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At least 19 recordsLinked to original sources
PubMed1993

The sulfonylurea drug, glimepiride, stimulates glucose transport, glucose transporter translocation, and dephosphorylation in insulin-resistant rat adipocytes in vitro.

Sulfonylurea drugs are widely used in the therapy of NIDDM. The improvement of glucose tolerance after long-term treatment of NIDDM patients with the drug can be explained by stimulation of glucose utilization in peripheral tissues that are characterized by insulin resistance in these patients. We studied whether the novel sulfonylurea drug, glimepiride, stimulates glucose transport into isolated insulin-resistant rat adipocytes. After long-term incubation of the cells in primary culture with high concentrations of glucose, glutamine, and insulin, stimulation of glucose transport by insulin was significantly reduced both with respect to maximal responsiveness (65% decrease of Vmax) and sensitivity (2.6-fold increase of ED50) compared with adipocytes cultured in medium containing a low concentration of glucose and no insulin. This reflects insulin resistance of glucose transport. In contrast, both responsiveness and sensitivity of glucose transport toward stimulation by glimepiride were only marginally reduced in insulin-resistant adipocytes (15% decrease of Vmax; 1.2-fold increase of ED50) versus control cells. Glimepiride, in combination with glucose and glutamine during the primary culture, caused desensitization of the glucose transport system toward stimulation by insulin, but to a lesser degree than insulin itself (50% reduction of Vmax; ninefold increase of ED50). Again, the maximal responsiveness and sensitivity of glucose transport toward stimulation by glimepiride were only slightly diminished. The presence of glimepiride during primary culture did not antagonize the induction of insulin resistance of glucose transport. The stimulation of glucose transport in insulin-resistant adipocytes by glimepiride is caused by translocation of glucose transporters from low-density microsomes to plasma membranes as demonstrated by subcellular fractionation and immunoblotting with anti-GLUT1 and anti-GLUT4 antibodies. Immunoprecipitation of GLUT4 from 32Pi- and [35S]methionine-labeled adipocytes revealed that the insulin resistance of GLUT4 translocation is accompanied by increased (three- to fourfold) phosphorylation of GLUT4 in both low-density microsomes and plasma membranes. Short-term treatment of desensitized adipocytes with glimepiride or insulin reduced GLUT4 phosphorylation by approximately 70 and 25%, respectively, in both fractions. We conclude that glimepiride activates glucose transport by stimulation of GLUT1 and GLUT4 translocation in rat adipocytes via interference at a site downstream of the putative molecular defect in the signaling cascade between the insulin receptor and the glucose transport system induced by high concentrations of glucose and insulin. The molecular site of glimepiride action is related to GLUT4 phosphorylation/dephosphorylation, which may regulate glucose transporter activity and translocation.(ABSTRACT TRUNCATED AT 400 WORDS)

Adipocytes↗
PubMed1991

Muscle insulin resistance in uremic humans: glucose transport, glucose transporters, and insulin receptors.

To determine the cellular basis for insulin resistance observed in patients with uremia, we investigated insulin action in vivo and in vitro using skeletal muscle obtained from patients with chronic renal failure. Uremic subjects had significantly reduced rates of insulin-stimulated glucose disposal, as determined by a 3-h intravenous glucose tolerance test and using the hyperinsulinemic euglycemic clamp technique. Hepatic glucose production was similar before (control, 76.2 +/- 6.3 vs. uremic, 74.2 +/- 6.9 mg.kg-1.min-1) and during insulin infusion at 40 mU.m-2.min-1 (control, -60.9 +/- 6.6 vs. uremic, -53.9 +/- 6.3 mg.kg-1.min-1). In incubated human skeletal muscle fiber strips, basal 2-deoxy-D-glucose transport was unchanged in uremic subjects compared with controls. However, the increase in insulin-stimulated glucose transport was significantly reduced by 50% in muscles from uremic patients (P = 0.012). In partially purified insulin receptors prepared from skeletal muscle, 125I-labeled insulin binding, beta-subunit receptor autophosphorylation, and tyrosine kinase activity were all unchanged in uremic subjects. The abundance of insulin-sensitive (muscle/fat, GLUT-4) glucose transporter protein measured by Western blot using Mab 1F8 or polyclonal antisera was similar in muscles of control and uremic patients. These findings suggest that the insulin resistance observed in skeletal muscle of uremic patients cannot be attributed to defects in insulin receptor function or depletion of the GLUT-4 glucose transporter protein. An alternative step in insulin-dependent activation of the glucose transport process may be involved.

