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PubMed1998

Trafficking pathway of GLUT4 glucose transporters in muscle (review).

Skeletal muscle is a major glucose-utilizing tissue in the absorptive state and alterations in muscle insulin-stimulated glucose uptake lead to derangements in whole body glucose disposal. The major glucose transporter expressed in skeletal muscle is the GLUT4 isoform. In the muscle fiber, GLUT4 undergoes insulin-stimulated translocation to T-tubules and to sarcolemma and it represents a pharmacological target for the treatment of diabetes mellitus, insulin-resistant states or in cardiac dysfunction. We review recent studies describing the characterization of the cellular steps followed by GLUT4 in muscle and we propose several working models for an integrated structure of the GLUT4 trafficking pathway.

Animals↗
PubMed1994

The major protein of GLUT4-containing vesicles, gp160, has aminopeptidase activity.

A glycoprotein of M(r) 160,000 (gp160) represents the major protein component of GLUT4-containing vesicles other than GLUT4 itself. These vesicles are the tissue-specific secretory-like microsomal structures that are responsible for insulin-dependent translocation of GLUT4 to the cell surface in fat and muscle cells. Our previous studies demonstrated that the expression of gp160 is also limited to fat and muscle tissues, where it is localized exclusively in GLUT4-containing vesicles, and thus, it represents a marker protein for insulin-activated glucose transport. We demonstrate here that gp160 has structural homology to aminopeptidase N and possesses aminopeptidase activity in vitro. Since aminopeptidase activity has also been found in a variety of secretory type vesicles from other tissues, it may be essential for the organization and functioning of secretory machinery in different cell types.

Adipocytes↗
PubMed1994

Characterization of a major protein in GLUT4 vesicles. Concentration in the vesicles and insulin-stimulated translocation to the plasma membrane.

GLUT4-enriched vesicles from fat and muscle cells contain a major protein of 165 kDa. In the present study we have prepared GLUT4 vesicles from a large number of rat adipocytes, isolated the 165-kDa protein by SDS-gel electrophoresis, and obtained the sequences of four tryptic peptides. Comparison of the sequences with those in protein data banks showed that the 165-kDa protein had not previously been sequenced. An antibody preparation against one of the peptides immunoblotted the 165-kDa protein. By this means it was found that the 165-kDa protein was concentrated in GLUT4 vesicles, and that insulin treatment of rat adipocytes caused a translocation of the protein to the plasma membrane that paralleled the translocation of GLUT4.

Adipocytes↗
PubMed1994

A Leu-Leu sequence is essential for COOH-terminal targeting signal of GLUT4 glucose transporter in fibroblasts.

In the insulin-responsive tissues, muscle and adipose, the GLUT4 glucose transporter isoform accounts for most of the increase in hexose flux in response to hormone. In these cell types, as well as in fibroblasts transfected with cDNAs encoding the transporters, GLUT1 and GLUT4 are sorted to different subcellular locations. In the latter, GLUT1 is found primarily at the cell surface whereas GLUT4 localizes to the interior of the cell in a perinuclear distribution. The construction and analysis of chimeras of these two transporter isoforms have allowed identification of the COOH-terminal 30 amino acids as a critical sorting signal for differential localization of the transporters. In this study, we show that 2 residues present in the GLUT4 COOH terminus, Leu-489 and Leu-490, are critical for the intracellular sequestration of this isoform in NIH3T3 cells.

3T3 Cells↗
PubMed2003

Acute and chronic leptin treatment mediate contrasting effects on signaling, glucose uptake, and GLUT4 translocation in L6-GLUT4myc myotubes.

