Alternative titles; symbols
HGNC Approved Gene Symbol: SLC2A4
Cytogenetic location: 17p13.1 Genomic coordinates (GRCh38): 17:7,281,718-7,288,257 (from NCBI)
Facilitated glucose transport by mammalian cells is not a property of a single protein but an activity associated with a family of structurally related proteins. From rat skeletal muscle, Birnbaum (1989) cloned a gene encoding an insulin-responsive glucose transporter protein. Bell et al. (1990) isolated and completely characterized the human GLUT4 gene.
Garvey et al. (1998) concluded that insulin (176730) alters the subcellular localization of GLUT4 vesicles in human muscle, and that this effect is impaired equally in insulin-resistant subjects with and without diabetes (see 125853). The translocation defect was associated with abnormal accumulation of GLUT4 in a dense membrane compartment demonstrable in basal muscle. They had previously observed a similar pattern of defects causing insulin resistance in human adipocytes. They proposed that human insulin resistance involves a defect in GLUT4 traffic and targeting leading to accumulation in a dense membrane compartment from which insulin is unable to recruit GLUT4 to the cell surface.
The stimulation of glucose uptake by insulin in muscle and adipose tissue requires translocation of the GLUT4 glucose transporter from intracellular storage sites to the cell surface. Activation of phosphatidylinositol-3-OH kinase (PI3K; see 601232) is required for this trafficking event, but it is not sufficient to produce GLUT4 translocation. Ribon et al. (1998) and Baumann et al. (2000) described a pathway involving the insulin-stimulated tyrosine phosphorylation of CBL (165360), which is recruited to the insulin receptor (147670) by the adaptor protein CAP (605264). On phosphorylation, CBL is translocated to lipid rafts. Blocking this step completely inhibits the stimulation of GLUT4 translocation by insulin. Chiang et al. (2001) showed that phosphorylated CBL recruits the CRK2-C3G (164762, 600303) complex to lipid rafts, where C3G specifically activates the small GTP-binding protein TC10 (605857). This process is independent of PI3K, but requires the translocation of CBL, CRK, and C3G to the lipid raft. The activation of TC10 is essential for insulin-stimulated glucose uptake and GLUT4 translocation. The TC10 pathway functions in parallel with PI3K to stimulate fully GLUT4 translocation in response to insulin.
Insulin stimulates glucose uptake in muscle and adipocytes by signaling the translocation of GLUT4 glucose transporters from intracellular membranes to the cell surface. The translocation of GLUT4 may involve signaling pathways that are both independent of and dependent on PI3K. This translocation also requires the actin cytoskeleton, and the rapid movement of GLUT4 along linear tracks may be mediated by molecular motors. Bose et al. (2002) reported that the unconventional myosin MYO1C (606538) is present in GLUT4-containing vesicles purified from 3T3-L1 adipocytes. MYO1C, which contains a motor domain, 3 IQ motifs, and a carboxy-terminal cargo domain, is highly expressed in primary and cultured adipocytes. Insulin enhances the localization of MYO1C with GLUT4 in cortical tubulovesicular structures associated with actin filaments, and this colocalization is insensitive to wortmannin. Insulin-stimulated translocation of GLUT4 to the adipocyte plasma membrane is augmented by the expression of wildtype MYO1C and inhibited by a dominant-negative cargo domain of MYO1C. A decrease in the expression of endogenous MYO1C mediated by small interfering RNAs inhibited insulin-stimulated uptake of 2-deoxyglucose. Thus, Bose et al. (2002) concluded that MYO1C functions in a PI3K-independent insulin signaling pathway that controls the movement of intracellular GLUT4-containing vesicles to the plasma membrane.
Inoue et al. (2003) showed that TC10 (605857) interacts with EXO70, a component of the exocyst complex. They found that EXO70 translocates to the plasma membrane in response to insulin through the activation of TC10, where it assembles as a multiprotein complex that includes SEC8 (608185) and SEC6 (608186). Overexpression of an EXO70 mutant blocked insulin-stimulated glucose uptake, but not the trafficking of GLUT4 to the plasma membrane. This mutant did, however, block the extracellular exposure of the GLUT4 protein. Inoue et al. (2003) concluded that the exocyst might have a crucial role in targeting the GLUT4 vesicle to the plasma membrane, perhaps directing the vesicle to the precise site of fusion.
