Disease relevance of Slc2a4

• We used adenovirus to overexpress the cytosolic domain of these syntaxin's and studied their effects on Glut4 traffic [1].
• We conclude that HIV protease inhibitors as a class are capable of selectively inhibiting the transport function of Glut4 and that this effect may be responsible for a major iatrogenic complication frequently observed in HIV patients [2].
• From insulin receptor signalling to Glut 4 translocation abnormalities in obesity and insulin resistance [3].
• In epididymal fat of L-Scap- mice, phosphorylated Akt, Glut-4 mRNA, and glucose uptake are also increased, indicating insulin hypersensitivity [4].

Psychiatry related information on Slc2a4

• However, the Glut4-selective abundance in cerebral motor areas supports its suggested role in providing the energy needed for the control of the motor activity [5].

High impact information on Slc2a4

• Insulin stimulates glucose transport by promoting exocytosis of the glucose transporter Glut4 (refs 1, 2) [6].
• The exocyst complex is required for targeting of Glut4 to the plasma membrane by insulin [6].
• Insulin resistance and the disruption of Glut4 trafficking in skeletal muscle [7].
• In EDL muscles from male or female Glut 4-null mice, basal deoxyglucose uptake was lower than in control muscles and was not stimulated by insulin [8].
• These results suggest that skeletal muscle glucose transport is rate-limiting for whole body glucose disposal and that the Glut4 protein is a potential target for pharmacological or genetic manipulation for treatment of patients with non-insulin-dependent diabetes mellitus [9].

Biological context of Slc2a4

• Adipose-specific Glut4 (also known as Slc2a4) knockout (adipose-Glut4(-/-)) mice show insulin resistance secondarily in muscle and liver [10].
• The other cDNA encodes a glucose transporter-like protein, termed GT2, that has a unique amino acid sequence and tissue distribution [11].
• Reduction of intracellular ATP using azide inhibited Glut 1 and Glut 4 translocation from the LDM to the plasma membrane, insulin receptor autophosphorylation, and IRS-1 tyrosine phosphorylation [12].
• Glut4 overexpression also increased glucose transport stimulated by muscle contractions [13].
• The nucleotide sequence of Glut4, a candidate gene for Nidd1nsy (a susceptibility gene for Type II diabetes) on Chromosome 11, encoding insulin-sensitive glucose transporter, was determined in NSY and C3H mice [14].

Anatomical context of Slc2a4

• Moreover, we observed that T0901317 produced in itself a significant increase over basal glucose uptake consistent with an increase of SLC2A4 protein content in plasma membrane, attributable to the activation of protein kinase zeta and/or the increase of Slc2a4 expression [15].
• In this study, we have quantified the absolute levels of expression of these proteins in murine 3T3-L1 adipocytes, with the objective of determining the stoichiometry of these proteins both relative to each other and also in comparison with previous estimates of Glut4 levels within these cells [16].
• Glut4 is targeted to specific vesicles in adipocytes of transgenic mice overexpressing Glut4 selectively in adipose tissue [17].
• Glut4-containing intracellular membranes from both cell types have a specific and narrow distribution in these gradients, i.e. behave as homogeneous vesicles with identical sedimentation coefficients and different buoyant densities [17].
• To study compartmentalization of intracellular Glut4 in these cells, we fractionated light microsomes prepared from transgenic and normal adipocytes in velocity and density sucrose gradients [17].

