
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19
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Heterogeneity of Glucose Transport in Lung Cancer. Biomolecules 2020; 10:biom10060868. [PMID: 32517099 PMCID: PMC7356687 DOI: 10.3390/biom10060868] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2020] [Revised: 05/28/2020] [Accepted: 05/29/2020] [Indexed: 02/06/2023] Open
Abstract
Increased glucose uptake is a known hallmark of cancer. Cancer cells need glucose for energy production via glycolysis and the tricarboxylic acid cycle, and also to fuel the pentose phosphate pathway, the serine biosynthetic pathway, lipogenesis, and the hexosamine pathway. For this reason, glucose transport inhibition is an emerging new treatment for different malignancies, including lung cancer. However, studies both in animal models and in humans have shown high levels of heterogeneity in the utilization of glucose and other metabolites in cancer, unveiling a complexity that is difficult to target therapeutically. Here, we present an overview of different levels of heterogeneity in glucose uptake and utilization in lung cancer, with diagnostic and therapeutic implications.
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20
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Ziegler GC, Almos P, McNeill RV, Jansch C, Lesch KP. Cellular effects and clinical implications of SLC2A3 copy number variation. J Cell Physiol 2020; 235:9021-9036. [PMID: 32372501 DOI: 10.1002/jcp.29753] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2019] [Revised: 04/04/2020] [Accepted: 04/21/2020] [Indexed: 12/19/2022]
Abstract
SLC2A3 encodes the predominantly neuronal glucose transporter 3 (GLUT3), which facilitates diffusion of glucose across plasma membranes. The human brain depends on a steady glucose supply for ATP generation, which consequently fuels critical biochemical processes, such as axonal transport and neurotransmitter release. Besides its role in the central nervous system, GLUT3 is also expressed in nonneural organs, such as the heart and white blood cells, where it is equally involved in energy metabolism. In cancer cells, GLUT3 overexpression contributes to the Warburg effect by answering the cell's increased glycolytic demands. The SLC2A3 gene locus at chromosome 12p13.31 is unstable and prone to non-allelic homologous recombination events, generating multiple copy number variants (CNVs) of SLC2A3 which account for alterations in SLC2A3 expression. Recent associations of SLC2A3 CNVs with different clinical phenotypes warrant investigation of the potential influence of these structural variants on pathomechanisms of neuropsychiatric, cardiovascular, and immune diseases. In this review, we accumulate and discuss the evidence how SLC2A3 gene dosage may exert diverse protective or detrimental effects depending on the pathological condition. Cellular states which lead to increased energetic demand, such as organ development, proliferation, and cellular degeneration, appear particularly susceptible to alterations in SLC2A3 copy number. We conclude that better understanding of the impact of SLC2A3 variation on disease etiology may potentially provide novel therapeutic approaches specifically targeting this GLUT.
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Affiliation(s)
- Georg C Ziegler
- Division of Molecular Psychiatry, Center of Mental Health, University of Würzburg, Germany.,Department of Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University of Würzburg, Germany
| | - Peter Almos
- Division of Molecular Psychiatry, Center of Mental Health, University of Würzburg, Germany.,Department of Psychiatry, University of Szeged, Hungary
| | - Rhiannon V McNeill
- Department of Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University of Würzburg, Germany
| | - Charline Jansch
- Division of Molecular Psychiatry, Center of Mental Health, University of Würzburg, Germany
| | - Klaus-Peter Lesch
- Division of Molecular Psychiatry, Center of Mental Health, University of Würzburg, Germany.,Department of Psychiatry and Neuropsychology, School of Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands.,Laboratory of Psychiatric Neurobiology, Institute of Molecular Medicine, I.M. Sechenov First Moscow State Medical University, Moscow, Russia
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21
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Gum Arabic improves the reproductive capacity through upregulation of testicular glucose transporters (GLUTs) mRNA expression in Alloxan induced diabetic rat. ACTA ACUST UNITED AC 2020. [DOI: 10.1016/j.bcdf.2020.100218] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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22
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L-Glucose: Another Path to Cancer Cells. Cancers (Basel) 2020; 12:cancers12040850. [PMID: 32244695 PMCID: PMC7225996 DOI: 10.3390/cancers12040850] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2020] [Revised: 03/24/2020] [Accepted: 03/30/2020] [Indexed: 01/31/2023] Open
Abstract
Cancerous tumors comprise cells showing metabolic heterogeneity. Among numerous efforts to understand this property, little attention has been paid to the possibility that cancer cells take up and utilize otherwise unusable substrates as fuel. Here we discuss this issue by focusing on l-glucose, the mirror image isomer of naturally occurring d-glucose; l-glucose is an unmetabolizable sugar except in some bacteria. By combining relatively small fluorophores with l-glucose, we generated fluorescence-emitting l-glucose tracers (fLGs). To our surprise, 2-NBDLG, one of these fLGs, which we thought to be merely a control substrate for the fluorescent d-glucose tracer 2-NBDG, was specifically taken up into tumor cell aggregates (spheroids) that exhibited nuclear heterogeneity, a major cytological feature of malignancy in cancer diagnosis. Changes in mitochondrial activity were also associated with the spheroids taking up fLG. To better understand these phenomena, we review here the Warburg effect as well as key studies regarding glucose uptake. We also discuss tumor heterogeneity involving aberrant uptake of glucose and mitochondrial changes based on the data obtained by fLG. We then consider the use of fLGs as novel markers for visualization and characterization of malignant tumor cells.
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Liu B, Wang Y, Zhang Y, Yan B. Mechanisms of Protective Effects of SGLT2 Inhibitors in Cardiovascular Disease and Renal Dysfunction. Curr Top Med Chem 2019; 19:1818-1849. [PMID: 31456521 DOI: 10.2174/1568026619666190828161409] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2019] [Revised: 07/09/2019] [Accepted: 07/25/2019] [Indexed: 02/07/2023]
Abstract
Type 2 diabetes mellitus is one of the most common forms of the disease worldwide. Hyperglycemia and insulin resistance play key roles in type 2 diabetes mellitus. Renal glucose reabsorption is an essential feature in glycaemic control. Kidneys filter 160 g of glucose daily in healthy subjects under euglycaemic conditions. The expanding epidemic of diabetes leads to a prevalence of diabetes-related cardiovascular disorders, in particular, heart failure and renal dysfunction. Cellular glucose uptake is a fundamental process for homeostasis, growth, and metabolism. In humans, three families of glucose transporters have been identified, including the glucose facilitators GLUTs, the sodium-glucose cotransporter SGLTs, and the recently identified SWEETs. Structures of the major isoforms of all three families were studied. Sodium-glucose cotransporter (SGLT2) provides most of the capacity for renal glucose reabsorption in the early proximal tubule. A number of cardiovascular outcome trials in patients with type 2 diabetes have been studied with SGLT2 inhibitors reducing cardiovascular morbidity and mortality. The current review article summarises these aspects and discusses possible mechanisms with SGLT2 inhibitors in protecting heart failure and renal dysfunction in diabetic patients. Through glucosuria, SGLT2 inhibitors reduce body weight and body fat, and shift substrate utilisation from carbohydrates to lipids and, possibly, ketone bodies. These pleiotropic effects of SGLT2 inhibitors are likely to have contributed to the results of the EMPA-REG OUTCOME trial in which the SGLT2 inhibitor, empagliflozin, slowed down the progression of chronic kidney disease and reduced major adverse cardiovascular events in high-risk individuals with type 2 diabetes. This review discusses the role of SGLT2 in the physiology and pathophysiology of renal glucose reabsorption and outlines the unexpected logic of inhibiting SGLT2 in the diabetic kidney.
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Affiliation(s)
- Ban Liu
- Department of Cardiology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Yuliang Wang
- Department of Immunology, Nanjing Medical University, Nanjing, China
| | - Yangyang Zhang
- Key Laboratory of Arrhythmias of the Ministry of Education of China, Tongji University School of Medicine, Shanghai, China.,Department of Cardiovascular Surgery, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Biao Yan
- Shanghai Key Laboratory of Visual Impairment and Restoration, Shanghai, China.,Eye Institute, Eye and ENT Hospital, Shanghai Medical College, Fudan University, Shanghai, China
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24
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Ubanako P, Xelwa N, Ntwasa M. LPS induces inflammatory chemokines via TLR-4 signalling and enhances the Warburg Effect in THP-1 cells. PLoS One 2019; 14:e0222614. [PMID: 31560702 PMCID: PMC6764657 DOI: 10.1371/journal.pone.0222614] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2019] [Accepted: 09/03/2019] [Indexed: 01/04/2023] Open
Abstract
The Warburg Effect has emerged as a potential drug target because, in some cancer cell lines, it is sufficient to subvert it in order to kill cancer cells. It has also been shown that the Warburg Effect occurs in innate immune cells upon infection. Innate immune cells play critical roles in the tumour microenvironment but the Warburg Effect is not fully understood in monocytes. Furthermore, it is important to understand the impact of infections on key players in the tumour microenvironment because inflammatory conditions often precede carcinogenesis and mutated oncogenes induce inflammation. We investigated the metabolic programme in the acute monocytic leukaemia cell line, THP-1 in the presence and absence of lipopolysaccharide, mimicking bacterial infections. We found that stimulation of THP-1 cells by LPS induces a subset of pro-inflammatory chemokines and enhances the Warburg Effect. Surprisingly, perturbation of the Warburg Effect in these cells does not lead to cell death in contrast to what was observed in non-myeloid cancer cell lines in a previous study. These findings indicate that the Warburg Effect and inflammation are activated by bacterial lipopolysaccharide and may have a profound influence on the microenvironment.
