title: GLUT2 (SLC2A2) is not the principal glucose transporter in human pancreatic beta cells: implications for understanding genetic association signals at this locus.
abstract: SLC2A2 encoding glucose transporter -2 (GLUT2) acts as the primary glucose transporter and sensor in rodent pancreatic islets and is widely assumed to play a similar role in humans. In healthy adults SLC2A2 variants are associated with elevated fasting plasma glucose (fpg) concentrations but physiological characterisation does not support a defect in pancreatic beta-cell function. Interspecies differences can create barriers for the follow up of disease association signals. We hypothesised that GLUT2 is not the principal glucose transporter in human beta-cells and that SLC2A2 variants exert their effect on fpg levels through defects in other tissues. SLC2A1-4 (GLUT 1-4) mRNA expression levels were determined in human and mouse islets, beta-cells, liver, muscle and adipose tissue by qRT-PCR whilst GLUT1-3 protein levels were examined by immunohistochemistry. The presence of all three glucose transporters was demonstrated in human and mouse islets and purified beta-cells. Quantitative expression profiling demonstrated that Slc2a2 is the predominant glucose transporter (expression >10 fold higher that Slc2a1) in mouse islets whilst SLC2A1 and SLC2A3 predominate in both human islets and beta-cells (expression 2.8 and 2.7 fold higher than SLC2A2 respectively). Our data therefore suggest that GLUT2 is unlikely to be the principal glucose transporter in human beta-cells and that SLC2A2 defects in other metabolic tissues drive the observed differences in glucose levels between carriers of SLC2A2 variants. Direct extrapolation from rodent to human islet glucose transporter activity is unlikely to be appropriate.
authors.affiliation: Oxford Centre for Diabetes Endocrinology and Metabolism, University of Oxford, Oxford, UK.
authors.forename: Laura J
authors.initials: LJ
authors.lastname: McCulloch
authors.forename: Martijn
authors.initials: M
authors.lastname: van de Bunt
authors.forename: Matthias
authors.initials: M
authors.lastname: Braun
authors.forename: Keith N
authors.initials: KN
authors.lastname: Frayn
authors.forename: Anne
authors.initials: A
authors.lastname: Clark
authors.forename: Anna L
authors.initials: AL
authors.lastname: Gloyn
mesh_terms: D002001:Adipose Tissue, Brown / Q000378:metabolism; D000818:Animals; D015870:Gene Expression; D056426:Genetic Loci; D051272:Glucose Transporter Type 1 / Q000235:genetics / Q000378:metabolism*; D051273:Glucose Transporter Type 2 / Q000235:genetics / Q000378:metabolism*; D051274:Glucose Transporter Type 3 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D051379:Mice; D018482:Muscle, Skeletal / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D050151:Subcutaneous Fat / Q000378:metabolism
chemical_list: D051272:Glucose Transporter Type 1; D051273:Glucose Transporter Type 2; D051274:Glucose Transporter Type 3; D012333:RNA, Messenger; C495677:SLC2A1 protein, human; C495680:SLC2A2 protein, human; C495687:SLC2A3 protein, human