Associations of Slc2a4 with chemical compounds

• Neomycin prevents the wortmannin inhibition of insulin-stimulated Glut4 translocation and glucose transport in 3T3-L1 adipocytes [18].
• Soleus muscles from male Glut 4-null mice took up twice more deoxyglucose in the absence of insulin than control muscles, but did not respond to insulin [8].
• To determine whether indinavir may be directly affecting the intrinsic transport activity of glucose transporters, the Glut1 and Glut4 isoforms were heterologously expressed and analyzed in Xenopus laevis oocytes [2].
• Subcellular fractionation experiments demonstrated that reduction in insulin-stimulated 2-deoxyglucose uptake by glucosamine was due to an inhibition of translocation of both Glut 1 and Glut 4 from the low density microsomes (LDM) to the plasma membrane [12].
• Increase of triglyceride content over culture time and mRNA expression of other adipocyte genes, such as PPARgamma and Glut-4, were found to be similar [19].
• Taken together, these data show that insulin signaling accelerates the transition from docking of GLUT4-containing vesicles to their fusion with the plasma membrane and promotes GLUT4 accumulation in clathrin-based endocytic structures on the plasma membrane [20].
• S21A-C/EBPalpha had impaired ability to activate the Glut4 promoter specifically, and S21A-C/EBPalpha expression resulted in diminished GLUT4 and adiponectin expression, as well as reduced insulin-stimulated glucose uptake [21].

Physical interactions of Slc2a4

• The mechanisms underlying insulin and insulin-like growth factor-I (IGF-I) action on glucose transport share similar processes leading to Glut 4 translocation after respective receptor activation [22].

Regulatory relationships of Slc2a4

• Insulin-stimulated plasma membrane fusion of Glut4 glucose transporter-containing vesicles is regulated by phospholipase D1 [23].
• It is well established that proteins of the VAMP- (synaptobrevin) and syntaxin-families play a fundamental role in the insulin-stimulated fusion of Glut4-containing vesicles with the plasma membrane [16].
• Based on these data, we conclude that major role of C/EBP alpha in the context of the NIH-PPAR gamma cells is to regulate Glut4 expression [24].
• Syntaxin 6 regulates Glut4 trafficking in 3T3-L1 adipocytes [1].
• These results provide evidence for a critical role of IRS-2 as a mediator of insulin-stimulated Glut4 translocation and glucose uptake in adipocytes [25].
• Rab10 knockdown resulted in an attenuation of insulin-induced GLUT4 redistribution to the plasma membrane and a concomitant 2-fold decrease in GLUT4 exocytosis rate [26].
• The addition of insulin increased the amount of Exo70 in the vicinity of the plasma membrane and stimulated the tethering and fusion of GLUT4 vesicles, but the rates of fusion and GLUT4 exposure were not affected by overexpression of Exo70 [27].

Other interactions of Slc2a4

• PLD1 is found on Glut4-containing vesicles, is activated by insulin signaling, and traffics with Glut4 to exocytic sites [23].
• The reason for the lack of insulin-responsive glucose uptake in the NIH-PPAR gamma cells is their virtual lack of the insulin-responsive glucose transporter, Glut4 [24].
• Our data suggest that syntaxin 6 is involved in a membrane-trafficking step that sequesters Glut4 away from traffic destined for the plasma membrane [1].
• Essential role of insulin receptor substrate-2 in insulin stimulation of Glut4 translocation and glucose uptake in brown adipocytes [25].
• We speculate that this is at the level of traffic of Glut4 into its unique storage compartment and that syntaxin 16 may be involved [1].

Analytical, diagnostic and therapeutic context of Slc2a4

• However, insulin also increased the total Glut4 immunogold reactivity in muscle ultrathin sections by up to 1.8-fold and dramatically increased the amount of Glut4 in muscle sections as observed by laser confocal immunofluorescence microscopy [28].
• The subcellular distributions of vp165 and Glut4 were determined by immunoisolation of vesicles with antibodies against both proteins, by immunofluorescence, and by subcellular fractionation and immunoblotting [29].
• Microinjection into 3T3-L1 adipocytes of a glutathione S-transferase (GST) fusion protein containing the cytosolic portion of IRAP (GST-IRAP-(1-109)), resulted in translocation of Glut4 to the cell surface [30].
• Northern blot analysis revealed that the expression of adipocyte-related differentiation marker genes including PPAR gamma (peroxisome proliferator-activated receptor gamma), aP2 and Glut4 increased over time in culture, whereas expression of type II collagen decreased [31].
• Crude membranes were prepared from those tissues, and Glut 4 was studied by Western blot analysis [32].

References