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Affiliation(s)
- Philemon Ubanako
- School of Molecular & Cell Biology, University of the Witwatersrand, Johannesburg, Republic of South Africa
| | - Ntombikayise Xelwa
- School of Molecular & Cell Biology, University of the Witwatersrand, Johannesburg, Republic of South Africa
| | - Monde Ntwasa
- Department of Life & Consumer Sciences, University of South Africa, Florida, Johannesburg, Republic of South Africa
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25
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Lechermeier CG, Zimmer F, Lüffe TM, Lesch KP, Romanos M, Lillesaar C, Drepper C. Transcript Analysis of Zebrafish GLUT3 Genes, slc2a3a and slc2a3b, Define Overlapping as Well as Distinct Expression Domains in the Zebrafish ( Danio rerio) Central Nervous System. Front Mol Neurosci 2019; 12:199. [PMID: 31507372 PMCID: PMC6718831 DOI: 10.3389/fnmol.2019.00199] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2019] [Accepted: 08/02/2019] [Indexed: 01/05/2023] Open
Abstract
The transport of glucose across the cell plasma membrane is vital to most mammalian cells. The glucose transporter (GLUT; also called SLC2A) family of transmembrane solute carriers is responsible for this function in vivo. GLUT proteins encompass 14 different isoforms in humans with different cell type-specific expression patterns and activities. Central to glucose utilization and delivery in the brain is the neuronally expressed GLUT3. Recent research has shown an involvement of GLUT3 genetic variation or altered expression in several different brain disorders, including Huntington's and Alzheimer's diseases. Furthermore, GLUT3 was identified as a potential risk gene for multiple psychiatric disorders. To study the role of GLUT3 in brain function and disease a more detailed knowledge of its expression in model organisms is needed. Zebrafish (Danio rerio) has in recent years gained popularity as a model organism for brain research and is now well-established for modeling psychiatric disorders. Here, we have analyzed the sequence of GLUT3 orthologs and identified two paralogous genes in the zebrafish, slc2a3a and slc2a3b. Interestingly, the Glut3b protein sequence contains a unique stretch of amino acids, which may be important for functional regulation. The slc2a3a transcript is detectable in the central nervous system including distinct cellular populations in telencephalon, diencephalon, mesencephalon and rhombencephalon at embryonic and larval stages. Conversely, the slc2a3b transcript shows a rather diffuse expression pattern at different embryonic stages and brain regions. Expression of slc2a3a is maintained in the adult brain and is found in the telencephalon, diencephalon, mesencephalon, cerebellum and medulla oblongata. The slc2a3b transcripts are present in overlapping as well as distinct regions compared to slc2a3a. Double in situ hybridizations were used to demonstrate that slc2a3a is expressed by some GABAergic neurons at embryonic stages. This detailed description of zebrafish slc2a3a and slc2a3b expression at developmental and adult stages paves the way for further investigations of normal GLUT3 function and its role in brain disorders.
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Affiliation(s)
- Carina G Lechermeier
- Child and Adolescent Psychiatry, Center of Mental Health, University Hospital of Würzburg, Würzburg, Germany.,Department of Physiological Chemistry, Biocenter, Am Hubland, University of Würzburg, Würzburg, Germany
| | - Frederic Zimmer
- Department of Physiological Chemistry, Biocenter, Am Hubland, University of Würzburg, Würzburg, Germany
| | - Teresa M Lüffe
- Child and Adolescent Psychiatry, Center of Mental Health, University Hospital of Würzburg, Würzburg, Germany.,Department of Physiological Chemistry, Biocenter, Am Hubland, University of Würzburg, Würzburg, Germany
| | - Klaus-Peter Lesch
- Division of Molecular Psychiatry, Center of Mental Health, University Hospital of Würzburg, Würzburg, Germany.,Laboratory of Psychiatric Neurobiology, Institute of Molecular Medicine, I.M. Sechenov First Moscow State Medical University, Moscow, Russia.,Department of Neuroscience, School for Mental Health and Neuroscience (MHeNS), Maastricht University, Maastricht, Netherlands
| | - Marcel Romanos
- Child and Adolescent Psychiatry, Center of Mental Health, University Hospital of Würzburg, Würzburg, Germany
| | - Christina Lillesaar
- Child and Adolescent Psychiatry, Center of Mental Health, University Hospital of Würzburg, Würzburg, Germany.,Department of Physiological Chemistry, Biocenter, Am Hubland, University of Würzburg, Würzburg, Germany
| | - Carsten Drepper
- Child and Adolescent Psychiatry, Center of Mental Health, University Hospital of Würzburg, Würzburg, Germany
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Thurgood LA, Dwyer ES, Lower KM, Chataway TK, Kuss BJ. Altered expression of metabolic pathways in CLL detected by unlabelled quantitative mass spectrometry analysis. Br J Haematol 2019; 185:65-78. [PMID: 30656643 DOI: 10.1111/bjh.15751] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2018] [Accepted: 11/26/2018] [Indexed: 12/27/2022]
Abstract
Chronic lymphocytic leukaemia (CLL) remains the most common incurable malignancy of B cells in the western world. Patient outcomes are heterogeneous and can be difficult to predict with current prognostic markers. Here, we used a quantitative label-free proteomic technique to ascertain differences in the B-cell proteome from healthy donors and CLL patients with either mutated (M-CLL) or unmutated (UM-CLL) IGHV to identify new prognostic markers. In peripheral B-CLL cells, 349 (22%) proteins were differentially expressed between normal B cells and B-CLL cells and 189 (12%) were differentially expressed between M-CLL and UM-CLL. We also examined the proteome of proliferating CLL cells in the lymph nodes, and identified 76 (~8%) differentially expressed proteins between healthy and CLL lymph nodes. B-CLL cells show over-expression of proteins involved in lipid and cholesterol metabolism. A comprehensive lipidomic analysis highlighted large differences in glycolipids and sphingolipids. A shift was observed from the pro-apoptotic lipid ceramide towards the anti-apoptotic/chemoresistant lipid, glucosylceramide, which was more evident in patients with aggressive disease (UM-CLL). This study details a novel quantitative proteomic technique applied for the first time to primary patient samples in CLL and highlights that primary CLL lymphocytes display markers of a metabolic shift towards lipid synthesis and breakdown.
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Affiliation(s)
- Lauren A Thurgood
- Discipline Molecular Medicine and Pathology, College of Medicine and Public Health, Flinders University, Adelaide, South Australia, Australia
| | - Eveline S Dwyer
- Discipline Molecular Medicine and Pathology, College of Medicine and Public Health, Flinders University, Adelaide, South Australia, Australia
| | - Karen M Lower
- Discipline Molecular Medicine and Pathology, College of Medicine and Public Health, Flinders University, Adelaide, South Australia, Australia
| | - Tim K Chataway
- Flinders Proteomic Facility, Department of Human Physiology, College of Medicine and Public Health, Flinders University, Adelaide, South Australia, Australia
| | - Bryone J Kuss
- Discipline Molecular Medicine and Pathology, College of Medicine and Public Health, Flinders University, Adelaide, South Australia, Australia.,Haematology, Molecular Medicine and Pathology, SA Pathology, Flinders Medical Centre, Adelaide, South Australia, Australia
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27
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Chemical biology probes of mammalian GLUT structure and function. Biochem J 2018; 475:3511-3534. [PMID: 30459202 PMCID: PMC6243331 DOI: 10.1042/bcj20170677] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2018] [Revised: 10/11/2018] [Accepted: 10/11/2018] [Indexed: 12/14/2022]
Abstract
The structure and function of glucose transporters of the mammalian GLUT family of proteins has been studied over many decades, and the proteins have fascinated numerous research groups over this time. This interest is related to the importance of the GLUTs as archetypical membrane transport facilitators, as key limiters of the supply of glucose to cell metabolism, as targets of cell insulin and exercise signalling and of regulated membrane traffic, and as potential drug targets to combat cancer and metabolic diseases such as type 2 diabetes and obesity. This review focusses on the use of chemical biology approaches and sugar analogue probes to study these important proteins.
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28
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Carreño D, Corro N, Torres-Estay V, Véliz LP, Jaimovich R, Cisternas P, San Francisco IF, Sotomayor PC, Tanasova M, Inestrosa NC, Godoy AS. Fructose and prostate cancer: toward an integrated view of cancer cell metabolism. Prostate Cancer Prostatic Dis 2018; 22:49-58. [PMID: 30104655 DOI: 10.1038/s41391-018-0072-7] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2018] [Revised: 06/13/2018] [Accepted: 06/29/2018] [Indexed: 01/07/2023]
Abstract
Activation of glucose transporter-1 (Glut-1) gene expression is a molecular feature of cancer cells that increases glucose uptake and metabolism. Increased glucose uptake is the basis for the clinical localization of primary tumors using positron emission tomography (PET) and 2-deoxy-2-[18F]-fluoro-D-glucose (FDG) as a radiotracer. However, previous studies have demonstrated that a considerable number of cancers, which include prostate cancer (CaP), express low to undetectable levels of Glut-1 and that FDG-PET has limited clinical applicability in CaP. This observation could be explained by a low metabolic activity of CaP cells that may be overcome using different hexoses, such as fructose, as the preferred energy source. However, these hypotheses have not been examined critically in CaP. This review article summarizes what is currently known about transport and metabolism of hexoses, and more specifically fructose, in CaP and provides experimental evidences indicating that CaP cells may have increased capacity to transport and metabolize fructose in vitro and in vivo. Moreover, this review highlights recent findings that allow better understanding of how metabolism of fructose may regulate cancer cell proliferation and how fructose uptake and metabolism, through the de novo lipogenesis pathway, may provide new opportunities for CaP early diagnosis, staging, and treatment.