We have previously shown that in L6-GLUT4myc rat skeletal muscle cells, acute treatment with leptin reduced insulin-stimulated glucose uptake without altering insulin-stimulated GLUT4 translocation. In contrast, we show here that the ability of leptin to increase phosphorylation of its receptor and to reduce insulin-stimulated glucose uptake was lost in cells that were continuously exposed to leptin for 24 h. This desensitization correlated with an increase in expression of suppressor of cytokine signaling-3 (SOCS-3). Time course analysis demonstrated that the transition from acute to chronic effects of leptin occurs after 2 h. The desensitization of leptin action at 24 h was not reversed by 30 min washout period prior to re-exposing cells to leptin. However, despite insulin-stimulated glucose uptake being unaffected upon 24 h preincubation with leptin, a small but significant decrease (37%) in insulin-stimulated GLUT4 translocation and phosphorylation of Akt on T308 was detected. Insulin-stimulated phosphorylation of Akt on S473 or of p38 MAPK were unaffected. These results suggest that the chronic leptin treatment leads to desensitization of leptin signaling yet can simultaneously decrease the ability of insulin to phosphorylate Akt on T308 and translocate GLUT4. However, this does not manifest as a reduction in total glucose uptake into L6 myotubes.

Animals↗
PubMed1994

Effect of high-fat diet on gene expression of GLUT4 and insulin receptor in soleus muscle.

Gene expression of GLUT4 and insulin receptor in soleus muscle of high-fat and high-carbohydrate diet fed rats was studied by measuring mRNA. High-fat diet feeding increased plasma glucose but decreased plasma insulin level. Glucose uptake in soleus muscle measured by 2-deoxy-D-glucose technique was lower in high-fat than high-carbohydrate diet fed rats. GLUT4 mRNA level in soleus muscle was significantly decreased but insulin receptor mRNA was similar in high-fat compared with high-carbohydrate diet fed rats. Insulin receptor exists in two forms generated by alternative splicing of a primary gene transcript. There was no difference in the relative expression of insulin receptor isoform mRNAs between high-fat and high-carbohydrate diet fed rats. These results suggest that high-fat diet impairs glucose metabolism in muscle by reducing transcription of GLUT4 without affecting gene expression of insulin receptor.

Alternative Splicing↗
PubMed1996

Regulation of GLUT4 mRNA stability by tumor necrosis factor-alpha: alterations in both protein binding to the 3' untranslated region and initiation of translation.

Previous studies from our laboratory have demonstrated that exposure of the 3T3-L1 adipocytes to TNF resulted in a 50% decrease in the half-life of the GLUT4 mRNA from 9.5h (control) to 4.5h (treated cells). In the current study we report that coincident with the alteration of the half-life of the message, TNF treatment resulted in an increase in the binding of a protein to the proximal 200 bases of the 3'UTR. In addition the distribution of GLUT4 mRNA in polysome profiles was altered such that message accumulated as a 40S preinitiation complex, consistent with an attenuation of initiation. In summary, our data suggest that enhanced decay of the GLUT4 mRNA may occur through a mechanism involving accumulation of a 40s preinitiation complex which correlates with increased protein binding to the 3'UTR.

3T3 Cells↗
PubMed1996

Clostridium botulinum C3 exoenzyme stimulates GLUT4-mediated glucose transport, but not glycogen synthesis, in 3T3-L1 adipocytes--a potential role of rho?

The signal transduction pathway by which insulin stimulates glucose transport is largely unknown, but a role of PI-3-kinase and small GTP-binding proteins has been proposed. In previous studies we, among many others, excluded a role for the ras/MAP kinase pathway in insulin-mediated glucose transport. In this study we examined a possible role of the small GTP-binding protein rho in this process. Pretreatment of 3T3-L1 adipocytes with botulinum C3 exoenzyme (C3), which is known to ADP-ribosylate and inactivate rho, potently stimulated glucose uptake to a level similar to insulin. Interestingly, glycogen synthesis was not affected by C3 treatment. Insulin stimulates glucose uptake by triggering the translocation of GLUT4, the insulin-sensitive glucose transporter isotype, from an intracellular compartment to the plasma membrane. Similarly, C3-induced glucose uptake was paralleled by GLUT4 translocation. These data point to an important and novel role of the target of C3 (likely rho) in the regulation of GLUT4-mediated glucose transport. Our data suggest that insulin might stimulate glucose uptake through inactivation of rho.

3T3 Cells↗
PubMed1997

Chronic high-fat feeding and middle-aging reduce in an additive fashion Glut4 expression in skeletal muscle and adipose tissue.

