Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P56851 (epididymal)
 11,273 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To elucidate the cellular mechanisms for impairment of glucose metabolism associated with aging, the facilitative glucose transporter protein and mRNA were studied in various tissues of young (7-week-old) and aged (20-month-old) rats. GLUT4 glucose transporter protein, a major glucose transporter isoform in the insulin-responsive tissues, was selectively decreased in the epididymal fat tissues of the aged rats compared with the young rats. This decrease is likely to be due to a decrease in protein synthesis rather than in protein stability, since GLUT4 mRNA per unit cellular total RNA was also decreased. GLUT4 mRNA in the skeletal muscle was rather increased in spite of the decreased level of GLUT4 protein in the aged rats, suggesting that the translational efficiency and/or stability of GLUT4 protein is decreased in the skeletal muscle of the aged rats compared with the young rats. In contrast to these alterations in GLUT4 expression, no apparent decrease in the GLUT1 protein amount was observed in the fat tissues, skeletal muscle and brain of the aged rats compared with the young rats. Thus, the tissue and isoform-specific alterations in glucose transporter expression are associated with aging and may contribute to impairment of glucose metabolism observed with aging.
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PMID:Expression of glucose transporter isoforms with aging. 145 71

With the identification of two different glucose transporter species in adipose cells it is crucial to determine the role of these transporters in the alterations in glucose transport activity associated with different metabolic and nutritional states. In the present study we assess levels of expression of Glut 1 and Glut 4 transporters and basal and insulin-stimulated glucose transport activity in adipocytes from Sprague-Dawley rats fed standard chow (control), combined liquid diet and standard chow (overfed), high fat diet, or energy-restricted diet for 7 weeks. High fat feeding was associated with relative postprandial hypoglycemia (P less than 0.05) and hypoinsulinemia (P less than 0.05). Although the high fat fed animals had lower body weights (P less than 0.05) than control rats, their body compositions showed obesity, with 36% heavier epididymal fat pads (P less than 0.05) and a 47% increase in adipocyte volume (P less than 0.05). Fat feeding caused a 78% reduction in insulin-stimulated glucose transport per adipocyte (P less than 0.05). In parallel we found 92% and 94% reductions in Glut 4 protein and mRNA per adipocyte, respectively, (P less than 0.01) in fat-fed rats. Substantial reductions were also seen in Glut 1 protein and mRNA per fat cell in the same rats (62% and 76%, respectively; P less than 0.05). However, the changes in Glut 1 expression were of the same magnitude as changes in the cytoskeletal protein beta-actin, reflecting a decreased expression of several proteins in this nutritional state. Even though overfeeding and energy restriction brought about opposite changes in adiposity, no significant alterations were demonstrated in glucose transport rate or glucose transporter expression. The impaired insulin-stimulated glucose transport in adipose cells from high fat-fed rats occurs in the presence of a dramatic decrease in the expression of the major insulin-responsive glucose transporter (Glut 4). The reduced gene expression may be caused by chronic hypoinsulinemia and may contribute to the insulin resistance observed in this state.
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PMID:High fat feeding causes insulin resistance and a marked decrease in the expression of glucose transporters (Glut 4) in fat cells of rats. 185 75

To elucidate the cellular mechanisms of glucose intolerance associated with aging, both the protein and mRNA levels of glucose transporter isoforms were studied in the various tissues of young (7-week-old) and aged (20-month-old) rats. GluT4 (adipose/muscle-type glucose transporter) protein, which is specifically expressed in insulin-responsive tissues, was selectively decreased per milligram of cellular membrane protein in both the epididymal fat tissues and the gastrocnemius muscle of the aged rats compared with the young rats. When the changes in total cellular membranes per gram of tissue are taken into account, a further decrease in GluT4 protein per gram of tissue was observed in the tissues of the aged rats compared with the young rats. The decreased amount of GluT4 protein in the fat tissues of the aged rats is probably due to the decreased protein synthesis rather than the stability, since GluT4 mRNA/micrograms of cellular total RNA was also decreased. In contrast, GluT4 mRNA in the gastrocnemius muscle was rather increased and a ratio of GluT4 protein/GluT4 mRNA was decreased by 70% in the aged rats, suggesting that the translational efficiency and/or stability of GluT4 protein is decreased in the skeletal muscle of the aged rats compared with the young rats. GluT2 (liver-type glucose transporter) protein and mRNA in the liver were also decreased in the aged rats, while no apparent decrease in GluT1 (HepG2/brain-type glucose transporter) protein/mg of cellular membrane protein was observed in the skeletal muscle and fat tissues of the aged rats compared with the young rats.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Altered expression of glucose transporter isoforms with aging in rats--selective decrease in GluT4 in the fat tissue and skeletal muscle. 191 52