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Affiliation(s)
- Daniela Carreño
- Department of Physiology, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Néstor Corro
- Department of Physiology, Pontificia Universidad Católica de Chile, Santiago, Chile
| | | | - Loreto P Véliz
- Department of Physiology, Pontificia Universidad Católica de Chile, Santiago, Chile
| | | | - Pedro Cisternas
- Centro de Envejecimiento y Regeneración (CARE), Department of Cell Biology, Pontificia Universidad Católica de Chile, Santiago, Chile
| | | | - Paula C Sotomayor
- Center for Integrative Medicine and Innovative Science, Faculty of Medicine, Universidad Andres Bello, Santiago, Chile
| | - Marina Tanasova
- Department of Chemistry, Michigan Technological University, Houghton, MI, 49931, USA
| | - Nibaldo C Inestrosa
- Centro de Envejecimiento y Regeneración (CARE), Department of Cell Biology, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Alejandro S Godoy
- Department of Physiology, Pontificia Universidad Católica de Chile, Santiago, Chile. .,Department of Urology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA.
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29
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Crouse MS, McLean KJ, Greseth NP, Crosswhite MR, Pereira NN, Ward AK, Reynolds LP, Dahlen CR, Neville BW, Borowicz PP, Caton JS. Maternal nutrition and stage of early pregnancy in beef heifers: Impacts on expression of glucose, fructose, and cationic amino acid transporters in utero-placental tissues. J Anim Sci 2018; 95:5563-5572. [PMID: 29293768 DOI: 10.2527/jas2017.1983] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023] Open
Abstract
We hypothesized that maternal nutrition and day of gestation would impact utero-placental mRNA expression of the nutrient transporters , , , , and in beef heifers. Crossbred Angus heifers (n = 49) were estrous synchronized, bred via AI, assigned to nutritional treatment (CON = 100% of NRC requirements for 0.45 kg/d gain and RES = 60% of CON) and ovariohysterectomized on d 16, 34, or 50 of gestation (n = 6 to 9/d); Non-bred, non-pregnant (NB-NP) controls were fed the CON diet, not bred, and were ovariohysterectomized on d 16 of the synchronized estrous cycle = 6). The resulting arrangement of treatments was a 2 × 3 factorial + 1 (CON vs. RES × d 16, 34, or 50 + NB-NP controls). Caruncle (CAR), intercaruncular endometrium (ICAR), and fetal membranes (FM [chorioallantois]), were obtained from the pregnant uterine horn (the uterine horn containing the conceptus) immediately after ovariohysterectomy. On d 50 cotyledons (COT), intercotyledonary placenta (ICOT) and amnion (AMN) were also collected. Relative expression of nutrient transporters was determined for each tissue utilizing NB-NP-CAR and NB-NP-ICAR tissues as the baseline. For FM, NB-NP endometrium served as the baseline. There was no interaction of day × treatment ( ≥ 0.20) for any genes in CAR. However, CAR expression of was greater ( < 0.01) on d 16 compared with d 34 and 50, and , , and were greater ( ≤ 0.05) on d 34 compared with d 16 and 50. In ICAR, was the only gene to be influenced by the day × treatment interaction ( = 0.01), being greater in d 50 CON compared with d 34 CON and d 16 and 50 RES. In ICAR, expression of was greater ( < 0.01) on d 16 compared with d 34, and expression of was greater ( < 0.01) on d 34 and 50 compared with d 16. In FM, expression of was greater ( = 0.04) on d 16 compared with d 50 of gestation, and expression of was greater ( < 0.01) on d 34 and 50 compared with d 16. On d 50, expression of , , and expression were all greater ( < 0.05) in AMN compared with COT and ICOT, and expression of was greater ( < 0.01) in ICOT compared with COT and AMN. These data indicate that day was a more influential factor for mRNA expression of utero-placental glucose and cationic AA transporters than maternal nutritional status in heifers during early pregnancy.
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30
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Liang H, Mokrani A, Chisomo-Kasiya H, Wilson-Arop OM, Mi H, Ji K, Ge X, Ren M. Molecular characterization and identification of facilitative glucose transporter 2 (GLUT2) and its expression and of the related glycometabolism enzymes in response to different starch levels in blunt snout bream (Megalobrama amblycephala). FISH PHYSIOLOGY AND BIOCHEMISTRY 2018; 44:869-883. [PMID: 29560575 DOI: 10.1007/s10695-018-0477-1] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/21/2017] [Accepted: 01/25/2018] [Indexed: 06/08/2023]
Abstract
Facilitative glucose transporters (GLUT) are transmembrane transporters involved in glucose transport across the plasma membrane. In this study, blunt snout bream GLUT2 gene was cloned, and its expression in various tissues and in liver in response to diets with different carbohydrate levels (17.1; 21.8; 26.4; 32.0; 36.3; and 41.9% of dry matter). Blunt snout bream GLUT2 was also characterized. A full-length cDNA fragment of 2577 bp was cloned, which contains a 5'-untranslated region (UTR) of 73 bp, a 3'-UTR of 992 bp, and an open reading frame of 1512 bp that encodes a polypeptide of 503 amino acids with predicted molecular mass of 55.046 kDa and theoretical isoelectric point was 7.52. The predicted GLUT2 protein has 12 transmembrane domains between amino acid residues at 7-29; 71-93; 106-123; 133-155; 168-190; 195-217; 282-301; 316-338; 345-367; 377-399; 412-434; and 438-460. Besides, the conservative structure domains located at 12-477 amino acids belong to the sugar porter family which is the major facilitator superfamily (MFS) of transporters. Blunt snout bream GLUT2 had the high degree of sequence identity to four GLUT2s from zebrafish, chicken, human, and mouse, with 91, 63, 57, and 54% identity, respectively. Quantitative real-time (qRT) PCR assays revealed that GLUT2 expression was high in the liver, intestine, and kidney; highest in the liver and was regulated by carbohydrate intake. Compared with the control group (17.1%), fed by 3 h with higher starch levels (32.0; 36.3; and 41.9%), increased plasma glucose levels and glycemic level went back to basal by 24 h after treatment. Furthermore, higher dietary starch levels significantly increase GLUT2, glucokinase (GK), and pyruvate kinase (PK) expression and concurrently decrease phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6P) mRNA levels (P < 0.05), and these changes were also back to basal levels after 24 h of any dietary treatment. These results indicate that the blunt snout bream is able to regulate their ability to metabolize glucose by improving GLUT2, GK, and PK expression levels and decreasing PEPCK and G6P expression levels.
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Affiliation(s)
- Hualiang Liang
- Wuxi Fisheries College, Nanjing Agricultural University, Wuxi, 214081, China
| | - Ahmed Mokrani
- Wuxi Fisheries College, Nanjing Agricultural University, Wuxi, 214081, China
| | | | | | - Haifeng Mi
- Key Laboratory for Genetic Breeding of Aquatic Animals and Aquaculture Biology, Freshwater Fisheries Research Center (FFRC), Chinese Academy of Fishery Sciences (CAFS), Wuxi, 214081, China
| | - Ke Ji
- Wuxi Fisheries College, Nanjing Agricultural University, Wuxi, 214081, China
| | - Xianping Ge
- Wuxi Fisheries College, Nanjing Agricultural University, Wuxi, 214081, China.
- Key Laboratory for Genetic Breeding of Aquatic Animals and Aquaculture Biology, Freshwater Fisheries Research Center (FFRC), Chinese Academy of Fishery Sciences (CAFS), Wuxi, 214081, China.
| | - Mingchun Ren
- Wuxi Fisheries College, Nanjing Agricultural University, Wuxi, 214081, China.
- Key Laboratory for Genetic Breeding of Aquatic Animals and Aquaculture Biology, Freshwater Fisheries Research Center (FFRC), Chinese Academy of Fishery Sciences (CAFS), Wuxi, 214081, China.
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31
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Zhang J, Jiang S, Wei J, Yip KP, Wang L, Lai EY, Liu R. Glucose dilates renal afferent arterioles via glucose transporter-1. Am J Physiol Renal Physiol 2018; 315:F123-F129. [PMID: 29513069 PMCID: PMC6335005 DOI: 10.1152/ajprenal.00409.2017] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Glomerular hyperfiltration occurs during the early stage of diabetes. An acute glucose infusion increases glomerular filtration rate. The involvement of tubuloglomerular feedback response and direct effect of glucose on the afferent arterioles (Af-Arts) have been suggested. However, the signaling pathways to trigger Af-Art dilatation have not been fully identified. Therefore, in the present study we tested our hypothesis that an increase in glucose concentration enhances endothelial nitric oxide synthesis activity and dilates the Af-Arts via glucose transporter-1 (GLUT1) using isolated mouse Af-Arts with perfusion. We isolated and microperfused the Af-Arts from nondiabetic C57BL/6 mice. The Af-Arts were preconstricted with norepinephrine (1 µM). When we switched the d-glucose concentration from low (5 mM) to high (30 mM) in the perfusate, the preconstricted Af-Arts significantly dilated by 37.8 ± 7.1%, but L-glucose did not trigger the dilation. GLUT1 mRNA was identified in microdisserted Af-Arts measured by RT-PCR. Changes in nitric oxide (NO) production in Af-Art were also measured using fluorescent probe when ambient glucose concentration was increased. When the d-glucose concentration was switched from 5 to 30 mM, NO generation in Af-Art was significantly increased by 19.2 ± 6.2% (84.7 ± 4.1 to 101.0 ± 9.3 U/min). l-Glucose had no effect on the NO generation. The GLUT1-selective antagonist 4-[({[4-(1,1-Dimethylethyl)phenyl]sulfonyl}amino)methyl]- N-3-pyridinylbenzamide and the nitric oxide synthase inhibitor NG-nitro-l-arginine methyl ester blocked the high glucose-induced NO generation and vasodilation. In conclusion, we demonstrated that an increase in glucose concentration dilates the Af-Art by stimulation of the endothelium-derived NO production mediated by GLUT1.