In the absence of insulin (176730), GLUT4 is sequestered intracellularly and is redistributed to the plasma membrane within minutes of insulin stimulation. Bogan et al. (2003) described a functional screen to identify proteins that modulate GLUT4 distribution, and identified TUG (606236) as a putative tether, containing a UBX domain, for GLUT4. In truncated form, TUG acts in a dominant-negative manner to inhibit insulin-stimulated GLUT4 redistribution in Chinese hamster ovary cells and 3T3-L1 adipocytes. Full-length TUG forms a complex specifically with GLUT4; in 3T3-L1 adipocytes, this complex is present in unstimulated cells and is largely disassembled by insulin. Endogenous TUG is localized with the insulin-mobilizable pool of GLUT4 in unstimulated 3T3-L1 adipocytes, and is not mobilized to the plasma membrane by insulin. Distinct regions of TUG are required to bind GLUT4 and to retain GLUT4 intracellularly in transfected, nonadipose cells. Bogan et al. (2003) concluded that TUG traps endocytosed GLUT4 and tethers it intracellularly, and that insulin mobilizes this pool of retained GLUT4 by releasing this tether.
Oshel et al. (2000) identified a region in the 5-prime UTR of GLUT4, designated domain I, that was required for full GLUT4 promoter function. By yeast 1-hybrid analysis, DNase footprint analysis, and electrophoretic mobility shift assays, they demonstrated that GEF (SLC2A4RG; 609493) specifically bound domain I of the GLUT4 promoter. GEF cooperated with MEF2 (see MEF2A; 600660), which has its own binding site, to regulate GLUT4 expression in transgenic animals.
By assaying reporter gene activity in transfected COS-7 cells, Knight et al. (2003) found that GEF, MEF2A, and MEF2D (600663) had weak activity individually in transactivating the GLUT4 promoter, but cotransfection of GEF and MEF2A showed significantly greater activity. Cotransfection of GEF and MEF2D or MEF2C (600662) did not increase GLUT4 promoter function. Coimmunoprecipitation assays indicated that GEF bound both MEF2A and MEF2D in vitro, and MEF2D interfered with the transcriptional activation promoted by the cooperative interaction of MEF2A and GEF.
Intracellular trafficking of the glucose transporter GLUT4 from storage compartments to the plasma membrane is triggered in muscle and fat during the body's response to insulin. Clathrin is involved in intracellular trafficking, and in humans, the clathrin heavy-chain isoform CHC22 (601273) is highly expressed in skeletal muscle. Vassilopoulos et al. (2009) found a role for CHC22 in the formation of insulin-responsive GLUT4 compartments in human muscle and adipocytes. CHC22 also associated with expanded GLUT4 compartments in muscle from type 2 diabetic patients. Tissue-specific introduction of CHC22 in mice, which have only a pseudogene for this protein, caused aberrant localization of GLUT4 transport pathway components in their muscle, as well as features of diabetes. Thus, Vassilopoulos et al. (2009) concluded that CHC22-dependent membrane trafficking constitutes a species-restricted pathway in human muscle and fat with potential implications for type 2 diabetes.
Herman et al. (2012) reported that adipose tissue GLUT4 regulates the expression of carbohydrate-responsive element-binding protein (CHREBP, also known as MLXIPL; 605678), a transcriptional regulator of lipogenic and glycolytic genes. Furthermore, adipose CHREBP is a major determinant of adipose tissue fatty acid synthesis and systemic insulin sensitivity. Herman et al. (2012) found a new mechanism for glucose regulation of CHREBP: glucose-mediated activation of the canonical CHREBP isoform (CHREBP-alpha) induces expression of a novel, potent isoform (CHREBP-beta) that is transcribed from an alternative promoter. CHREBP-beta expression in human adipose tissue predicts insulin sensitivity.
Using mouse 3T3-L1 cells, Davey et al. (2012) found that Tbc1d13 (616218) inhibited insulin-stimulated Glut4 translocation to the plasma membrane by acting as a GTPase-activating protein for Rab35 (604199).