Insulin's rapid action to increase glucose transport is believed to occur primarily through the translocation of glucose transporters from an intracellular pool to the plasma membrane. To better understand the mechanism involved, we studied the role of protein synthesis in glucose transporter translocation by using the protein synthesis inhibitor, cycloheximide. Isolated rat epididymal adipose cells were incubated in the presence or absence of cycloheximide (10 micrograms/ml) for a total of 120 min. Insulin (7 nM) was added to half of the cells from both groups for the final 30 min. Protein synthesis was inhibited by approximately 90%, as measured by [14C]leucine incorporation, in the cells exposed to cycloheximide. The 3-O-methylglucose uptake in intact cells was slightly increased in the basal state with cycloheximide treatment, but the insulin-stimulated 3-O-methylglucose uptake was unchanged by cycloheximide. The distribution of glucose transporters in the different subcellular membrane fractions, as measured by the cytochalasin B binding assay, was unchanged by cycloheximide. These results suggest that insulin's stimulation of glucose transport and translocation of glucose transporters can occur without acute protein synthesis.
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PMID:Acute effects of cycloheximide on the translocation of glucose transporters in rat adipose cells. 265 70

Rat epididymal fat cell membrane proteins were extracted from adipocyte ghosts with octylglucoside and incorporated by detergent dialysis into unilamellar phosphatidylcholine vesicles approx. 200 nm in diameter. The rate of glucose transport into the vesicles under zero-trans conditions was substrate dependent, saturable and inhibited by phloretin and cytochalasin B. Their maximum specific transport activity was 35.6 mumol/min per mg protein, and their half saturation constant for glucose was 15 mM. Glucose transport into the reconstituted vesicles was inhibited by only those sugars which competitively inhibited glucose transport into intact adipocytes. A major protein component of the vesicles was a 100 kDa protein which we had previously found to react with the affinity label maltosyl isothiocyanate (Malchoff, D.M., Olansky, L., Pohl, S. and Langdon, R.G. (1981) Fed. Proc. 40, 1893). Removal of adipocyte ghost membrane extrinsic proteins with dimethylmaleic anhydride followed by extraction of the resulting membrane pellet with octylglucoside yielded a solution which contained two major proteins, of Mr 100 000 and 85 000, with very small quantities of lower Mr proteins. Vesicles into which these proteins were incorporated had average specific transport activities of 624 mumol/min per mg protein and half saturation constants of 22 mM. Our results strongly indicate that the native glucose transporter of the rat adipocyte, like that of the human erythrocyte (Shelton, R.L. and Langdon, R.G. (1983) Biochim. Biophys. Acta 733, 25-33), is a 100 kDa protein.
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PMID:Reconstitution of the glucose transport activity of rat adipocytes. 404 Mar 93