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Affiliation(s)
- Jie Zhang
- Department of Molecular Pharmacology and Physiology, University of South Florida College of Medicine , Tampa, Florida
| | - Shan Jiang
- Department of Molecular Pharmacology and Physiology, University of South Florida College of Medicine , Tampa, Florida.,Department of Physiology, Zhejiang University School of Medicine , Zhejiang , China
| | - Jin Wei
- Department of Molecular Pharmacology and Physiology, University of South Florida College of Medicine , Tampa, Florida
| | - Kay-Pong Yip
- Department of Molecular Pharmacology and Physiology, University of South Florida College of Medicine , Tampa, Florida
| | - Lei Wang
- Department of Molecular Pharmacology and Physiology, University of South Florida College of Medicine , Tampa, Florida
| | - En Yin Lai
- Department of Physiology, Zhejiang University School of Medicine , Zhejiang , China
| | - Ruisheng Liu
- Department of Molecular Pharmacology and Physiology, University of South Florida College of Medicine , Tampa, Florida
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32
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Amir Shaghaghi M, Zhouyao H, Tu H, El-Gabalawy H, Crow GH, Levine M, Bernstein CN, Eck P. The SLC2A14 gene, encoding the novel glucose/dehydroascorbate transporter GLUT14, is associated with inflammatory bowel disease. Am J Clin Nutr 2017; 106:1508-1513. [PMID: 28971850 PMCID: PMC5698836 DOI: 10.3945/ajcn.116.147603] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2016] [Accepted: 09/01/2017] [Indexed: 01/16/2023] Open
Abstract
Background: Variations in intestinal antioxidant membrane transporters are implicated in the initiation and progression of inflammatory bowel disease (IBD). Facilitated glucose transporter member 14 (GLUT14), encoded by the solute carrier family 2 member 14 (SLC2A14) gene, is a putative transporter for dehydroascorbic acid and glucose. Although information on the gene is limited, shorter and longer GLUT14 isoforms have been identified. We hypothesized that GLUT14 mediates glucose and dehydroascorbic acid uptake. If this function could be validated, then genetic variations may associate with IBD.Objective: This study aimed to determine the substrate(s) for the GLUT14 protein and interrogated genetic associations of SLC2A14 with IBD.Design: The uptake of radiolabeled substrates into Xenopus laevis oocytes expressing the 2 GLUT14 isoforms was assessed. Examination of gene-targeted genetic association in the Manitoba Inflammatory Bowel Disease Cohort Study was conducted through the genotyping of single nucleotide polymorphisms (SNPs) representing linkage blocks of the SLC2A14 gene.Results: Both GLUT14 isoforms mediated the uptake of dehydroascorbic acid and glucose into X. laevis oocytes. Three alleles in the SLC2A14 gene associated independently with IBD. The odds of having ulcerative colitis (UC) or Crohn disease (CD) were elevated in carriers of the SLC2A14 SNP rs2889504-T allele (OR: 3.60; 95% CI: 1.95, 6.64 and OR: 4.68; 95% CI: 2.78, 8.50, respectively). Similarly, the SNP rs10846086-G allele was associated with an increased risk of both UC and CD (OR: 2.91; 95% CI: 1.49, 5.68 and OR: 3.00; 95% CI: 1.55, 5.78, respectively). Moreover, the SNP rs12815313-T allele associated with increased susceptibility to CD and UC (OR: 2.12; 95% CI: 1.33, 3.36 and OR: 1.61; 95% CI: 1.01, 2.57, respectively).Conclusion: These findings strengthen the hypothesis that genetically determined local dysregulation of dietary vitamin C or antioxidants transport contributes to IBD development. These transporter proteins are targetable by dietary interventions, opening the avenue to a precision intervention for patients of specific genotypes with IBD. This trial was registered at clinicaltrials.gov as NCT03262649.
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Affiliation(s)
| | | | - Hongbin Tu
- Molecular and Clinical Nutrition Section, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, MD
| | | | | | - Mark Levine
- Molecular and Clinical Nutrition Section, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, MD
| | - Charles N Bernstein
- Internal Medicine, and,IBD Clinical and Research Centre, University of Manitoba, Winnipeg, Canada; and
| | - Peter Eck
- Departments of Human Nutritional Sciences,
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A Glimpse of Membrane Transport through Structures—Advances in the Structural Biology of the GLUT Glucose Transporters. J Mol Biol 2017; 429:2710-2725. [DOI: 10.1016/j.jmb.2017.07.009] [Citation(s) in RCA: 49] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2017] [Revised: 07/13/2017] [Accepted: 07/15/2017] [Indexed: 01/17/2023]
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Merker S, Reif A, Ziegler GC, Weber H, Mayer U, Ehlis AC, Conzelmann A, Johansson S, Müller-Reible C, Nanda I, Haaf T, Ullmann R, Romanos M, Fallgatter AJ, Pauli P, Strekalova T, Jansch C, Vasquez AA, Haavik J, Ribasés M, Ramos-Quiroga JA, Buitelaar JK, Franke B, Lesch KP. SLC2A3 single-nucleotide polymorphism and duplication influence cognitive processing and population-specific risk for attention-deficit/hyperactivity disorder. J Child Psychol Psychiatry 2017; 58:798-809. [PMID: 28224622 DOI: 10.1111/jcpp.12702] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/14/2016] [Indexed: 12/19/2022]
Abstract
BACKGROUND Attention-deficit/hyperactivity disorder (ADHD) is a common, highly heritable neurodevelopmental disorder with profound cognitive, behavioral, and psychosocial impairments with persistence across the life cycle. Our initial genome-wide screening approach for copy number variants (CNVs) in ADHD implicated a duplication of SLC2A3, encoding glucose transporter-3 (GLUT3). GLUT3 plays a critical role in cerebral glucose metabolism, providing energy for the activity of neurons, which, in turn, moderates the excitatory-inhibitory balance impacting both brain development and activity-dependent neural plasticity. We therefore aimed to provide additional genetic and functional evidence for GLUT3 dysfunction in ADHD. METHODS Case-control association analyses of SLC2A3 single-nucleotide polymorphisms (SNPs) and CNVs were conducted in several European cohorts of patients with childhood and adult ADHD (SNP, n = 1,886 vs. 1,988; CNV, n = 1,692 vs. 1,721). These studies were complemented by SLC2A3 expression analyses in peripheral cells, functional EEG recordings during neurocognitive tasks, and ratings of food energy content. RESULTS Meta-analysis of all cohorts detected an association of SNP rs12842 with ADHD. While CNV analysis detected a population-specific enrichment of SLC2A3 duplications only in German ADHD patients, the CNV + rs12842 haplotype influenced ADHD risk in both the German and Spanish cohorts. Duplication carriers displayed elevated SLC2A3 mRNA expression in peripheral blood cells and altered event-related potentials reflecting deficits in working memory and cognitive response control, both endophenotypic traits of ADHD, and an underestimation of energy units of high-caloric food. CONCLUSIONS Taken together, our results indicate that both common and rare SLC2A3 variation impacting regulation of neuronal glucose utilization and energy homeostasis may result in neurocognitive deficits known to contribute to ADHD risk.