The interaction of middle-aging and chronic high-fat feeding on glucose transport in skeletal muscle and adipose tissue was examined. To this end, we studied the effects of 6 month treatment with a high-fat diet in 12-month old rats. Chronic high-fat feeding led to a substantial reduction in GLUT4 glucose transporter expression both in adipose tissue and in skeletal muscle, which was additive to the reduction in GLUT4 protein content detected in aged rats. In parallel, the high-fat diet led to a reduced insulin-stimulated glucose transport in the incubated soleus muscle and isolated adipocytes; insulin resistance induced by high-fat feeding was superimposed to the decreased insulin response detected in aged rats. Different mechanisms were responsible for GLUT4 repression in response to high-fat feeding or aging in skeletal muscles and adipose tissue.

Adipose Tissue↗
PubMed1995

Mutation of two conserved arginine residues in the glucose transporter GLUT4 supresses transport activity, but not glucose-inhibitable binding of inhibitory ligands.

Two arginine residues (RR333/334) in the conserved GRR motif located in the endofacial loop between helix 8 and 9 of the glucose transporter GLUT4 were substituted for leucine and alanine, respectively. Reconstituted glucose transport activity of the construct (GLUT4-RR333/4LA) expressed in COS-7 or LM(TK-) cells was less than 10% of that of the wild-type GLUT4. In contrast, binding of the inhibitory ligand cytochalasin B and glucose-inhibitable photolabeling with IAPS-forskolin were not significantly affected. Exchange of a histidine residue (H337Q) previously believed to be involved in the binding of inhibitory ligands failed to affect any of the investigated parameters. These data suggest that positive charges in the GRR motif at the cytoplasmic surface of the transporter participate in the conformational changes of the carrier protein during the process of facilitated diffusion.

Animals↗
PubMed1996

Bradykinin enhances GLUT4 translocation through the increase of insulin receptor tyrosine kinase in primary adipocytes: evidence that bradykinin stimulates the insulin signalling pathway.

It has been suggested that bradykinin stimulates glucose uptake in experiments in vivo and in cultured cells. However, its mechanism has not yet been fully elucidated. In this study, the effects of bradykinin on the insulin signalling pathway were evaluated in isolated dog adipocytes. The bradykinin receptor binding study revealed that dog adipocytes possessed significant numbers of bradykinin receptors (Kd = 83 pmol/l, binding sites = 1.7 x 10(4) site/ cell). Reverse transcription-polymerase chain reaction amplification showed the mRNA specific for bradykinin B2 receptor in the adipocytes. Bradykinin alone did not increase 2-deoxyglucose uptake in adipocytes; however, in the presence of insulin (10(-7) mol/l) it significantly increased 2-deoxyglucose uptake in a dose-dependent manner. Bradykinin also enhanced insulin stimulated GLUT4 translocation from the intracellular fraction to the cell membrane, and insulin induced phosphorylation of the insulin receptor beta subunit and insulin receptor substrate-1 (IRS-1) without affecting the binding affinities or numbers of cell surface insulin receptors in dog adipocytes. The time-course of insulin stimulated phosphorylation of the insulin receptor beta subunit revealed that phosphorylation reached significantly higher levels at 10 min, and stayed at the higher levels until 120 min in the presence of bradykinin, suggesting that bradykinin delayed the dephosphorylation of the insulin receptor. It is concluded that bradykinin could potentiate insulin induced glucose uptake through GLUT4 translocation. This effect could be explained by the potency of bradykinin to upregulate the insulin receptor tyrosine kinase activity which stimulates phosphorylation of IRS-1, followed by GLUT4 translocation.

Adipocytes↗
PubMed1999

GLUT4 trafficking in insulin-sensitive cells. A morphological review.

In recent years, there have been major advances in the understanding of both the cell biology of vesicle trafficking between intracellular compartments and the molecular targeting signals intrinsic to the trafficking proteins themselves. One system to which these advances have been profitably applied is the regulation of the trafficking of a glucose transporter, GLUT4, from intracellular compartment(s) to the cell surface in response to insulin. The unique nature of the trafficking of GLUT4 and its expression in highly differentiated cells makes this a question of considerable interest to cell biologists. Unraveling the tangled web of molecular events coordinating GLUT4 trafficking will eventually lead to a greater understanding of mammalian glucose metabolism, as well as fundamental cell biological principles related to organelle biogenesis and protein trafficking.

