Disease relevance of SLC2A4

• Analysis of the gene sequences of the insulin receptor and the insulin-sensitive glucose transporter (GLUT-4) in patients with common-type non-insulin-dependent diabetes mellitus [1].
• SSCP analysis was used to screen patients with diabetes mellitus and normal, healthy nondiabetic individuals for mutations at the GLUT4 locus [2].
• We also investigated whether body weight influences GLUT4 expression in this syndrome [3].
• A role of lipin in human obesity and insulin resistance: relation to adipocyte glucose transport and GLUT4 expression [4].
• 57% of the breast cancer tissues showed positivity for Glut 1, 43% for Glut 4 [5].

Psychiatry related information on SLC2A4

• Taken together, the results suggest that feeding behavior influences GLUT4 gene expression pattern through changes in sympathetic activity, especially during long-term starvation periods [6].
• Based on the possible dependency of GLUT4 expression on volume, we hypothesize that the reduced GLUT4 expression in obesity and type 2 diabetes may partly be compensated for by physical activity [7].

High impact information on SLC2A4

• Because skeletal muscle is the main site of insulin-stimulated glucose uptake, the role of adipose tissue GLUT4 downregulation in the pathogenesis of insulin resistance and diabetes is unclear [8].
• The glucose transporter GLUT4 mediates insulin-stimulated glucose uptake in adipocytes and muscle by rapidly moving from intracellular storage sites to the plasma membrane [8].
• In insulin-resistant states such as obesity and type 2 diabetes, GLUT4 expression is decreased in adipose tissue but preserved in muscle [8].
• To determine the role of adipose GLUT4 in glucose homeostasis, we used Cre/loxP DNA recombination to generate mice with adipose-selective reduction of GLUT4 (G4A-/-) [8].
• Whereas heterozygous GLUT4 knockout mice show moderate glucose intolerance, homozygous whole-body GLUT4 knockout (GLUT4-null) mice have only mild perturbations in glucose homeostasis and have growth retardation, depletion of fat stores, cardiac hypertrophy and failure, and a shortened life span [9].

Chemical compound and disease context of SLC2A4

• We have recently examined the exons encoding the insulin receptor tyrosine kinase domain and GLUT 4 in 30 subjects with Type 2 (non-insulin-dependent) diabetes mellitus using a molecular scanning approach [10].
• GLUT-4 constructs containing NH2-terminal deletions or alanine substitutions within the NH2 terminus were expressed in CHO cells using a Sindbis virus expression system [11].
• We assessed the relative functional contribution of GLUT4 in experimental models of skeletal muscle and adipocytes using the HIV-1 protease inhibitor indinavir [12].
• In streptozocin-induced diabetes of the rat with normal fasting insulin levels and marked hyperglycemia, the number of cytochalasin B-binding sites and of GLUT4 proteins diminishes in the PM whereas the GLUT1 proteins increase to a new ratio of about 1.5:1 GLUT4:GLUT1 [13].
• The rates of glucose transport and of glycolysis and the expression of the glucose transporters GLUT-1 through GLUT-4 were measured in T47D human breast cancer cells that underwent differentiation by retinoic acid [14].
• In cirrhosis GLUT4 protein content was quantitatively intact, while limiting glucose tolerance [15].

Biological context of SLC2A4

• RESULTS: NR1HR agonists ameliorate TNFalpha-induced insulin resistance restoring completely insulin-stimulated glucose uptake and SLC2A4 translocation to plasma membrane [16].
• We have shown, by using transgenic mice, that the human GLUT4 promoter is regulated through the cooperative function of two distinct regulatory elements, domain 1 and the myocyte enhancer factor 2 (MEF2) domain [17].
• Here, we report that a cell-permeable phosphoinositide-binding peptide induced GLUT4 translocation to the plasma membrane without inhibiting IRAP (insulin-responsive aminopeptidase) endocytosis [18].
• Free fatty acids repress the GLUT4 gene expression in cardiac muscle via novel response elements [19].
• In type 2 diabetic adipocytes, the basal phosphorylation status of these MAP kinases was significantly elevated and was associated with decreased IRS-1 and GLUT4 in these fat cells [20].

Anatomical context of SLC2A4

• In muscle and fat cells, insulin stimulates the delivery of the glucose transporter GLUT4 from an intracellular location to the cell surface, where it facilitates the reduction of plasma glucose levels [21].
• Overexpression of GLUT4 in skeletal muscle enhances whole-body insulin action [22].
• Perhaps consistent with a less efficient insulin signaling, a twofold reduction in GLUT4, glycogen synthase, and leptin mRNA expression was observed in omental adipose tissue [23].
• Here, we report that an Eps15 homology (EH) domain-containing protein, EHD1, controls the normal perinuclear localization of GLUT4-containing membranes and is required for insulin-stimulated recycling of these membranes in cultured adipocytes [24].
• GLUT4 trafficking between endosomes and trans-Golgi network was regulated via an acidic targeting motif in the carboxy terminus of GLUT4, because a mutant lacking this motif was retained in endosomes [25].