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Affiliation(s)
- Sören Merker
- Division of Molecular Psychiatry, ADHD Clinical Research Unit, Laboratory of Translational Neuroscience, Center of Mental Health, University of Würzburg, Würzburg, Germany
| | - Andreas Reif
- Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt, Frankfurt, Germany
| | - Georg C Ziegler
- Division of Molecular Psychiatry, ADHD Clinical Research Unit, Laboratory of Translational Neuroscience, Center of Mental Health, University of Würzburg, Würzburg, Germany
| | - Heike Weber
- Division of Molecular Psychiatry, ADHD Clinical Research Unit, Laboratory of Translational Neuroscience, Center of Mental Health, University of Würzburg, Würzburg, Germany.,Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt, Frankfurt, Germany
| | - Ute Mayer
- Division of Molecular Psychiatry, ADHD Clinical Research Unit, Laboratory of Translational Neuroscience, Center of Mental Health, University of Würzburg, Würzburg, Germany
| | - Ann-Christine Ehlis
- Department of Psychiatry and Psychotherapy, University of Tübingen, Tübingen, Germany
| | - Annette Conzelmann
- Department of Psychology I, University of Würzburg, Würzburg, Germany.,Department of Child and Adolescent Psychiatry, University of Tübingen, Tübingen, Germany
| | - Stefan Johansson
- K.G. Jebsen Centre for Neuropsychiatric Disorders, Department of Clinical Science, University of Bergen, Bergen, Norway
| | | | - Indrajit Nanda
- Department of Human Genetics, Biozentrum, University of Würzburg, Würzburg, Germany
| | - Thomas Haaf
- Department of Human Genetics, Biozentrum, University of Würzburg, Würzburg, Germany
| | - Reinhard Ullmann
- Max-Planck Institute for Molecular Genetics, Berlin, Germany.,Bundeswehr Institute of Radiobiology, University of Ulm, Ulm, Germany
| | - Marcel Romanos
- Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University of Würzburg, Würzburg, Germany
| | - Andreas J Fallgatter
- Department of Psychiatry and Psychotherapy, University of Tübingen, Tübingen, Germany
| | - Paul Pauli
- Department of Psychology I, University of Würzburg, Würzburg, Germany
| | - Tatyana Strekalova
- Division of Molecular Psychiatry, ADHD Clinical Research Unit, Laboratory of Translational Neuroscience, Center of Mental Health, University of Würzburg, Würzburg, Germany.,Laboratory of Psychiatric Neurobiology, Institute of Molecular Medicine, I.M. Sechenov First Moscow State Medical University, Moscow, Russia.,Department of Translational Neuroscience, School of Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands
| | - Charline Jansch
- Division of Molecular Psychiatry, ADHD Clinical Research Unit, Laboratory of Translational Neuroscience, Center of Mental Health, University of Würzburg, Würzburg, Germany
| | - Alejandro Arias Vasquez
- Departments of Human Genetics and Psychiatry, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.,Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Jan Haavik
- Division of Psychiatry, Haukeland University Hospital, Bergen, Norway.,Department of Biomedicine, K.G. Jebsen Centre for Neuropsychiatric Disorders, University of Bergen, Bergen, Norway
| | - Marta Ribasés
- Psychiatric Genetics Unit, Institute Vall d'Hebron Research (VHIR), Universitat Autonoma de Barcelona, Barcelona, Spain.,Biomedical Network Research Centre on Mental Health (CIBERSAM), Barcelona, Spain
| | - Josep Antoni Ramos-Quiroga
- Psychiatric Genetics Unit, Institute Vall d'Hebron Research (VHIR), Universitat Autonoma de Barcelona, Barcelona, Spain.,Biomedical Network Research Centre on Mental Health (CIBERSAM), Barcelona, Spain.,Department of Psychiatry and Legal Medicine, Universitat Autonoma de Barcelona, Barcelona, Spain
| | - Jan K Buitelaar
- Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Barbara Franke
- Departments of Human Genetics and Psychiatry, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Klaus-Peter Lesch
- Division of Molecular Psychiatry, ADHD Clinical Research Unit, Laboratory of Translational Neuroscience, Center of Mental Health, University of Würzburg, Würzburg, Germany.,Laboratory of Psychiatric Neurobiology, Institute of Molecular Medicine, I.M. Sechenov First Moscow State Medical University, Moscow, Russia.,Department of Translational Neuroscience, School of Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands
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McMillin SL, Schmidt DL, Kahn BB, Witczak CA. GLUT4 Is Not Necessary for Overload-Induced Glucose Uptake or Hypertrophic Growth in Mouse Skeletal Muscle. Diabetes 2017; 66:1491-1500. [PMID: 28279980 PMCID: PMC5440020 DOI: 10.2337/db16-1075] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2016] [Accepted: 02/24/2017] [Indexed: 12/23/2022]
Abstract
GLUT4 is necessary for acute insulin- and contraction-induced skeletal muscle glucose uptake, but its role in chronic muscle loading (overload)-induced glucose uptake is unknown. Our goal was to determine whether GLUT4 is required for overload-induced glucose uptake. Overload was induced in mouse plantaris muscle by unilateral synergist ablation. After 5 days, muscle weights and ex vivo [3H]-2-deoxy-d-glucose uptake were assessed. Overload-induced muscle glucose uptake and hypertrophic growth were not impaired in muscle-specific GLUT4 knockout mice, demonstrating that GLUT4 is not necessary for these processes. To assess which transporters mediate overload-induced glucose uptake, chemical inhibitors were used. The facilitative GLUT inhibitor cytochalasin B, but not the sodium-dependent glucose cotransport inhibitor phloridzin, prevented overload-induced uptake demonstrating that GLUTs mediate this effect. To assess which GLUT, hexose competition experiments were performed. Overload-induced [3H]-2-deoxy-d-glucose uptake was not inhibited by d-fructose, demonstrating that the fructose-transporting GLUT2, GLUT5, GLUT8, and GLUT12 do not mediate this effect. To assess additional GLUTs, immunoblots were performed. Overload increased GLUT1, GLUT3, GLUT6, and GLUT10 protein levels twofold to fivefold. Collectively, these results demonstrate that GLUT4 is not necessary for overload-induced muscle glucose uptake or hypertrophic growth and suggest that GLUT1, GLUT3, GLUT6, and/or GLUT10 mediate overload-induced glucose uptake.
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Affiliation(s)
- Shawna L McMillin
- Department of Kinesiology, East Carolina University, Greenville, NC
- Department of Biochemistry and Molecular Biology, East Carolina University, Greenville, NC
- Department of Physiology, East Carolina University, Greenville, NC
- Brody School of Medicine, East Carolina University, Greenville, NC
- East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, NC
| | - Denise L Schmidt
- Department of Kinesiology, East Carolina University, Greenville, NC
- Department of Biochemistry and Molecular Biology, East Carolina University, Greenville, NC
- Department of Physiology, East Carolina University, Greenville, NC
- Brody School of Medicine, East Carolina University, Greenville, NC
- East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, NC
| | - Barbara B Kahn
- Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA
| | - Carol A Witczak
- Department of Kinesiology, East Carolina University, Greenville, NC
- Department of Biochemistry and Molecular Biology, East Carolina University, Greenville, NC
- Department of Physiology, East Carolina University, Greenville, NC
- Brody School of Medicine, East Carolina University, Greenville, NC
- East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, NC
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Crouse MS, Caton JS, McLean KJ, Borowicz PP, Reynolds LP, Dahlen CR, Neville BW, Ward AK. RAPID COMMUNICATION: Isolation of glucose transporters and in bovine uteroplacental tissues from days 16 to 50 of gestation. J Anim Sci 2017; 94:4463-4469. [PMID: 27898848 DOI: 10.2527/jas.2016-0808] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023] Open
Abstract
Glucose transporter solute carrier family 2 member 14 () is a duplicon of glucose transporter solute carrier family 2 member 3 () with a 95% shared homology to and has not previously been isolated in ruminant uteroplacental tissues. The transporter has been previously isolated in Holstein heifer uterine epithelium but not in ovine epithelium. We hypothesized that and its duplicon would be found in bovine uteroplacental tissues and that maternal nutrition and day of gestation would impact mRNA expression of and . Crossbred Angus heifers ( = 49) were estrus synchronized, bred via AI, and assigned to nutritional treatment (CON = 100% of requirements to gain 0.45 kg/d; RES = 60% of CON) at breeding. Ovariohysterectomy was performed on d 16, 34, or 50 of gestation ( = 6 to 9/d); nonpregnant (NP) controls were not bred and ovariohysterectomized on d 16 of the synchronized estrous cycle ( = 6). The resulting treatment arrangement was a 2 × 3 factorial + 1. Uteroplacental tissues (caruncle, CAR; intercaruncular endometrium, ICAR; and fetal membrane [chorioallantois], FM) were obtained from the pregnant uterine horn immediately after ovariohysterectomy. For NP controls, only CAR and ICAR were obtained. There were no day × treatment interactions for or gene expression in CAR, ICAR, or FM. Expression of in CAR was greater ( = 0.03) on d 50 compared with d 16. In ICAR, was greatest ( = 0.02) on d 50 compared with d 16 and 34 of gestation. In FM, was greater ( = 0.04) on d 16 compared with d 50. Expression of was greater ( = 0.05) in pregnant compared with nonpregnant heifers. Additionally, expression of was greater ( = 0.01) on d 34 and 50 compared with d 16. Expression of in CAR was greater ( = 0.03) on d 50 compared to d 16 and 34. In CAR, tended ( = 0.07) to be greater on d 34 and 50 than on d 16 and was greater ( = 0.02) on d 50 than on d 34. There was no effect of treatment for either or in CAR, ICAR, or FM. These data demonstrate that glucose transporters and are expressed in beef heifer uteroplacental tissues and that they are expressed differentially by day of gestation in bovine uteroplacental tissues.
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Avian and Mammalian Facilitative Glucose Transporters. MICROARRAYS 2017; 6:microarrays6020007. [PMID: 28379195 PMCID: PMC5487954 DOI: 10.3390/microarrays6020007] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/29/2016] [Revised: 03/15/2017] [Accepted: 03/15/2017] [Indexed: 12/17/2022]
Abstract
The GLUT members belong to a family of glucose transporter proteins that facilitate glucose transport across the cell membrane. The mammalian GLUT family consists of thirteen members (GLUTs 1-12 and H⁺-myo-inositol transporter (HMIT)). Humans have a recently duplicated GLUT member, GLUT14. Avians express the majority of GLUT members. The arrangement of multiple GLUTs across all somatic tissues signifies the important role of glucose across all organisms. Defects in glucose transport have been linked to metabolic disorders, insulin resistance and diabetes. Despite the essential importance of these transporters, our knowledge regarding GLUT members in avians is fragmented. It is clear that there are no chicken orthologs of mammalian GLUT4 and GLUT7. Our examination of GLUT members in the chicken revealed that some chicken GLUT members do not have corresponding orthologs in mammals. We review the information regarding GLUT orthologs and their function and expression in mammals and birds, with emphasis on chickens and humans.