3T3 Cells↗
PubMed2005

Enhanced insulin-stimulated glycogen synthesis in response to insulin, metformin or rosiglitazone is associated with increased mRNA expression of GLUT4 and peroxisomal proliferator activator receptor gamma co-activator 1.

AIMS/HYPOTHESIS: The aim of this study was to determine the effect of several antidiabetic agents on insulin-stimulated glycogen synthesis, as well as on mRNA expression. METHODS: Cultured primary human skeletal myotubes obtained from six healthy subjects were treated for 4 or 8 days without or with glucose (25 mmol/l), insulin (400 pmol/l), rosiglitazone (10 micromol/l), metformin (20 micromol/l) or the AMP-activated kinase activator 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) (200 micromol/l). After this, insulin-stimulated glycogen synthesis was determined. mRNA levels of the glucose transporters GLUT1 and GLUT4, the peroxisomal proliferator activator receptor gamma (PPAR gamma) co-activator 1 (PGC1) and the myocyte-specific enhancer factors (MEF2), MEF2A, MEF2C and MEF2D were determined using real-time PCR analysis after 8 days exposure to the various antidiabetic agents. RESULTS: Insulin-stimulated glycogen synthesis was significantly increased in cultured human myotubes treated with insulin, rosiglitazone or metformin for 8 days, compared with non-treated cells. Furthermore, an 8-day exposure of myotubes to 25 mmol/l glucose impaired insulin-stimulated glycogen synthesis. In contrast, treatment with AICAR was without effect on insulin-mediated glycogen synthesis. Exposure to insulin, rosiglitazone or metformin increased mRNA expression of PGC1 and GLUT4, while AICAR or 25 mmol/l glucose treatment increased GLUT1 mRNA expression. Metformin also increased mRNA expression of the MEF2 isoforms. 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. These data show that chronic treatment of human myotubes with insulin, metformin or rosiglitazone has a direct positive effect on insulin action and mRNA expression.

Adult↗
PubMed2006

Exercise training increases insulin-stimulated glucose disposal and GLUT4 (SLC2A4) protein content in patients with type 2 diabetes.

AIMS/HYPOTHESIS: Exercise enhances insulin-stimulated glucose transport in skeletal muscle through changes in signal transduction and gene expression. The aim of this study was to assess the impact of acute and short-term exercise training on whole-body insulin-mediated glucose disposal and signal transduction along the canonical insulin signalling cascade. METHODS: A euglycaemic-hyperinsulinaemic clamp, with vastus lateralis skeletal muscle biopsies, was performed at baseline and 16 h after an acute bout of exercise and short-term exercise training (7 days) in obese non-diabetic (n=7) and obese type 2 diabetic (n=8) subjects. RESULTS: Insulin-mediated glucose disposal was unchanged following acute exercise in both groups. Short-term exercise training increased insulin-mediated glucose disposal in obese type 2 diabetic (p<0.05), but not in obese non-diabetic subjects. Insulin activation of (1) IRS1, (2) IRS2, (3) phosphotyrosine-associated phosphatidylinositol-3 kinase activity and (4) the substrate of phosphorylated Akt, AS160, a functional Rab GTPase activating protein important for GLUT4 (now known as solute carrier family 2 [facilitated glucose transporter], member 4 [SLC2A4]) translocation, was unchanged after acute or chronic exercise in either group. GLUT4 protein content was increased in obese type 2 diabetic subjects (p<0.05), but not in obese non-diabetic subjects following chronic exercise. CONCLUSIONS/INTERPRETATION: Exercise training increased whole-body insulin-mediated glucose disposal in obese type 2 diabetic patients. These changes were independent of functional alterations in the insulin-signalling cascade and related to increased GLUT4 protein content.

Biopsy↗
PubMed1991

Differential expression of the GLUT1 and GLUT4 glucose transporters during differentiation of L6 muscle cells.