Using DNA array analyses, Kraus et al. (2014) compared gene expression in white adipose tissue from adipose-specific Glut4 knockout or adipose-specific Glut4-overexpressing mice with their respective controls. They found that NNMT (600008), encoding nicotinamide N-methyltransferase, was the most strongly reciprocally regulated gene. NNMT methylates nicotinamide using S-adenosylmethionine (SAM) as a methyl donor. Nicotinamide is a precursor of NAD+, an important cofactor linking cellular redox states with energy metabolism. SAM provides propylamine for polyamine biosynthesis and donates a methyl group for histone methylation. Polyamine flux, including synthesis, catabolism, and excretion, is controlled by the rate-limiting enzymes ornithine decarboxylase (ODC; 165640) and spermidine-spermine N(1)-acetyltransferase (SSAT1; 313020) and by polyamine oxidase (PAOX; 615853), and has a major role in energy metabolism. Kraus et al. (2014) reported that Nnmt expression is increased in white adipose tissue and liver of obese and diabetic mice. Nnmt knockdown in white adipose tissue and liver protects against diet-induced obesity by augmenting cellular energy expenditure. NNMT inhibition increases adipose SAM and NAD+ levels and upregulates ODC and SSAT1 activity as well as expression, owing to the effects of NNMT on histone H3 lysine-4 methylation in adipose tissue. Direct evidence for increased polyamine flux resulting from NNMT inhibition includes elevated urinary excretion and adipocyte secretion of diacetylspermine, a product of polyamine metabolism. NNMT inhibition in adipocytes increases oxygen consumption in an ODC-, SSAT1-, and PAOX-dependent manner. Thus, Kraus et al. (2014) concluded that NNMT is a novel regulator of histone methylation, polyamine flux, and NAD(+)-dependent SIRT1 (604479) signaling, and is a unique and attractive target for treating obesity and type 2 diabetes.
Increased adipose tissue lipogenesis is associated with enhanced insulin sensitivity. Yore et al. (2014) observed that mice overexpressing the Glut4 glucose transporter in adipocytes had elevated lipogenesis and increased glucose tolerance, despite being obese with elevated circulating fatty acids. Lipidomic analysis of adipose tissue revealed the existence of branched fatty acid esters of hydroxy fatty acids (FAHFAs) that were elevated 16- to 18-fold in these mice. FAHFA isomers differ by the branched ester position on the hydroxy fatty acid (e.g., palmitic-acid-9-hydroxy-stearic-acid, 9-PAHSA). PAHSAs are synthesized in vivo and regulated by fasting and high-fat feeding. PAHSA levels correlate highly with insulin sensitivity and are reduced in adipose tissue and serum of insulin-resistant humans. PAHSA administration in mice lowered ambient glycemia and improved glucose tolerance while stimulating GLP1 (see GCG, 138030) and insulin secretion. PAHSAs also reduced adipose tissue inflammation. In adipocytes, PAHSAs signal through GPR120 (609044) to enhance insulin-stimulated glucose uptake. Yore et al. (2014) thus concluded that FAHFAs are endogenous lipids with the potential to treat type 2 diabetes.
Sun et al. (2016) found that overexpression of Elmo2 (606421) in mouse adipocytes and rat skeletal muscle cells enhanced insulin-dependent Glut4 membrane translocation. In contrast, knockdown of Elmo2 suppressed Glut4 translocation. Elmo2 was required for insulin-induced Rac1 (602048) GTP loading and Akt (AKT1; 164730) membrane association, but not Akt activation, in rat skeletal muscle cells. Sun et al. (2016) concluded that ELMO2 regulates insulin-dependent GLUT4 membrane translocation by modulating RAC1 activity and AKT membrane compartmentalization.
Bell et al. (1990) determined that the GLUT4 gene spans 8,000 bp and contains 11 exons.
By hybridization of cDNA probes to a panel of somatic cell hybrids and by in situ hybridization, Fan et al. (1989) showed that the insulin-responsive glucose transporter gene maps to 17p13.