Adult↗
PubMed1972

Effects of organic mercurials on mammalian pancreatic -cells. Insulin release, glucose transport, glucose oxidation, membrane permeability and ultrastructure.

The effects of p-chloromercuribenzoic acid and chloromercuribenzene-p-sulphonic acid on pancreatic islets were studied in vitro. Obese-hyperglycaemic mice were used as the source of microdissected islets containing more than 90% beta-cells. p-Chloromercuribenzoic acid and chloromercuribenzene-p-sulphonic acid stimulated insulin release at concentrations of 0.01mm or above. This stimulation was significantly inhibited by the omission of Ca(2+) or the addition of adrenaline, diazoxide or 2,4-dinitrophenol. p-Chloromercuribenzoic acid or chloromercuribenzene-p-sulphonic acid did not interfere with the insulin-releasing ability of glucose. Micro-perifusion experiments revealed that the release of insulin in response to organic mercurial occurred almost instantaneously, was reversible, and was biphasic. The two mercurials inhibited glucose transport as well as glucose oxidation, and increased the mannitol and sucrose spaces of isolated islets. Compared with the effects on insulin release, those on glucose transport and membrane permeability were characterized by a longer latency and/or required higher concentrations of organic mercurial. Apart from a seemingly higher proportion of beta-cells exhibiting certain degenerative features, in islets exposed to 0.1mm-chloromercuribenzene-p-sulphonic acid for 60min, no significant differences with respect to beta-cell fine structure were noted between non-incubated islets and islets incubated with chloromercuribenzene-p-sulphonic acid or glucose or both. It is suggested that insulin release may be regulated by relatively superficial thiol groups in the beta-cell plasma membrane.

Animals↗
PubMed1997

Listeria monocytogenes Scott A transports glucose by high-affinity and low-affinity glucose transport systems.

Listeria monocytogenes transported glucose by a high-affinity phosphoenolpyruvate-dependent phosphotransferase system and a low-affinity proton motive force-mediated system. The low-affinity system (Km = 2.9 mM) was inhibited by 2-deoxyglucose and 6-deoxyglucose, whereas the high-affinity system (Km = 0.11 mM) was inhibited by 2-deoxyglucose and mannose but not 6-deoxyglucose. Cells and vesicles artificially energized with valinomycin transported glucose or 2-deoxyglucose at rates greater than those of de-energized cells, indicating that a membrane potential could drive uptake by the low-affinity system.

Biological Transport↗
PubMed1993

The role of skeletal muscle in glucose transport, glucose homeostasis, and insulin resistance: implications for physical therapy.

Skeletal muscle has a fundamentally important role in the maintenance of normal glucose homeostasis and in regulating whole-body carbohydrate metabolism. In this review, we discuss the regulation of skeletal muscle glucose transport by muscular activity and inactivity. A large number of patients routinely seen by physical therapists exhibit some form of skeletal muscle insulin resistance. Therefore, we discuss how skeletal muscle insulin resistance can be localized to a relatively small muscle mass, or in other circumstances can affect a large proportion of the muscle mass leading to disturbances in whole-body glucose homeostasis. We review the mechanisms and regulation of skeletal muscle glucose transport as background for understanding how defects in this process may contribute to the underlying pathogenesis of insulin resistance. Research into the events regulating glucose entry into skeletal muscles has considerable impact on how physical therapy exercise prescriptions may benefit patients with disturbances in carbohydrate metabolism. With an understanding of the principles of proper exercise prescription, physical therapists can use exercise training as a primary therapeutic intervention to improve local muscle and whole-body glucose utilization, and thereby minimize insulin resistance.

Blood Glucose↗
PubMed1988

Effects of insulin on glucose transport and glucose transporters in rat heart.