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Upregulation of SLC2 (GLUT) family genes is related to poor survival outcomes in papillary thyroid carcinoma: Analysis of data from The Cancer Genome Atlas. Surgery 2017; 161:188-194. [DOI: 10.1016/j.surg.2016.04.050] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2016] [Revised: 04/06/2016] [Accepted: 04/10/2016] [Indexed: 01/08/2023]
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Amir Shaghaghi M, Murphy B, Eck P. The SLC2A14 gene: genomic locus, tissue expression, splice variants, and subcellular localization of the protein. Biochem Cell Biol 2016; 94:331-5. [PMID: 27460888 DOI: 10.1139/bcb-2015-0089] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023] Open
Abstract
The SLC2A14 gene encodes for GLUT14, an orphan member of the facilitated membrane glucose transporter family, which was originally described to be exclusively expressed in human testis. However, genetic variations in SLC2A14 are associated with chronic diseases such as Alzheimer's disease and Inflammatory Bowel Disease, which cannot be explained by a strictly testicular expression. Therefore we analyzed available information on the SLC2A14 gene to update knowledge of the locus and its encoded products. This report presents an expanded SLC2A14 gene locus and a more diverse tissue expression, concurring with the existing evidence for disease associations. The exon utilization is tissue specific, with major expression in testis. When the 2 major testicular protein isoforms were expressed in mammalian cells, they located to the plasmalemma membrane, providing early evidence that GLUT14 could function as a membrane transporter.
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Affiliation(s)
- Mandana Amir Shaghaghi
- a Department of Human Nutritional Sciences, University of Manitoba, Winnipeg, MB R3T 2N2, Canada
| | - Brent Murphy
- b Department of Plant Science, University of Manitoba, Winnipeg, MB, Canada
| | - Peter Eck
- a Department of Human Nutritional Sciences, University of Manitoba, Winnipeg, MB R3T 2N2, Canada
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40
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Barron CC, Bilan PJ, Tsakiridis T, Tsiani E. Facilitative glucose transporters: Implications for cancer detection, prognosis and treatment. Metabolism 2016; 65:124-39. [PMID: 26773935 DOI: 10.1016/j.metabol.2015.10.007] [Citation(s) in RCA: 298] [Impact Index Per Article: 33.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2015] [Revised: 09/22/2015] [Accepted: 10/01/2015] [Indexed: 12/11/2022]
Abstract
It is long recognized that cancer cells display increased glucose uptake and metabolism. In a rate-limiting step for glucose metabolism, the glucose transporter (GLUT) proteins facilitate glucose uptake across the plasma membrane. Fourteen members of the GLUT protein family have been identified in humans. This review describes the major characteristics of each member of the GLUT family and highlights evidence of abnormal expression in tumors and cancer cells. The regulation of GLUTs by key proliferation and pro-survival pathways including the phosphatidylinositol 3-kinase (PI3K)-Akt, hypoxia-inducible factor-1 (HIF-1), Ras, c-Myc and p53 pathways is discussed. The clinical utility of GLUT expression in cancer has been recognized and evidence regarding the use of GLUTs as prognostic or predictive biomarkers is presented. GLUTs represent attractive targets for cancer therapy and this review summarizes recent studies in which GLUT1, GLUT3, GLUT5 and others are inhibited to decrease cancer growth.
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Affiliation(s)
- Carly C Barron
- Department of Health Sciences, Brock University, St. Catharines, ON, L2S 3A1, Canada
| | - Philip J Bilan
- Program in Cell Biology, Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, Toronto, ON, M5G 0A4, Canada
| | - Theodoros Tsakiridis
- Department of Oncology, and Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, L8S 4L8, Canada
| | - Evangelia Tsiani
- Department of Health Sciences, Brock University, St. Catharines, ON, L2S 3A1, Canada.
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Stringer DM, Zahradka P, Taylor CG. Glucose transporters: cellular links to hyperglycemia in insulin resistance and diabetes. Nutr Rev 2016; 73:140-54. [PMID: 26024537 DOI: 10.1093/nutrit/nuu012] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023] Open
Abstract
Abnormal expression and/or function of mammalian hexose transporters contribute to the hallmark hyperglycemia of diabetes. Due to different roles in glucose handling, various organ systems possess specific transporters that may be affected during the diabetic state. Diabetes has been associated with higher rates of intestinal glucose transport, paralleled by increased expression of both active and facilitative transporters and a shift in the location of transporters within the enterocyte, events that occur independent of intestinal hyperplasia and hyperglycemia. Peripheral tissues also exhibit deregulated glucose transport in the diabetic state, most notably defective translocation of transporters to the plasma membrane and reduced capacity to clear glucose from the bloodstream. Expression of renal active and facilitative glucose transporters increases as a result of diabetes, leading to elevated rates of glucose reabsorption. However, this may be a natural response designed to combat elevated blood glucose concentrations and not necessarily a direct effect of insulin deficiency. Functional foods and nutraceuticals, by modulation of glucose transporter activity, represent a potential dietary tool to aid in the management of hyperglycemia and diabetes.
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Affiliation(s)
- Danielle M Stringer
- D.M. Stringer was with the Department of Human Nutritional Sciences, University of Manitoba, and the Canadian Centre for Agri-Food Research in Health and Medicine, St. Boniface Hospital Research Centre, Winnipeg, MB, Canada at the time of manuscript preparation. C.G. Taylor is with the Department of Human Nutritional Sciences, University of Manitoba; the Department of Physiology, University of Manitoba; and the Canadian Centre for Agri-Food Research in Health and Medicine, St. Boniface Hospital Research Centre, Winnipeg, Manitoba, Canada. P. Zahradka is with the Department of Human Nutritional Sciences, University of Manitoba; the Department of Physiology, University of Manitoba; and the Canadian Centre for Agri-Food Research in Health and Medicine, St. Boniface Hospital Research Centre, Winnipeg, Manitoba, Canada.
| | - Peter Zahradka
- D.M. Stringer was with the Department of Human Nutritional Sciences, University of Manitoba, and the Canadian Centre for Agri-Food Research in Health and Medicine, St. Boniface Hospital Research Centre, Winnipeg, MB, Canada at the time of manuscript preparation. C.G. Taylor is with the Department of Human Nutritional Sciences, University of Manitoba; the Department of Physiology, University of Manitoba; and the Canadian Centre for Agri-Food Research in Health and Medicine, St. Boniface Hospital Research Centre, Winnipeg, Manitoba, Canada. P. Zahradka is with the Department of Human Nutritional Sciences, University of Manitoba; the Department of Physiology, University of Manitoba; and the Canadian Centre for Agri-Food Research in Health and Medicine, St. Boniface Hospital Research Centre, Winnipeg, Manitoba, Canada
| | - Carla G Taylor
- D.M. Stringer was with the Department of Human Nutritional Sciences, University of Manitoba, and the Canadian Centre for Agri-Food Research in Health and Medicine, St. Boniface Hospital Research Centre, Winnipeg, MB, Canada at the time of manuscript preparation. C.G. Taylor is with the Department of Human Nutritional Sciences, University of Manitoba; the Department of Physiology, University of Manitoba; and the Canadian Centre for Agri-Food Research in Health and Medicine, St. Boniface Hospital Research Centre, Winnipeg, Manitoba, Canada. P. Zahradka is with the Department of Human Nutritional Sciences, University of Manitoba; the Department of Physiology, University of Manitoba; and the Canadian Centre for Agri-Food Research in Health and Medicine, St. Boniface Hospital Research Centre, Winnipeg, Manitoba, Canada
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Abstract
The heart is adapted to utilize all classes of substrates to meet the high-energy demand, and it tightly regulates its substrate utilization in response to environmental changes. Although fatty acids are known as the predominant fuel for the adult heart at resting stage, the heart switches its substrate preference toward glucose during stress conditions such as ischemia and pathological hypertrophy. Notably, increasing evidence suggests that the loss of metabolic flexibility associated with increased reliance on glucose utilization contribute to the development of cardiac dysfunction. The changes in glucose metabolism in hypertrophied hearts include altered glucose transport and increased glycolysis. Despite the role of glucose as an energy source, changes in other nonenergy producing pathways related to glucose metabolism, such as hexosamine biosynthetic pathway and pentose phosphate pathway, are also observed in the diseased hearts. This article summarizes the current knowledge regarding the regulation of glucose transporter expression and translocation in the heart during physiological and pathological conditions. It also discusses the signaling mechanisms governing glucose uptake in cardiomyocytes, as well as the changes of cardiac glucose metabolism under disease conditions.