The expression of sodium-potassium pumps and glucose transporters in pure adipocyte plasma membranes from a hyperthyroid animal model was studied. Hyperthyroidism was induced by enteral administration of five doses of 90 micrograms of triiodothyronine every second day to 8-week-old rats. Following isolation of epididymal adipocytes, 3-O-methylglucose transport was measured and the number of Na/K-ATPase-(alpha 1- and alpha 2-isoforms) and glucose transporter (GLUT1 and GLUT4) molecules in sheets of adipocyte plasma membrane were determined by quantitative immunoelectron microscopy, using gold labelling. Maximal in vitro insulin stimulation of adipocytes increased the glucose transport rate and the amount of GLUT4 in the plasma membrane 15-fold, whereas the amount of alpha 2 was unaffected. In adipocytes from hyperthyroid rats, mean adipocyte volume was decreased by 18% and the quantities of GLUT4 per unit area of plasma membrane (maximal insulin stimulation) and of alpha 2 were decreased by 19% and 15%, respectively. Thus, hypotrophia of fat tissue in the hyperthyroid state is associated with a decreased expression in the plasma membrane of the glucose transporter GLUT4 and the alpha 2-isoform of Na/K-ATPase.
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PMID:Quantity of Na/K-ATPase and glucose transporters in the plasma membrane of rat adipocytes is reduced by in vivo triiodothyronine. 758 95

(+/-)-5-([4-[2-Methyl-2(pyridylamino)ethoxy]phenyl]methyl) 2,4-thiazolidinedione (BRL 49653) is a new potent antidiabetic agent that improves insulin sensitivity in animal models of NIDDM. In C57BL/6 obese (ob/ob) mice, BRL 49653, included in the diet for 8 days, improved glucose tolerance. The half-maximal effective dose was 3 mumol/kg diet, which is equivalent to approximately 0.1 mg/kg body wt. Improvements in glucose tolerance were accompanied by significant reductions in circulating triacylglycerol, nonesterified fatty acids, and insulin. The insulin receptor number of epididymal white adipocytes prepared from obese mice treated with BRL 49653 (30 mumol/kg diet) for 14 days was increased twofold. The affinity of the receptor for insulin was unchanged. In the absence of added insulin, the rates of glucose transport in adipocytes from untreated and BRL 49653-treated obese mice were similar. Insulin (73 nmol/l) produced only a 1.5-fold increase in glucose transport in adipocytes from control obese mice, whereas after BRL 49653 treatment, insulin stimulated glucose transport 2.8-fold. BRL 49653 did not alter the sensitivity of glucose transport to insulin. The increase in insulin responsiveness was accompanied by a 2.5-fold increase in the total tissue content of the glucose transporter GLUT4. Glucose transport in adipocytes from lean littermates was not altered by BRL 49653. To establish the contribution of changes in glucose transporter trafficking to the BRL 49653-mediated increase in insulin action, the cell-impermeant bis-mannose photolabel 2-N-[4-(1-azi-2,2,2-trifluoroethyl)benzoyl]-1,3-bis-(D-mannos++ +-4-yloxy) -2-[2-3H]-propylamine was used to measure adipocyte cell-surface-associated glucose transporters.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Repeat treatment of obese mice with BRL 49653, a new potent insulin sensitizer, enhances insulin action in white adipocytes. Association with increased insulin binding and cell-surface GLUT4 as measured by photoaffinity labeling. 765 33

High fat feeding is associated with impaired insulin action, an obese body composition, and down-regulation of glucose transporter-4 (GLUT4) expression in adipocytes. We recently showed that overexpression of GLUT4 selectively in adipocytes of transgenic mice using the aP2 (fatty acid-binding protein) promoter/enhancer results in enhanced glucose tolerance and adipocyte hyperplasia. Here, we fed these GLUT4-overexpressing transgenic mice a high fat (55%) or a low fat (10%) diet for 13-15 weeks to determine the role of alterations in GLUT4 expression in adipocytes in the development of insulin resistance and obesity, which are characteristic of high fat consumption. In nontransgenic mice, high fat feeding results in 45-50% reduction of GLUT4 levels in white and brown adipose tissue, with a parallel decrease in insulin-stimulated glucose transport. In transgenic mice receiving the low fat diet, GLUT4 is overexpressed 20-fold in white and 4-fold in brown adipose tissue. Glucose transport in epididymal adipocytes is increased 20-fold in the basal state and 6-fold in the insulin-stimulated state. Even after transgenic mice are fed a high fat diet, GLUT4 expression and glucose transport in their adipocytes remains 14- to 30-fold greater than that in nontransgenic mice receiving the same diet. Despite these marked effects at the adipose cell level, glucose tolerance is not improved, probably due to insulin resistance in skeletal muscle and liver, where the transgene is not expressed. During the low fat diet, transgenic mice have 80% more body lipid than nontransgenics. High fat feeding increases body lipid 76% and adipocyte size 65% in nontransgenic mice, but has no effect in transgenic mice. Thus, overexpression of GLUT4 selectively in adipocytes protects against a further increase in adiposity. Furthermore, by using a heterologous promoter, high level overexpression of GLUT4 can be maintained even under metabolic conditions where it is normally down-regulated in adipocytes. This overexpression results in markedly increased glucose transport at the cellular level, but adipose-specific GLUT4 overexpression does not prevent the decrease in glucose tolerance associated with high fat feeding.
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PMID:High level overexpression of glucose transporter-4 driven by an adipose-specific promoter is maintained in transgenic mice on a high fat diet, but does not prevent impaired glucose tolerance. 786 10