Associations of SLC2A4 with chemical compounds

• This indicates that mitochondrial dysfunction decreases insulin-stimulated SLC2A4 translocation and glucose uptake [26].
• Sequence analysis of the GLUT-4 gene revealed that one patient was heterozygous for a mutation in which isoleucine (ATC) was substituted for valine (GTC) at position 383 [1].
• Insulin receptor number, activation of the insulin receptor tyrosine kinase in situ and after solubilization, and the total pool of glucose transporters (GLUT4) were unaffected, and glycogen synthase was activated by glucosamine pretreatment [27].
• Reporter studies in H9C2 cardiomyotubes showed that HL in vitro, induced by high levels of arachidonic (AA) stearic, linoleic, and oleic acids (24 h, 200 mum) repressed transcription from the GLUT4 promoter; AA also repressed transcription from the PPARgamma1 and PPARgamma2 promoters [19].
• The sequence of the protein-coding region of the GLUT4 gene and all intron-exon junctions was determined for a single diabetic Pima Indian and was identical to that of the cloned gene and cDNA [2].

Physical interactions of SLC2A4

• These data demonstrate that exercise increases MEF2 and GEF DNA binding and imply that these transcription factors could be potential targets for modulating GLUT4 expression in human skeletal muscle [28].
• Insulin and AICAR increased glucose transport and cell-surface GLUT4 content to a similar extent in control subjects [29].
• Together these data demonstrated that MEF2 binding activity is necessary for regulation of the GLUT4 gene promoter in muscle and adipose tissue [30].
• These findings strongly suggest that EHD2 interacts with GLUT4 in rat adipocytes and may play a key role in insulin-induced GLUT4 recruitment to the plasma membrane [31].
• Heterologous expression of rab4 reduces glucose transport and GLUT4 abundance at the cell surface in oocytes [32].

Co-localisations of SLC2A4

• Synapsin IIb co-localizes with Glut4 in perinuclear vesicle clusters [33].

Regulatory relationships of SLC2A4

• Role of EHD1 and EHBP1 in perinuclear sorting and insulin-regulated GLUT4 recycling in 3T3-L1 adipocytes [24].
• Activation of AMPK is an attractive strategy to enhance glucose transport through increased cell surface GLUT4 content in insulin-resistant skeletal muscle [29].
• In contrast, insulin- and AICAR-stimulated responses on glucose transport and cell-surface GLUT4 content were impaired in subjects with type 2 diabetes [29].
• We recently reported that the Krüppel-like zinc finger transcription factor KLF15 can induce adipocyte maturation and GLUT4 expression [34].
• These data strongly suggest that the MEF2A-MEF2D heterodimer is selectively decreased in insulin-deficient diabetes and is responsible for hormonally regulated expression of the GLUT4 gene [35].

Other interactions of SLC2A4

• Mechanistically, we show that nephrin allows the GLUT1- and GLUT4-rich vesicles to fuse with the membrane of this cell [36].
• Insulin receptor substrate 1 mediates the stimulatory effect of insulin on GLUT4 translocation in transfected rat adipose cells [37].
• Similarly, small interfering RNA-mediated depletion of endogenous EHD1 protein also markedly dispersed perinuclear GLUT4 in cultured adipocytes [24].
• RBP4 was positively correlated with GLUT4 expression in adipose tissue, independent of any obesity-associated variable [38].
• Moreover, EHD1 is shown to interact through its EH domain with the protein EHBP1, which is also required for insulin-stimulated GLUT4 movements and hexose transport [24].

Analytical, diagnostic and therapeutic context of SLC2A4

• Oligonucleotide primer pairs were selected that allowed the protein-coding region of the human GLUT4 gene to be amplified by PCR [2].
• Using this animal model, we found that stimulation of glucose uptake into brown adipocytes involves both GLUT4 translocation and activation [39].
• In situ hybridization to prometaphase chromosomes indicated that GLUT4 was in band p13 [40].
• CONCLUSIONS/INTERPRETATION: Enhanced insulin-stimulated glycogen synthesis in human skeletal muscle cell culture coincides with increased GLUT4 and PGC1 mRNA expression following treatment with various antidiabetic agents [41].
• GLUT4 mRNA content was examined by real-time quantitative RT-PCR and immunostaining reaction in the endometrial tissue of nine normal subjects, nine lean and eight obese hyperinsulinemic (h-INS), and eight lean and 10 obese normoinsulinemic (n-INS) PCOSs [3].

References