Skeletal muscle is the main tissue responsible for glucose utilization in the fed state, and it expresses the ubiquitous GLUT1 glucose transporter and the muscle/fat specific GLUT4 glucose transporter. Here we investigated the expression of these transporters during muscle cell differentiation in vitro. Rat L6 muscle cells were grown to the stages of myoblasts, alignment and fused myotubes. Glucose (2-deoxy-D-glucose) transport was higher in myoblasts, decreasing with the progression of alignment and cell fusion. Conversely, insulin-stimulated glucose uptake was negligible in myoblasts, and increased with cell alignment and fusion. The cellular content of GLUT1 transporters decreased and that of GLUT4 transporters increased with cell fusion. Insulin rapidly stimulated glucose uptake in fused myotubes maintained in 2% serum but not in 10% serum. In 10% serum, basal glucose uptake increased as did the cellular content of GLUT1 transporters, while GLUT4 transporter content did not change. These results indicate that both transporters are regulated oppositely during muscle cell differentiation, and that high serum concentrations override the capacity of insulin to regulate transport by inducing overexpression of the GLUT1 transporter.

Animals↗
PubMed1992

Epinephrine administration stimulates GLUT4 translocation but reduces glucose transport in muscle.

Epinephrine opposes glucose transport in muscle. Therefore, we investigated the effects of epinephrine administration (25 micrograms/100g body weight) on glucose transport and glucose transporters in rat muscle. Ninety minutes after epinephrine injection 3-O-methyl glucose transport was reduced (approximately 47%) in perfused muscles of the rat hindlimb. Translocation of the insulin-regulatable glucose transporter (GLUT4) in the epinephrine-injected animals was confirmed by the marked increments in the GLUT-4 in the plasma membranes and their concomitant reduction in the intracellular membranes. We speculate a) that it is epinephrine which translocated GLUT4 via a cAMP-linked pathway, and b) that the intrinsic activity reductions are caused either by the glycation of the transporter by the persistent hyperglycemia and/or by epinephrine via the phosphorylation of the GLUT4 transporter protein in muscle.

3-O-Methylglucose↗
PubMed1996

Early changes in the expression of GLUT4 protein in the heart of senescence-accelerated mouse.

The content of facilitative glucose transporter proteins in the heart, lung, liver, testis and cerebellum of SAMP8, a substrain of senescence-accelerated prone mouse, was investigated. The increase in the expression of facilitative glucose transporter proteins, estimated by the D-glucose inhibitable cytochalasin B binding assay, was observed only in the heart of 4-8 week old SAMP8 in comparison with SAMR1, a substrain of senescence-accelerated resistant mouse. The increase in cytochalasin B binding protein in SAMP8 was restricted at 4-8 weeks old, thereafter no significant difference was observed between the two substrains. Furthermore, the immunoblotting revealed that the content of the GLUT4 (glucose transporter isoform 4) protein in the crude membranes prepared from 4-8 week old SAMP8 was greater than that of SAMR1, without the difference in the content of the GLUT1 (glucose transporter isoform 1) protein. Additionally, the increased GLUT4 protein in SAMP8 was localized in the intracellular membranes. These results suggest that an accelerated ageing of SAMP8 is possibly related to the overproduction of the energy in the heart through the increase in glucose uptake after the translocation of GLUT4 from the intracellular pools to the plasma membranes.

Aging↗
PubMed1996

Expression and localization of insulin-regulatable glucose transporter (GLUT4) in rat brain.

The localization of glucose transporters (GLUTs) was examined in various regions of the rat brain. The mRNA of GLUT1 and GLUT3 were found ubiquitously in every brain region (cortex, hippocampus, midbrain, striatum, hypothalamus, medulla oblongata and cerebellum). The mRNA and protein of GLUT4, an insulin-regulatable glucose transporter in peripheral tissues, were also identified, particularly abundantly in the cerebellum. In situ hybridization analysis revealed that GLUT4 mRNA was present in some discrete cells, such as Purkinje cells in the cerebellum, the vestibular nucleus in the medulla oblongata and also in ependymal cells along the cerebral ventricles. The GLUT4 mRNA level in the cerebellum changed little in fasted or experimentally induced diabetic rats while those in adipose tissues decreased much. The results suggest that insulin-sensitive glucose uptake may occur in some specific cells of the brain but is regulated in a different manner from those in peripheral cells.

Adipose Tissue↗