The effect of insulin on glucose transport and glucose transporters was studied in perfused rat heart. Glucose transport was measured by the efflux of labelled 3-O-methylglucose from hearts preloaded with this hexose. Insulin stimulated 3-O-methylglucose transport by: (a) doubling the maximal velocity (Vmax); (b) decreasing the Kd from 6.9 to 2.7 mM; (c) increasing the Hill coefficient toward 3-O-methylglucose from 1.9 to 3.1; (d) increasing the efficiency of the transport process (k constant). Glucose transporters in enriched plasma and microsomal membranes from heart were quantified by the [3H]cytochalasin-B-binding assay. When added to normal hearts, insulin produced the following changes in the glucose transporters: (a) it increased the translocation of transporters from an intracellular pool to the plasma membranes; (b) it increased (from 1.6 to 2.7) the Hill coefficient of the transporters translocated into the plasma membranes toward cytochalasin B, suggesting the existence of a positive co-operativity among the transporters appearing in these membranes; (c) it increased the affinity of the transporters (and hence, possibly, of glucose) for cytochalasin B. The data provide evidence that the stimulatory effect of insulin on glucose transport may be due not to the sole translocation of intracellular glucose transporters to the plasma membrane, but to changes in the functional properties thereof.

3-O-Methylglucose↗
PubMedDate not supplied

[Recent data on the regulation of glucose transport and glucose transporters in insulin-sensitive tissues].

This review concerns the acute and long-term regulation of glucose transport. In insulin-sensitive tissues, the acute effect of insulin on this process occurs mainly through the translocation of glucose transport proteins (glucose transporters) from an intracellular pool to the plasma membrane. Some other factors are also able to modify acutely glucose transport by the translocation mechanism. However, recent data are reported which indicate that in addition, modifications of the glucose transporters activity are involved. The long-term regulation of the glucose transport capacity has been less studied. In different types of cultured cells, a role of two factors, glucose and insulin, has been clearly shown. The availability of cDNA probes encoding for glucose transporters, has given the opportunity to study the molecular regulation of glucose transport. However, it appears that different sub-types of glucose transport proteins exist which might be regulated in a specific manner depending on the cell-type and the regulatory factor. The existence of an insulin-sensitive glucose transporter is strongly suggested. The regulation of this protein, which could be specifically involved in insulin resistant physiopathological situations, remains to be studied.

Adipose Tissue↗
PubMed1996

Okadaic acid exerts a full insulin-like effect on glucose transport and glucose transporter 4 translocation in human adipocytes. Evidence for a phosphatidylinositol 3-kinase-independent pathway.

The effects of the serine/threonine phosphatase inhibitor, okadaic acid, and insulin on glucose transport activity, glucose transporter 4 translocation to the plasma membrane, and the signaling pathway of insulin were examined in human adipocytes. Okadaic acid consistently produced a greater increase than insulin in the rate of glucose transport, and both agents together had a partial additive effect. Both insulin alone and okadaic acid alone stimulated the translocation of glucose transporter 4 to the plasma membrane. Insulin, but not okadaic acid, stimulated phosphatidylinositol 3-kinase (PI 3-kinase) activity, and wortmannin completely inhibited the effect of insulin on glucose transport. When the cells were incubated with both agents, okadaic acid inhibited insulin-stimulated PI 3-kinase activity but did not block the association of the p85 or p110 subunits of PI 3-kinase with insulin receptor substrate 1. Insulin-stimulated tyrosine phosphorylation of insulin receptor substrate 1 was only slightly reduced (15-30%) by okadaic acid. These data demonstrate that okadaic acid exerts a full insulin-like effect independent of the activation of PI 3-kinase. Thus, PI 3-kinase lipid kinase is not essential for glucose transporter 4 translocation in human adipocytes, and different pathways exist that lead to glucose transporter 4 translocation and increased glucose transport.

Adipocytes↗
PubMed1995

Pioglitazone treatment for 7 days failed to correct the defect in glucose transport and glucose transporter translocation in obese Zucker rat (fa/fa) skeletal muscle plasma membranes.