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Affiliation(s)
- Dan Shao
- Mitochondria and Metabolism Center, University of Washington, Seattle, Washington, USA
| | - Rong Tian
- Mitochondria and Metabolism Center, University of Washington, Seattle, Washington, USA
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Cabezas-Cruz A, Valdés JJ, Lancelot J, Pierce RJ. Fast evolutionary rates associated with functional loss in class I glucose transporters of Schistosoma mansoni. BMC Genomics 2015; 16:980. [PMID: 26584526 PMCID: PMC4653847 DOI: 10.1186/s12864-015-2144-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2015] [Accepted: 10/26/2015] [Indexed: 11/24/2022] Open
Abstract
Background The trematode parasite, Schistosoma mansoni, has evolved to switch from oxidative phosphorylation to glycolysis in the presence of glucose immediately after invading the human host. This metabolic switch is dependent on extracellular glucose concentration. Four glucose transporters are encoded in the genome of S. mansoni, however, only two were shown to facilitate glucose diffusion. Results By modeling the phase of human host infection, we showed that transporter transcript expression profiles of recently transformed schistosomula have two opposing responses to increased glucose concentrations. Concurring with the transcription profiles, our phylogenetic analyses revealed that S. mansoni glucose transporters belong to two separate clusters, one associated with class I glucose transporters from vertebrates and insects, and the other specific to parasitic Platyhelminthes. To study the evolutionary paths of both groups and their functional implications, we determined evolutionary rates, relative divergence times, genomic organization and performed structural analyses with the protein sequences. We finally used the modelled structures of the S. mansoni glucose transporters to biophysically (i) analyze the dynamics of key residues during glucose binding, (ii) test glucose stability within the active site, and (iii) demonstrate glucose diffusion. The two S. mansoni Platyhelminthes-specific glucose transporters, which seem to be younger than the other two, exhibit slower rates of molecular evolution, are encoded by intron-poor genes, and transport glucose. Interestingly, our molecular dynamic analyses suggest that S. mansoni class I glucose transporters are not able to transport glucose. Conclusions The glucose transporter family in S. mansoni exhibit different evolutionary histories. Our results suggested that S. mansoni class I glucose transporters lost their capacity to transport glucose and that this function evolved independently in the Platyhelminthes-specific glucose transporters. Finally, taking into account the differences in the dynamics of glucose transport of the Platyhelminthes-specific transporters of S. mansoni compared to that of humans, we conclude that S. mansoni glucose transporters may be targets for rationally designed drugs against schistosomiasis. Electronic supplementary material The online version of this article (doi:10.1186/s12864-015-2144-6) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Alejandro Cabezas-Cruz
- Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019 - UMR 8204 - CIIL - Centre d'Infection et d'Immunité de Lille, F-59000, Lille, France.
| | - James J Valdés
- Institute of Parasitology, Biology Centre of the Academy of Sciences of the Czech Republic, 37005, České Budějovice, Czech Republic.
| | - Julien Lancelot
- Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019 - UMR 8204 - CIIL - Centre d'Infection et d'Immunité de Lille, F-59000, Lille, France.
| | - Raymond J Pierce
- Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019 - UMR 8204 - CIIL - Centre d'Infection et d'Immunité de Lille, F-59000, Lille, France.
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Berlth F, Mönig S, Pinther B, Grimminger P, Maus M, Schlösser H, Plum P, Warnecke-Eberz U, Harismendy O, Drebber U, Bollschweiler E, Hölscher A, Alakus H. Both GLUT-1 and GLUT-14 are Independent Prognostic Factors in Gastric Adenocarcinoma. Ann Surg Oncol 2015; 22 Suppl 3:S822-31. [PMID: 26183839 DOI: 10.1245/s10434-015-4730-x] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2015] [Indexed: 01/14/2023]
Abstract
BACKGROUND The role of glucose transporter 14 (GLUT-14/SLC2A14) in tumor biology is entirely unknown, and the significance of hypoxia inducible factor 1-alpha (HIF1-α) for gastric adenocarcinoma is controversial. The impact of GLUT-1/SLC2A1 has never been confirmed in a Caucasian cohort. METHODS Between 1996 and 2007, 124 patients underwent gastrectomy for gastric adenocarcinoma. Tumor sections were incubated with GLUT-1, GLUT-14, and HIF1-α antibodies. Expression was analyzed for correlations with histopathology, marker coexpression, and patient survival by uni- and multivariate analyses. RESULTS Expressions of GLUT-1, GLUT-14, and HIF1-α were detectable in 50, 77.4, and 27.1 %, respectively. Expression of GLUT-1 was associated with pT-category (p = 0.019), pN-category (p = 0.019), tubular (WHO, p = 0.008), and intestinal (Lauren classification; p = 0.002) histologic subtypes. Expression of GLUT-14 was correlated with pT category (p = 0.043), whereas HIF1-α did not show any correlation with histopathology or survival. The median survival period was 14 months (95 % confidence interval [CI] 9.2-18.8 months) for GLUT-1-positive patients and 55 months (95 % CI 25.8-84.2; p = 0.01) for GLUT-1-negative patients. An inferior prognosis also was seen for GLUT-14-positive cases compared with GLUT-14-negative cases (p = 0.004). Thus, worst survival was seen with both GLUT-1- and GLUT-14-positive expression followed by single-positive and then double-negative cases (p = 0.004). In multivariate analysis including International Union Against Cancer (UICC) stages, R category, Lauren classification, surgery alone versus neoadjuvant/perioperative chemotherapy, and marker expression as covariates, GLUT-1 (p = 0.011) and GLUT-14 (p = 0.025) kept their prognostic independence. CONCLUSIONS The study findings suggest that detection of GLUT-1 and GLUT-14 is of high prognostic value. It gives additional information to UICC stages and identifies patients with inferior prognosis. If confirmed in prospective studies, these markers need to be considered for future classification systems.
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Affiliation(s)
- Felix Berlth
- Department of General, Visceral and Cancer Surgery, University of Cologne, Cologne, Germany
| | - Stefan Mönig
- Department of General, Visceral and Cancer Surgery, University of Cologne, Cologne, Germany
| | - Berit Pinther
- Department of General, Visceral and Cancer Surgery, University of Cologne, Cologne, Germany
| | - Peter Grimminger
- Department of General, Visceral and Cancer Surgery, University of Cologne, Cologne, Germany.,Department of General, Abdominal and Transplant Surgery, University of Mainz, Mainz, Germany
| | - Martin Maus
- Department of General, Visceral and Cancer Surgery, University of Cologne, Cologne, Germany
| | - Hans Schlösser
- Department of General, Visceral and Cancer Surgery, University of Cologne, Cologne, Germany
| | - Patrick Plum
- Department of General, Visceral and Cancer Surgery, University of Cologne, Cologne, Germany
| | - Ute Warnecke-Eberz
- Department of General, Visceral and Cancer Surgery, University of Cologne, Cologne, Germany
| | - Olivier Harismendy
- Division of Biomedical Informatics and Moores Cancer Center, University of California San Diego, La Jolla, USA
| | - Uta Drebber
- Department of Pathology, University of Cologne, Cologne, Germany
| | - Elfriede Bollschweiler
- Department of General, Visceral and Cancer Surgery, University of Cologne, Cologne, Germany
| | - Arnulf Hölscher
- Department of General, Visceral and Cancer Surgery, University of Cologne, Cologne, Germany
| | - Hakan Alakus
- Department of General, Visceral and Cancer Surgery, University of Cologne, Cologne, Germany.
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Silva Filho TJD, Oliveira DHIPD, Moura IDS, Medeiros LKDS, Gonzaga AKG, Brasil VLM, Queiroz LMG. Importance of GLUT1 in differential diagnosis of vascular anomalies. J Vasc Bras 2015. [DOI: 10.1590/1677-5449.0069] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Vascular anomalies (VAs) include a group of distinct lesions, such as vascular system congenital malformations, as well as benign and malignant vascular tumors. These lesions may present similar clinical and histopathological features, leading to mistaken diagnoses and incorrect treatment choices. It is important that professionals responsible for monitoring the development of VAs conduct precise investigations and use the appropriate terminology. The human glucose transporter protein isoform 1 (GLUT1) has been proposed as a tool to aid in differential diagnosis between different VAs, given that it is a sensitive and specific marker for identification of infantile hemangiomas (HIs) in any organ. This article presents a review of the literature on this protein as an effective tool for identification and possible differential diagnosis between several VAs.
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46
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Mlynarski E, Sheridan M, Xie M, Guo T, Racedo S, McDonald-McGinn D, Gai X, Chow E, Vorstman J, Swillen A, Devriendt K, Breckpot J, Digilio M, Marino B, Dallapiccola B, Philip N, Simon T, Roberts A, Piotrowicz M, Bearden C, Eliez S, Gothelf D, Coleman K, Kates W, Devoto M, Zackai E, Heine-Suñer D, Shaikh T, Bassett A, Goldmuntz E, Morrow B, Emanuel B. Copy-Number Variation of the Glucose Transporter Gene SLC2A3 and Congenital Heart Defects in the 22q11.2 Deletion Syndrome. Am J Hum Genet 2015; 96:753-64. [PMID: 25892112 DOI: 10.1016/j.ajhg.2015.03.007] [Citation(s) in RCA: 56] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2014] [Accepted: 03/11/2015] [Indexed: 12/13/2022] Open
Abstract
The 22q11.2 deletion syndrome (22q11DS; velocardiofacial/DiGeorge syndrome; VCFS/DGS) is the most common microdeletion syndrome and the phenotypic presentation is highly variable. Approximately 65% of individuals with 22q11DS have a congenital heart defect (CHD), mostly of the conotruncal type, and/or an aortic arch defect. The etiology of this phenotypic variability is not currently known. We hypothesized that copy-number variants (CNVs) outside the 22q11.2 deleted region might increase the risk of being born with a CHD in this sensitized population. Genotyping with Affymetrix SNP Array 6.0 was performed on two groups of subjects with 22q11DS separated by time of ascertainment and processing. CNV analysis was completed on a total of 949 subjects (cohort 1, n = 562; cohort 2, n = 387), 603 with CHDs (cohort 1, n = 363; cohort 2, n = 240) and 346 with normal cardiac anatomy (cohort 1, n = 199; cohort 2, n = 147). Our analysis revealed that a duplication of SLC2A3 was the most frequent CNV identified in the first cohort. It was present in 18 subjects with CHDs and 1 subject without (p = 3.12 × 10(-3), two-tailed Fisher's exact test). In the second cohort, the SLC2A3 duplication was also significantly enriched in subjects with CHDs (p = 3.30 × 10(-2), two-tailed Fisher's exact test). The SLC2A3 duplication was the most frequent CNV detected and the only significant finding in our combined analysis (p = 2.68 × 10(-4), two-tailed Fisher's exact test), indicating that the SLC2A3 duplication might serve as a genetic modifier of CHDs and/or aortic arch anomalies in individuals with 22q11DS.
