Disease relevance of Slc2a4

• We therefore conclude that the presence of fish oil, in contrast to olive oil, prevents insulin resistance and hypertriglyceridemia in rats on a sucrose diet, and restores Glut-4 protein quantity in adipocytes but not in muscle at basal levels [1].
• Thus, changes in Glut 4 expression are a major cause of alteration in insulin-stimulated glucose uptake of adipocytes during evolution of obesity and diabetes in Zucker rats [2].
• We conclude that maternal diabetes causing fetal hyperglycemia with normoinsulinemia suppresses fetal myocardial Glut 1 and Glut 4 and fetal skeletal muscle Glut 1 [3].
• In contrast, sepsis did not alter the amount of Glut-4 protein and mRNA or insulin receptor protein [4].
• In contrast, in the absence of a change in fetal skeletal muscle Glut 1 levels (48 kDa), a 70% increase was observed in the 1d IUGR with no concomitant change in either fetal or postnatal Glut 4 levels (45 kDa) [5].

High impact information on Slc2a4

• Desmoyokin-AHNAK-positive vesicles exist in a variety of cells and tissues and are distinct from the endoplasmic reticulum, Golgi, trans-Golgi, endosomes and lysosomes, and from Glut4 and constitutive secretion vesicles [6].
• Glucose-induced activation of DAG/PKC signaling in microsomes was not associated with a change in the translocation of Glut-4 transporters from microsomes to the plasma membrane, a biological response that is known to be stimulated by agonists, e.g., phorbol esters, which increase DAG/PKC signaling in plasma membranes, as well as in microsomes [7].
• Divergent regulation of the Glut 1 and Glut 4 glucose transporters in isolated adipocytes from Zucker rats [2].
• We have studied the relationship between glucose uptake rate and Glut 1 and Glut 4 protein and mRNA levels per fat cell in lean (FA/FA) and obese (fa/fa) Zucker rats at 5, 10, and 20 wk of age, and after induction of acute diabetes with streptozotocin [2].
• Acute diabetes in 20 wk obese rats causes a profound downregulation of glucose uptake and a concomitant reduction of both Glut 1 and Glut 4 protein levels [2].

Chemical compound and disease context of Slc2a4

• Effects of gestational hypoxia on mRNA levels of Glut3 and Glut4 transporters, hypoxia inducible factor-1 and thyroid hormone receptors in developing rat brain [8].

Biological context of Slc2a4

• As the concentration required to significantly inhibit insulin-stimulated glucose uptake in primary rat adipocytes is well within the physiologic range achieved in therapy, we conclude that direct inhibition of Glut4 contributes to the insulin resistance observed in patients receiving this drug [9].
• The mutated Glut4 was inhibited by pCMB or pCMBS and the IC50 of HgCl2 decreased to 47 microM, whereas K(m), substrate specificity and the sensitivity to cytochalasin B were not significantly changed, indicating that the existence of exofacial cysteine contributed only to increase SH sensitivity in Glut4 [10].
• Phosphorylation of several vesicle proteins including Glut4 itself is rapidly activated by insulin [11].
• H-raslys12-transformed brown adipocytes showed a 10-fold higher expression of Glut1 mRNA and protein than parental cells, Glut4 gene expression being completely down-regulated [12].
• RESULTS: Compared with native insulin, the receptor binding activity of E,D-insulin was 31 %; the stimulating activity of E,D-insulin in glucose transport and lipogenesis were 45 % and 40 % respectively; the stimulations of Glut4 translocation and insulin receptor autophosphorylation of E,D-insulin were about 58 % and 46 % respectively [13].