Insulin resistance in the obese (fa/fa) Zucker rat is associated with decreased insulin stimulated glucose transport in skeletal muscle, due primarily to a failure of insulin to stimulate GLUT4 translocation to the plasma membrane from an intracellular pool (1). The thiazolidinedione analog Pioglitazone (PIO) has been shown to improve glucose tolerance in this and other animal models of insulin resistance. The current study was designed to determine whether 7 days of Pioglitazone treatment (20 mg/kg/day by gavage) would improve glucose transport and/or glucose transporter translocation and intrinsic activity in plasma membranes prepared from hindlimb skeletal muscle of obese Zucker (fa/fa) rats. Basal plasma glucose and insulin concentrations in these animals were unchanged by Pioglitazone, while basal plasma triglyceride and nonesterified fatty acid concentrations (NEFA) were reduced by Pioglitazone treatment (501 +/- 88 vs 161 +/- 13 mg/dl, P < 0.0001) and (678 +/- 95 vs 467 +/- 75 microM, P < 0.05) respectively. Pioglitazone had no effect on basal or insulin stimulated glucose influx (Vmax or Km) into plasma membrane vesicles determined under equilibrium exchange conditions compared to controls. Plasma membrane glucose transporter number (R0) (measured by cytochalasin B binding) under basal or insulin stimulated conditions was unchange by Pioglitazone and R0 failed to increase following insulin stimulation in either group. Glucose transporter turnover number (Vmax/R0) increased 2-fold with insulin stimulation compared to basal in both control and Pioglitazone groups, similar to turnover numbers observed in normal rats. These data confirm that impaired glucose transporter translocation in muscle of the Zucker rat is a major factor contributing to its insulin resistance. We conclude that the improved glucose tolerance observed in fa/fa rats following Pioglitazone treatment is not due to an improvement in basal or insulin stimulated skeletal muscle plasma membrane glucose transport or glucose transporter translocation and that Pioglitazone treatment does not affect transporter intrinsic activity.

Animals↗
PubMed1995

Multiple roles of phosphatidylinositol 3-kinase in regulation of glucose transport, amino acid transport, and glucose transporters in L6 skeletal muscle cells.

Phosphatidylinositol 3-kinase (PI3k) activity is required for the insulin stimulation of glucose transport in adipocytes and Chinese hamster ovary cells. Wortmannin (WM), an inhibitor of PI3k, inhibits the stimulation of glucose transport by insulin and the gain of glucose transporters at the cell surface. However, the effect of inhibition of PI3k on the maintenance of the basal and the insulin-stimulated glucose transport and on the intracellular donor pool of glucose transporters has not been clarified. Here we show that in L6 skeletal muscle cells in culture WM significantly inhibits the basal PI3k activity (by 40%), decreases the levels of phosphatidylinositol 3,4-phosphate and 3,4,5-phosphate (by about 50%) and abolishes the activation of the enzyme by insulin. WM inhibited the basal rate of transport of glucose (by 45%) and of amino acids through system A (by 25%) and abolished their stimulation by insulin. Insulin caused a transient increase in PI3k activity and PI3k products that returned to basal levels within 40 min, whereas glucose and amino acid transport remained elevated. Under these conditions, WM reduced the rate of glucose and amino acid transport back to basal levels. In unstimulated cells, WM decreased significantly the GLUT4 glucose transporter content at the plasma membrane and prevented the ability of insulin to recruit transporters to this membrane. Interestingly, the intracellular pools of the GLUT3 and GLUT4 glucose transporters were significantly reduced in response to WM treatment alone. We conclude that in muscle cells PI3k activity is required to maintain basal and insulin-stimulated glucose and amino acid transport, as well as to develop the stimulation of the two transport processes in response to the hormone. We hypothesize that PI3k, likely through production of phosphatidylinositol 3,4-phosphate and 3,4,5-phosphate, regulates the basal plasma membrane glucose transporter recycling and the organization of the transporter intracellular pool, in addition to being an insulin signal.

Amino Acids↗
PubMed1997

Glucose transport and glucose transporter GLUT4 are regulated by product(s) of intermediary metabolism in cardiomyocytes.