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Dias TR, Alves MG, Silva BM, Oliveira PF. Sperm glucose transport and metabolism in diabetic individuals. Mol Cell Endocrinol 2014; 396:37-45. [PMID: 25128846 DOI: 10.1016/j.mce.2014.08.005] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2014] [Revised: 08/07/2014] [Accepted: 08/07/2014] [Indexed: 12/31/2022]
Abstract
Individuals with diabetes mellitus (DM) present marked reduction in sperm quality and higher DNA damage in spermatozoa, evidencing that this metabolic disorder impairs male fertility. These effects are related to defective testicular metabolic pathways and signaling, resulting in altered sperm metabolism. Spermatozoa metabolize several substrates to ensure energy supplies and any alteration in this feature compromise sperm quality. For ATP production, spermatozoa require substrate availability and the involvement of specific hexose membrane carriers. DM is known to modulate the spermatozoa substrate consumption and/or production due to altered glycolytic behavior. In fact, glucose uptake and metabolism is highly deregulated in diabetic individuals. Herein, we present an overview of the implications of DM in sperm glucose uptake and metabolism. The understanding of these processes is essential to identify key mechanisms associated with DM-related male (in)fertility. Moreover, it may contribute to the development of therapeutics to counteract the dysfunction induced by DM in sperm metabolism.
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Affiliation(s)
- Tânia R Dias
- CICS - UBI - Health Sciences Research Centre, University of Beira Interior, 6201-506 Covilhã, Portugal
| | - Marco G Alves
- CICS - UBI - Health Sciences Research Centre, University of Beira Interior, 6201-506 Covilhã, Portugal
| | - Branca M Silva
- CICS - UBI - Health Sciences Research Centre, University of Beira Interior, 6201-506 Covilhã, Portugal
| | - Pedro F Oliveira
- CICS - UBI - Health Sciences Research Centre, University of Beira Interior, 6201-506 Covilhã, Portugal; Department of Microscopy, Laboratory of Cell Biology, Institute of Biomedical Sciences Abel Salazar (ICBAS) and Unit for Multidisciplinary Research in Biomedicine (UMIB), University of Porto, Portugal.
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Qian Y, Wang X, Chen X. Inhibitors of glucose transport and glycolysis as novel anticancer therapeutics. World J Transl Med 2014; 3:37-57. [DOI: 10.5528/wjtm.v3.i2.37] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2014] [Revised: 03/25/2014] [Accepted: 05/29/2014] [Indexed: 02/06/2023] Open
Abstract
Metabolic reprogramming and altered energetics have become an emerging hallmark of cancer and an active area of basic, translational, and clinical cancer research in the recent decade. Development of effective anticancer therapeutics may depend on improved understanding of the altered cancer metabolism compared to that of normal cells. Changes in glucose transport and glycolysis, which are drastically upregulated in most cancers and termed the Warburg effect, are one of major focuses of this new research area. By taking advantage of the new knowledge and understanding of cancer’s mechanisms, numerous therapeutic agents have been developed to target proteins and enzymes involved in glucose transport and metabolism, with promising results in cancer cells, animal tumor models and even clinical trials. It has also been hypothesized that targeting a pathway or a process, such as glucose transport or glucose metabolism, rather than a specific protein or enzyme in a signaling pathway may be more effective. This is based on the observation that cancer somehow can always bypass the inhibition of a target drug by switching to a redundant or compensatory pathway. In addition, cancer cells have higher dependence on glucose. This review will provide background information on glucose transport and metabolism in cancer, and summarize new therapeutic developments in basic and translational research in these areas, with a focus on glucose transporter inhibitors and glycolysis inhibitors. The daunting challenges facing both basic and clinical researchers of the field are also presented and discussed.
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Sahoo S, Aurich MK, Jonsson JJ, Thiele I. Membrane transporters in a human genome-scale metabolic knowledgebase and their implications for disease. Front Physiol 2014; 5:91. [PMID: 24653705 PMCID: PMC3949408 DOI: 10.3389/fphys.2014.00091] [Citation(s) in RCA: 64] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2013] [Accepted: 02/17/2014] [Indexed: 01/18/2023] Open
Abstract
Membrane transporters enable efficient cellular metabolism, aid in nutrient sensing, and have been associated with various diseases, such as obesity and cancer. Genome-scale metabolic network reconstructions capture genomic, physiological, and biochemical knowledge of a target organism, along with a detailed representation of the cellular metabolite transport mechanisms. Since the first reconstruction of human metabolism, Recon 1, published in 2007, progress has been made in the field of metabolite transport. Recently, we published an updated reconstruction, Recon 2, which significantly improved the metabolic coverage and functionality. Human metabolic reconstructions have been used to investigate the role of metabolism in disease and to predict biomarkers and drug targets. Given the importance of cellular transport systems in understanding human metabolism in health and disease, we analyzed the coverage of transport systems for various metabolite classes in Recon 2. We will review the current knowledge on transporters (i.e., their preferred substrates, transport mechanisms, metabolic relevance, and disease association for each metabolite class). We will assess missing coverage and propose modifications and additions through a transport module that is functional when combined with Recon 2. This information will be valuable for further refinements. These data will also provide starting points for further experiments by highlighting areas of incomplete knowledge. This review represents the first comprehensive overview of the transporters involved in central metabolism and their transport mechanisms, thus serving as a compendium of metabolite transporters specific for human metabolic reconstructions.
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Affiliation(s)
- Swagatika Sahoo
- Center for Systems Biology, University of Iceland Reykjavik, Iceland ; Molecular Systems Physiology Group, Luxembourg Centre for Systems Biomedicine, University of Luxembourg Belval, Luxembourg
| | - Maike K Aurich
- Center for Systems Biology, University of Iceland Reykjavik, Iceland ; Molecular Systems Physiology Group, Luxembourg Centre for Systems Biomedicine, University of Luxembourg Belval, Luxembourg
| | - Jon J Jonsson
- Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Iceland Reykjavik, Iceland ; Department of Genetics and Molecular Medicine, Landspitali, National University Hospital of Iceland Reykjavik, Iceland
| | - Ines Thiele
- Center for Systems Biology, University of Iceland Reykjavik, Iceland ; Molecular Systems Physiology Group, Luxembourg Centre for Systems Biomedicine, University of Luxembourg Belval, Luxembourg
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Kim E, Seok HH, Lee SY, Lee DR, Moon J, Yoon TK, Lee WS, Lee KA. Correlation between Expression of Glucose Transporters in Granulosa Cells and Oocyte Quality in Women with Polycystic Ovary Syndrome. Endocrinol Metab (Seoul) 2014; 29:40-7. [PMID: 24741453 PMCID: PMC3970285 DOI: 10.3803/enm.2014.29.1.40] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2013] [Accepted: 10/11/2013] [Indexed: 11/22/2022] Open
Abstract
BACKGROUND The glucose transporters (GLUTs) exhibit different tissue-specific expression. This study aimed to investigate the types of GLUTs expressed in human granulosa cells (GCs) obtained from women with polycystic ovary syndrome (PCOS) and their relationship with insulin resistance (IR) and the outcomes of in vitro maturation (IVM) of immature oocytes. METHODS Expression of GLUTs was evaluated in GCs from women with PCOS with or without IR. Thirty-six women with PCOS undergoing an IVM program were included. Differential gene expression between the insulin sensitive (IS) and IR group was measured by reverse transcription polymerase chain reaction. RESULTS Expression of GLUTs 1, 3, 5, 8, and 13 was constitutive, whereas expression of GLUTs 2 and 7 was not observed in human GCs. The remaining GLUTs, 4, 6, 9, 10, 11, and 12, were differentially expressed among patients according to metabolic status, such as insulin sensitivity. A higher number of GCs from patients with IR (92%) expressed GLUT6 than GCs from IS PCOS patients (46.3%). Logistic regression showed that expression of GLUTs 9, 11, and 12 correlates with rates of IVM at 48 hours, fertilization, and implantation, respectively. CONCLUSION This is the first report describing the expression pattern of all 13 members of the GLUT family in human GCs. Results of the present study suggest that patients' insulin sensitivity regulates GLUT expression in GCs in PCOS patients, and this may control oocyte quality for IVM and subsequent processes such as fertilization and implantation in patients taking part in an in vitro fertilization program.
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Affiliation(s)
- Eunju Kim
- Department of Biomedical Science, CHA University, Seoul, Korea
| | - Hyun Ha Seok
- Fertility Center, CHA Gangnam Medical Center, CHA University, Seoul, Korea
| | - Su-Yeon Lee
- Department of Biomedical Science, CHA University, Seoul, Korea
| | - Dong Ryul Lee
- Department of Biomedical Science, CHA University, Seoul, Korea
- Fertility Center, CHA Gangnam Medical Center, CHA University, Seoul, Korea
| | - Jisook Moon
- Department of Applied Bioscience, CHA University, Seoul, Korea
| | - Tae Ki Yoon
- Fertility Center, CHA Gangnam Medical Center, CHA University, Seoul, Korea
| | - Woo Sik Lee
- Fertility Center, CHA Gangnam Medical Center, CHA University, Seoul, Korea
| | - Kyung-Ah Lee
- Department of Biomedical Science, CHA University, Seoul, Korea
- Fertility Center, CHA Gangnam Medical Center, CHA University, Seoul, Korea
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