Anatomical context of Slc2a4

• Expression of a constitutively active, membrane-associated Akt-1 (PKB alpha) construct in 3T3L1 adipocytes was shown to induce glucose uptake in the absence of insulin by stimulating Glut4 translocation to the plasma membrane (Kohn, A. D., Summers, S. A., Birnbaum, M. J., and Roth, R. A. (1996) J. Biol. Chem. 271, 31372-31378) [14].
• The distribution of Akt-2 in resting adipocytes was found to substantially overlap with that of Glut4 when light microsomes were subfractionated by a sucrose velocity gradient indicating possible co-localization [14].
• The t1/2 values for ER to Golgi transit for Glut1 and Glut4 were < 1 and 24 h, respectively, in oocytes and approximately 5 and 20 min, respectively, in 3T3-L1 adipocytes [15].
• Treatment of neonatal cardiac myocytes with the hypertrophic agonist 12-O-tetradecanoylphorbol-13-acetate or phenylephrine increased expression of Glut1 mRNA relative to Glut4 mRNA [16].
• The rate of movement of the glucose transporter isoforms Glut1 and Glut4 from the endoplasmic reticulum (ER) to the Golgi apparatus was investigated by pulse labeling and monitoring endoglycosidase H resistance in mRNA-injected Xenopus oocytes and in 3T3-L1 adipocytes, a cell line that naturally expresses both transporter isoforms [15].

Associations of Slc2a4 with chemical compounds

• Indinavir inhibits the glucose transporter isoform Glut4 at physiologic concentrations [9].
• CONCLUSIONS: Indinavir appears to be a relatively selective inhibitor of the Glut4 isoform [9].
• To examine the role of the exofacial cysteine, we replaced Met-455 of Glut4 (corresponding to Cys-429 of Glut1) with cysteine [10].
• Pulse-chase in conjunction with sucrose density gradient analysis revealed that the rate-limiting step in the ER to Golgi processing of Glut4 was exit from the ER and not retention in an early Golgi compartment [15].
• The GTBP70 binding to Glut4 was not affected by the presence of 2 mM EDTA, 2.4 mM Ca2+, or 150 mM K+ [17].

Physical interactions of Slc2a4

• Akt-2 binds to Glut4-containing vesicles and phosphorylates their component proteins in response to insulin [11].

Co-localisations of Slc2a4

• By means of sucrose gradient centrifugation, immunoadsorption, and confocal microscopy, we have shown that virtually all cellugyrin is co-localized with Glut4 in the same vesicles [18].
• GLUT4 colocalized with ACTN4 along the insulin-induced cortical actin mesh and ACTN4 knockdown prevented GLUT4-actin colocalization without impeding actin remodeling or Akt phosphorylation, maintaining GLUT4 in a tight perinuclear location [19].

Other interactions of Slc2a4

• Insulin increases the association of Akt-2 with Glut4-containing vesicles [14].
• We have identified a 70-kDa cytosolic protein (GTBP70) in rat adipocytes that binds to glutathione S-transferase fusion proteins corresponding to the cytoplasmic domains of the facilitative glucose transporter isoforms Glut1, Glut2, and Glut4 [17].
• Neither Glut 3 nor Glut 4 mRNA could be detected in STZ-treated and control fetal muscle [20].
• Furthermore, insulin-stimulated translocation of both Glut4 and PKB to the plasma membrane was virtually abolished [21].
• In skeletal muscle, insulin receptor substrate 1 and Glut4 are up-regulated at the end of the food restriction period, just the opposite of what we found in adipose tissue [22].

Analytical, diagnostic and therapeutic context of Slc2a4

• E2-stimulated changes in the steady state levels of messenger RNA (mRNA) and protein were measured for Glut1 and Glut4 by quantitative competitive RT-PCR and Western blots [23].
• Simultaneous measurement of multiple mRNAs with a single control by quantitative competitive reverse transcriptase-polymerase chain reaction: glucose transporters Glut1 and Glut4 [24].
• Theoretical considerations for extending the application of quantitative competitive polymerase chain reaction (qc-PCR) to include the simultaneous measurement of multiple mRNAs, specifically the mammalian glucose transporters Glut1 and Glut4, are presented with experimental data in which the accuracy and flexibility of the system are examined [24].
• This study was performed to evaluate at the light microscopy level the expression of Glut-4 and Glut-1 transporters in normal and denervated diaphragm by immunohistochemistry method with specific Gluts antibodies [25].
• These data indicated that (1) Glut-4 and Glut-1 transporters were observed in diaphragm; and (2) there were alterations in the expression of both glucose transporters after denervation [25].

References