Alternative substrates of energy metabolism are thought to contribute to the impairment of heart and muscle glucose utilization in insulin-resistant states. We have investigated the acute effects of substrates in isolated rat cardiomyocytes. Exposure to lactate, pyruvate, propionate, acetate, palmitate, beta-hydroxybutyrate or alpha-oxoglutarate led to the depression of glucose transport by up to 50%, with lactate, pyruvate and propionate being the most potent agents. The percentage inhibition was greater in cardiomyocytes in which glucose transport was stimulated with the alpha-adrenergic agonist phenylephrine or with a submaximal insulin concentration than in basal or fully insulin-stimulated cells. Cardiomyocytes from fasted or diabetic rats displayed a similar sensitivity to substrates as did cells from control animals. On the other hand, the amination product of pyruvate (alanine), as well as valine and the aminotransferase inhibitors cycloserine and amino-oxyacetate, stimulated glucose transport about 2-fold. In addition, the effect of pyruvate was counteracted by cycloserine. Since reversible transamination reactions are known to affect the pool size of the citrate cycle, the influence of substrates, amino acids and aminotransferase inhibitors on citrate, malate and glutamate content was examined. A significant negative correlation was found between alterations in glucose transport and the levels of citrate (P < 0.01) or malate (P < 0.01), and there was a positive correlation between glucose transport and glutamate levels (P < 0.05). In contrast, there was no correlation with changes in [1-(14)C]pyruvate oxidation or in glucose-6-phosphate levels. Finally, pyruvate decreased the abundance of GLUT4 glucose transporters at the surface of phenylephrine- or insulin-stimulated cells by 34% and 27 % respectively, as determined by using the selective photoaffinity label [3H]ATB-BMPA [[3H]2-N-[4-(1-azi-2,2,2-trifluoroethyl)benzoyl]-1,3-bis-(D-man nos-4-yloxy)propyl-2-amine]. In conclusion, cardiomyocyte glucose transport is subject to counter-regulation by alternative substrates. The glucose transport system appears to be controlled by (a) compound(s) of intermediary metabolism (other than glucose 6-phosphate), but in a different way than pyruvate dehydrogenase. Transport inhibition eventually occurs via a decrease in the amount of glucose transporters in the plasma membrane.

3-Hydroxybutyric Acid↗
PubMed1995

Direct stimulation of myocardial glucose transport and glucose transporter-1 (GLUT1) and GLUT4 protein expression by the sulfonylurea glimepiride.

Freshly isolated and primary cultured cardiac myocytes from adult rats were used to elucidate acute and chronic effects of the sulfonylurea drug glimepiride on basal and insulin-stimulated glucose transport and on expression of the transporter isoforms glucose transporter-1 (GLUT1) and GLUT4. A 30-min incubation with glimepiride (100 microM) was unable to modify the initial rates of 3-O-methylglucose transport in freshly isolated cardiocytes, both in the absence or presence of insulin (10(-7) M). Cells were then kept in serum-free culture for 20 h in the presence of glimepiride (10 microM) and a physiological insulin dose. Under these conditions, the sulfonylurea induced an increase in 2-deoxyglucose uptake to 186% of control. This drug effect was dose dependent and could also be demonstrated in the absence of insulin during the culture period. The acute action of insulin on glucose transport was additive to the effect of glimepiride, and the insulin responsiveness of glucose transport remained unaltered in sulfonylurea-treated cultures. Western blot analysis of crude membrane fractions obtained from cultured cardiocytes showed that glimepiride increased the expression of both GLUT1 and GLUT4 to 164% +/- 21% and 148% +/- 5% of control, respectively. We concluded that glimepiride increases cardiac glucose uptake by an insulin-independent pathway, probably involving an increased protein expression of GLUT1 and GLUT4. The increased expression of GLUT4 may have a therapeutic impact on the treatment of insulin-resistant states.

3-O-Methylglucose↗
PubMed1997

Regulation of glucose transport, and glucose transporters expression and trafficking in the heart: studies in cardiac myocytes.

Cardiac muscle is characterized by a high rate of glucose consumption. In the absence of insulin, glucose transport into cardiomyocytes limits the rate of glucose utilization and therefore it is important to understand the regulation of glucose transporters. Cardiac muscle cells express 2 distinct glucose transporters, GLUT4 and GLUT1; although GLUT4 is quantitatively the more important glucose transporter expressed in heart, GLUT1 is also expressed at a substantial level. In isolated rat cardiomyocytes, insulin acutely stimulates glucose transport and translocates both GLUT4 and GLUT1 from an intracellular site to the cell surface. Recent evidence indicates the existence of at least 2 distinct intracellular membrane populations enriched in GLUT4 with a different protein composition. Elucidation of the intracellular location of these 2 GLUT4 vesicle pools in cardiac myocytes, their role in GLUT4 trafficking, and their relation to insulin-induced GLUT4 translocation needs to be addressed.