The description of cDNA clones encoding GLUT4 and a KpnI RFLP associated with this locus were reported by Bell et al. (1989). Muraoka et al. (1991) identified a polymorphic marker in exon 4a of GLUT4 in Japanese. Unlike GLUT1 (138140), GLUT4 polymorphic markers showed no association
Possible Association with Noninsulin-Dependent Diabetes Mellitus
In a patient with noninsulin-dependent diabetes mellitus (NIDDM; 125853), Kusari et al. (1991) identified a val383-to-ile mutation (V383I; 138190.0001) caused by a GTC-to-ATC substitution in the GLUT4 gene.
Baroni et al. (1992) found no association between GLUT4 polymorphic markers and NIDDM in the Italian population.
Buse et al. (1992) screened a large and racially diverse group of diabetic individuals and controls for the V383I variant and found no statistically significant difference in the frequency of the I383 allele among individuals classified by racial group or disease status. Buse et al. (1992) concluded that V383I is not associated with diabetes.
Ikemoto et al. (1995) found that transgenic mice harboring the entire GLUT4 gene, as well as 7 kb of 5-flanking and 1 kb of 3-flanking sequence, expressed 2 or more times the normal level of GLUT4 mRNA and protein in skeletal muscle and adipose tissue. This modest tissue-specific increase in GLUT4 expression led to an unexpectedly rapid blood glucose clearance rate following oral glucose administration. In nontransgenic animals, exercise caused a 1.5-fold increase in expression of GLUT4 mRNA and protein, as well as a significant improvement of glycemic control. In transgenic animals harboring the minigene, exercise increased expression of GLUT4 mRNA and protein derived from the transgene and endogenous gene and led to a further improvement of glycemic control. The findings were interpreted as indicating that GLUT4 plays a pivotal role in glucose homeostasis in vivo.
Katz et al. (1995) disrupted the Glut4 gene in 'knockout' mice and found that, surprisingly, the Glut4-null mice had nearly normal glycemia but that Glut4 was absolutely essential for sustained growth, normal cellular glucose and fat metabolism, and expected longevity. They observed increased expression of other glucose transporters in the liver (Glut2) and heart (Glut1) but not in skeletal muscle. Insulin tolerance tests indicated that these mice were less sensitive to insulin action.
Stenbit et al. (1997) disrupted the mouse Glut4 gene by homologous recombination and studied the results in male mice. Unexpectedly, Glut4-null mice were not diabetic, although they did have decreased insulin sensitivity, as measured by an insulin tolerance test, and developed many other abnormalities, including growth retardation, severely reduced adipose tissue, hypertrophic hearts, and a shortened life span. In contrast, mice heterozygous for the Glut4 disruption did not become obese but exhibited hyperinsulinemia and eventually hyperglycemia, with reduced muscle glucose uptake, hypertension, and diabetic histopathology in heart and liver that resembled the phenotype of humans with noninsulin-dependent diabetes mellitus (NIDDM; 125853), including hepatic micro- and macrosteatosis and hypertrophic myocardiocytes. Stenbit et al. (1997) concluded that Glut4 +/- male mice represent a good model for studying the development of NIDDM without the complications associated with obesity.
Glucose enters the heart via GLUT1 and GLUT4 glucose transporters. GLUT4-deficient mice develop striking cardiac hypertrophy and die prematurely, but it was unclear whether their cardiac changes were caused primarily by GLUT4 deficiency in cardiomyocytes or by metabolic changes resulting from the absence of GLUT4 in skeletal muscle and adipose tissue. To determine the role of GLUT4 in the heart, Abel et al. (1999) used Cre-loxP recombination to generate mice in which GLUT4 expression was abolished in the heart but present in skeletal muscle and adipose tissue. Life span and serum concentrations of insulin, glucose, free fatty acids, lactate, and beta-hydroxybutyrate were normal. Basal cardiac glucose transport and GLUT1 expression were both increased approximately 3-fold in homozygous deficient mice, but insulin-stimulated glucose uptake was abolished. Homozygous deficient mice developed modest cardiac hypertrophy associated with increased myocyte size and induction of atrial natriuretic and brain natriuretic peptide gene expression in the ventricles. Myocardial fibrosis did not occur. Basal and isoproterenol-stimulated isovolumic contractile performance was preserved. Thus, selective ablation of GLUT4 in the heart initiated a series of events that resulted in compensated cardiac hypertrophy.