To gain insight into the molecular pathogenesis of obesity and specifically the role of nutrient partitioning in the development of obesity, we overexpressed the insulin-responsive glucose transporter (GLUT4) in transgenic mice under the control of the fat-specific aP2 fatty acid-binding protein promoter/enhancer. Two lines of transgenic mice were generated, which overexpressed GLUT4 6-9-fold in white fat and 3-5-fold in brown fat with no overexpression in other tissues. In vivo glucose tolerance was enhanced in transgenic mice. In isolated epididymal, parametrial, and subcutaneous adipose cells from transgenic mice, basal glucose transport was 20-34-fold greater than in nontransgenic littermates. Insulin-stimulated glucose transport was 2-4-fold greater in cells from transgenic mice. Total body lipid was increased 2-3-fold in transgenic mice overexpressing GLUT4 in fat. Surprisingly, fat cell size was unaltered and fat cell number was increased > 2-fold. This is the first animal model in which increased fat mass results solely from adipocyte hyperplasia and it will be a valuable model for understanding the mechanisms responsible for fat cell replication and/or differentiation in vivo.
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PMID:Adipose cell hyperplasia and enhanced glucose disposal in transgenic mice overexpressing GLUT4 selectively in adipose tissue. 822 28

The effects of englitazone in male Wistar rats fed a high-fat diet (59% of calories as fat) were compared with control rats fed a high-carbohydrate diet (69% of calories as carbohydrate) (5-15 animals per group). Insulin-stimulated (17 nmol/l) 2-deoxy-D-glucose (2-DG) uptake was inhibited 31% in adipocytes isolated from rats on the high-fat diet for 3 weeks, but englitazone (50 mg/kg for the last 7 days) normalized the response. There was a selective decrease in GLUT4 (54 +/- 5% of high-carbohydrate) in epididymal fat from rats on the high-fat diet for 3 weeks, but englitazone treatment did not reverse the defect in GLUT4 (43 +/- 8% of high-carbohydrate) or increase GLUT1 (81 +/- 12% of high-carbohydrate). Englitazone normalized oral glucose (1 g/kg body wt) intolerance and excessive (210% of high-carbohydrate) liver glycogen deposition (from [14C]glucose) caused by the high-fat diet. The high-fat diet tended to decrease insulin receptor substrate-1 (IRS-1) and phosphatidylinositol-3'-kinase (PI-3-kinase) expression in epididymal fat (26% decrease; P < 0.1). Englitazone did not reverse this decrease in IRS-1 and PI-3-kinase levels in fat from high-fat-fed rats (there was a further 25-30% decrease, P < 0.05), nor did it increase PI-3-kinase activity in 3T3-L1 adipocytes under conditions (48 h incubation) where it stimulated 2-DG uptake sixfold or enhanced insulin-stimulated 2-DG uptake. In summary, englitazone prevented the insulin resistance associated with a high-fat diet, but the mechanism of action does not involve changes in fat or muscle glucose transporter content and may not involve activation of the insulin signaling pathway via PI-3-kinase.
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PMID:The antihyperglycemic agent englitazone prevents the defect in glucose transport in rats fed a high-fat diet. 852 61


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