Animals↗
PubMed1990

Glucose transport and glucose transporters in muscle and their metabolic regulation.

Skeletal muscle is the primary tissue responsible for insulin-dependent glucose uptake in vivo; therefore, glucose uptake by this tissue plays an important role in determining glycemia. Glucose uptake in muscle occurs by a system of facilitated diffusion involving at least two distinct glucose transporters, GLUT-1 and GLUT-4. Both bind the fungal metabolite and inhibitor of glucose transport cytochalasin B. In human skeletal muscle, both types of transporters are detected immunologically, and corresponding mRNA transcripts of both transporter forms are detected. In human skeletal muscle cells in culture, in which contamination by other tissues is ruled out, a 50,000-Mr polypeptide is photolabeled with cytochalasin B. In rat skeletal muscle, acute treatment with insulin in vivo increases glucose-transport activity and the number of specific cytochalasin B-binding sites at the plasma membrane. In mildly diabetic (streptozocin-induced) rats, the number of cytochalasin B-binding sites is decreased in total membranes, and preferentially in the plasma membrane. In response to acute insulin treatment, however, there is still recruitment of glucose transporters to the plasma membrane from an intracellular membrane store. Hence, migration of transporters does occur in this form of diabetes. In L6 muscle cells in culture, acute treatment (1 h) with insulin causes recruitment of glucose transporters to the plasma membrane, and prolonged exposure to insulin or to glucose-deprived medium causes increased expression of GLUT-1 mRNA and GLUT-1 protein. Prolonged exposure (24 h) to high glucose in the medium causes a decrease in the number of glucose transporters in the plasma membrane. Hence, in those cells the expression of the GLUT-1 glucose transporter is modulated by insulin.

Animals↗
PubMed1992

Restoration of insulin responsiveness in skeletal muscle of morbidly obese patients after weight loss. Effect on muscle glucose transport and glucose transporter GLUT4.

A major defect contributing to impaired insulin action in human obesity is reduced glucose transport activity in skeletal muscle. This study was designed to determine whether the improvement in whole body glucose disposal associated with weight reduction is related to a change in skeletal muscle glucose transport activity and levels of the glucose transporter protein GLUT4. Seven morbidly obese (body mass index = 45.8 +/- 2.5, mean +/- SE) patients, including four with non-insulin-dependent diabetes mellitus (NIDDM), underwent gastric bypass surgery for treatment of their obesity. In vivo glucose disposal during a euglycemic clamp at an insulin infusion rate of 40 mU/m2 per min was reduced to 27% of nonobese controls (P less than 0.01) and improved to 78% of normal after weight loss of 43.1 +/- 3.1 kg (P less than 0.01). Maximal insulin-stimulated glucose transport activity in incubated muscle fibers was reduced by approximately 50% in obese patients at the time of gastric bypass surgery but increased twofold (P less than 0.01) to 88% of normal in five separate patients after similar weight reduction. Muscle biopsies obtained from vastus lateralis before and after weight loss revealed no significant change in levels of GLUT4 glucose transporter protein. These data demonstrate conclusively that insulin resistance in skeletal muscle of mobidly obese patients with and without NIDDM cannot be causally related to the cellular content of GLUT4 protein. The results further suggest that morbid obesity contributes to whole body insulin resistance through a reversible defect in skeletal muscle glucose transport activity. The mechanism for this improvement may involve enhanced transporter translocation and/or activation.

Adult↗
PubMed1993

Glucose transporters and glucose transport in skeletal muscles of 1- to 25-mo-old rats.