To determine the role of adipose GLUT4 in glucose homeostasis, Abel et al. (2001) used Cre/loxP DNA recombination to generate mice with adipose-selective reduction of GLUT4 (G4A -/-). G4A -/- mice had normal growth and adipose mass despite markedly impaired insulin-stimulated glucose uptake in adipocytes. Although GLUT4 expression is preserved in muscle, these mice developed insulin resistance in muscle and liver, manifested by decreased biologic responses and impaired activation of phosphatidylinositol-3-OH kinase (PI3K; see 601232). G4A -/- mice developed glucose intolerance and hyperinsulinemia. Thus, downregulation of GLUT4 and glucose transport selectively in adipose tissue can cause insulin resistance and thereby increase the risk of developing diabetes. In G4A -/- mice, mean plasma leptin levels were normal and plasma leptin concentrations showed the same linear relationship with body weight in G4A -/- mice as in control littermates. Thus, normal glucose uptake in adipocytes is not necessary to maintain normal plasma leptin levels. Elevated TNF-alpha (191160) was noted in G4A -/- mice.
Zisman et al. (2000) generated mice with selective disruption of GLUT4 in muscle. A profound reduction in basal glucose transport and near-absence of stimulation by insulin or contraction resulted. The mice showed severe insulin resistance and glucose intolerance from an early age. Thus, GLUT4-mediated glucose transport in muscle is essential to the maintenance of normal glucose homeostasis.
Kim et al. (2001) found that Glut4 knockout mice had a 92% decrease in insulin-stimulated glucose uptake in skeletal muscle as well as a decrease in insulin-induced glucose uptake in adipose tissue compared to controls. Hepatic glucose production was also decreased in the mutant mice. Whole body glucose uptake was decreased by 55%, indicating severe insulin resistance. The authors concluded that a primary defect in muscle glucose transport can lead to secondary defects in insulin action in adipose tissue and liver due to glucose toxicity; the secondary defects likely contribute to insulin resistance and the development of diabetes.
To clarify the physiologic function of STXBP3 (608339) in insulin-stimulated GLUT4 exocytosis, Kanda et al. (2005) generated mouse embryos deficient in the syntaxin-4 (see 186591)-binding protein Stxbp3 and developed Stxbp3 -/- adipocytes from their mesenchymal fibroblasts. The insulin-induced appearance of Glut4 at the cell surface was enhanced in Stxbp3 -/- adipocytes compared to +/+ cells. Wortmannin, an inhibitor of PI3K, inhibited insulin-stimulated Glut4 externalization in +/+ but not -/- adipocytes. Kanda et al. (2005) suggested that disruption of the interaction between syntaxin-4 and STXBP3 in adipocytes might result in enhancement of insulin-stimulated GLUT4 externalization.
This variant, formerly titled DIABETES MELLITUS, NONINSULIN-DEPENDENT (NIDDM; 125853), has been reclassified based on the findings of Buse et al. (1992) and Esposito et al. (1995).
Kusari et al. (1991) sequenced the entire coding region of the GLUT4 gene in 6 patients with noninsulin-dependent diabetes mellitus. One patient was heterozygous for a mutation in which isoleucine (ATC) was substituted for valine (GTC) at position 383. Subsequently, the GLUT4 sequence at position 383 was determined in 24 additional NIDDM patients and 30 nondiabetic controls and all showed only the normal sequence. The authors concluded that the great majority of patients with NIDDM do not have genetic variation in the coding sequence of GLUT4, but suggested that a subpopulation of patients may have variation in this gene.
Buse et al. (1992) screened a large and racially diverse group of diabetic individuals and controls for the V383I polymorphism and found that it was present in heterozygosity in 1 (0.7%) of 147 patients with insulin-dependent diabetes mellitus (IDDM; 222100), 2 (0.7%) of 268 patients with NIDDM, and 4 (1.5%) of 261 controls. There were no homozygotes. One of the NIDDM V383I carriers had a similarly affected sister, who did not carry the variant allele. Buse et al. (1992) concluded that the V383I variant is not associated with diabetes.
Esposito et al. (1995) screened a cohort of 68 Italian NIDDM patients and 65 controls for GLUT4 V383I and did not find the variant in any patients or controls. The authors concluded that the V383I variant is not involved in the development of NIDDM in the Italian population.
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