It is widely thought that aging results in development of insulin resistance in skeletal muscle. In this study, we examined the effects of growth and aging on the concentration of the GLUT-4 glucose transporter and on glucose transport activity in skeletal muscles of female Long-Evans rats. Relative amounts of immunoreactive GLUT-4 protein were measured in muscle homogenates of 1-, 10-, and 25-mo-old rats by immunoblotting with a polyclonal antibody directed against GLUT-4. In the epitrochlearis, plantaris, and the red and white regions of the quadriceps muscles, GLUT-4 immunoreactivity decreased by 14-33% between 1 and 10 mo of age and thereafter remained constant. In flexor digitorum brevis (FDB) and soleus muscles, GLUT-4 concentration was similar at all three ages studied. Glucose transport activity was assessed in epitrochlearis and FDB muscles by incubation with 2-deoxyglucose under the following conditions: basal, submaximal insulin, and either maximal insulin or maximal insulin combined with contractile activity. Glucose transport in the epitrochlearis muscle decreased by approximately 60% between 1 and 4 mo of age and then did not decline further between 4 and 25 mo of age. Transport activity in the FDB assessed with a maximally effective insulin concentration decreased only slightly (< 20%) between 1 and 7 mo of age. Aging, i.e., the transition from young adulthood to old age, was not associated with a decrease in glucose transport activity in either the epitrochlearis or the FDB.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗
PubMed1990

Skeletal muscle plasma membrane glucose transport and glucose transporters after exercise.

Recent reports have shown that immediately after an acute bout of exercise the glucose transport system of rat skeletal muscle plasma membranes is characterized by an increase in both glucose transporter number and intrinsic activity. To determine the duration of the exercise response we examined the time course of these changes after completion of a single bout of exercise. Male rats were exercised on a treadmill for 1 h (20 m/min, 10% grade) or allowed to remain sedentary. Rats were killed either immediately or 0.5 or 2 h after exercise, and red gastrocnemius muscle was used for the preparation of plasma membranes. Plasma membrane glucose transporter number was elevated 1.8- and 1.6-fold immediately and 30 min after exercise, although facilitated D-glucose transport in plasma membrane vesicles was elevated 4- and 1.8-fold immediately and 30 min after exercise, respectively. By 2 h after exercise both glucose transporter number and transport activity had returned to nonexercised control values. Additional experiments measuring glucose uptake in perfused hindquarter muscle produced similar results. We conclude that the reversal of the increase in glucose uptake by hindquarter skeletal muscle after exercise is correlated with a reversal of the increase in the glucose transporter number and activity in the plasma membrane. The time course of the transport-to-transporter ratio suggests that the intrinsic activity response reverses more rapidly than that involving transporter number.

Animals↗
PubMed1995

Action of metformin on glucose transport and glucose transporter GLUT1 and GLUT4 in heart muscle cells from healthy and diabetic rats.

The effects of the antidiabetic drug metformin on glucose transport were investigated in freshly isolated heart muscle cells from healthy and streptozotocin-diabetic rats. In vivo treatment of diabetic rats with metformin failed to affect the basal and insulin-stimulated rate of glucose transport measured in isolated cells. In vitro exposure to therapeutic concentrations (< or = 10(-4) M) of metformin did not influence glucose transport, even upon incubation times up to 5 h or in the presence of high glucose (20 nM). In contrast, higher metformin concentrations produced an 8- to 12-fold increase in glucose uptake (with a lag of 90 min, and a maximum at 180 min and approximately 5 mM). In the presence of submaximal insulin concentrations (< or = 3.10(-10) M), the effects of metformin (5 mM) and of insulin were more than additive, whereas, at saturating insulin concentrations (10(-8) M), partial additivity was observed. Like insulin, metformin caused an approximately 1.6-fold increase in the content of both glucose transporter isoforms GLUT1 and GLUT4 in the plasma membrane of cardiac myocytes, with a corresponding decrease in an intracellular membrane fraction. cAMP-elevating treatments depressed the metformin-, but not the insulin-dependent glucose uptake, by 20-30%. In myocytes from diabetic rats, the rate of metformin-activated glucose transport was similar to that of cells from control animals, whereas basal and insulin-stimulated transport were substantially diminished. Finally, metformin (5 mM) induced a slight depression of oxygen consumption and energy metabolism of myocytes (as determined by measuring their level of energy-rich phosphates) comparable to the effects of hypoxia in rat hearts. In conclusion, these data do not provide evidence in favor of the hypothesis that glucose uptake by muscle tissue represents the site of metformin's therapeutic action in vivo. On the other hand, the large, insulin-independent effect of metformin at high concentrations (approximately mM) in vitro may be related to the action of hypoxia and occurs through a redistribution of glucose carriers from an intracellular locus to the plasma membrane. The mechanism (or signal) involved in metformin's action is likely to differ from that triggered by insulin and is not impaired in the diabetic state.

Animals↗