Assessment of the antidiabetic potential of selected medicinal plants using in vitro bioassays of muscle glucose transport and liver glucose production

Exercise stimulates insulin-independent glucose transport in skeletal muscle and also increases the sensitivity of the glucose transport process in muscle to insulin. A previous study [D. A. Young, H. Wallberg-Henriksson, M. D. Sleeper, and J. O. Holloszy. Am. J. Physiol. 253 (Endocrinol. Metab. 16): E331–E335, 1987] showed that the exercise-induced increase in glucose transport activity disappears rapidly when rat epitrochlearis muscles are incubated for 3 h in vitro in the absence of insulin and that 7.5 microU/ml insulin in the incubation medium apparently slowed the loss of enhanced sugar transport. We examined whether addition of insulin several hours after exercise increases glucose transport to the same extent as continuous insulin exposure. Addition of 7.5 microU/ml insulin 2.5 h after exercise (when glucose transport has returned to basal levels) increased sugar transport to the same level as that which resulted from continuous insulin exposure. This finding provides evidence for an increase in insulin sensitivity rather than a slowing of reversal of the exercise-induced increase in insulin-independent glucose transport activity. Glucose transport was enhanced only at submaximal, not at maximal, insulin concentrations. Exposure to a high concentration of glucose and a low insulin concentration reduced the exercise-induced increase in insulin-sensitive glucose transport. Incubation with a high concentration of 2-deoxy-D-glucose (2-DG) did not alter the increase in insulin sensitivity, even though a large amount of 2-DG entered the muscle and was phosphorylated.(ABSTRACT TRUNCATED AT 250 WORDS)

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Muscle glucose transport: interactions of in vitro contractions, insulin, and exercise

Journal of Applied Physiology ◽

10.1152/jappl.1988.64.6.2329 ◽

1988 ◽

Vol 64 (6) ◽

pp. 2329-2332 ◽

Cited By ~ 66

Author(s):

S. H. Constable ◽

R. J. Favier ◽

G. D. Cartee ◽

D. A. Young ◽

J. O. Holloszy

Keyword(s):

Glucose Transport ◽

Prolonged Exposure ◽

Contractile Activity ◽

Intracellular Water ◽

Control Value ◽

High Insulin ◽

Muscle Glucose Transport ◽

High Insulin Concentration

Exercise increases permeability of muscle to glucose. Normally, the effects of exercise and a maximal insulin stimulus on glucose transport are additive. However, the combined effect on rat epitrochlearis muscle permeability to 3-O-methylglucose (3-MG) of a maximal insulin stimulus followed by in vitro contractile activity of 1.24 +/- 0.06 mumol.10 min-1.ml intracellular water-1 was no greater than that of either stimulus alone. We found that this absence of an additive effect was caused by prolonged exposure to an unphysiologically high insulin concentration (20,000 microU/ml for 60 min), which, in addition to stimulating glucose transport, appears to prevent further increases in permeability to glucose. When the treatments were reversed and muscles were first stimulated to contract and then incubated with 20,000 microU/ml insulin, 3-MG uptake (mumol.10 min-1.ml intracellular water-1) increased from a control value of 0.26 +/- 0.03 to 1.80 +/- 0.15, compared with 1.04 +/- 0.06 for contractile activity alone, 1.21 +/- 0.08 for insulin, and 1.88 +/- 0.11 for exercise (swimming) plus insulin. Swimming plus in vitro contractile activity did not have a greater effect than contractile activity alone. Our results provide evidence that 1) the effect of exercise on muscle permeability to glucose is mediated solely by a process associated with contractile activity, and 2) it is advisable to avoid the use of unphysiologically high insulin concentrations in studies designed to elucidate in vivo actions of insulin.

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Exercise increases susceptibility of muscle glucose transport to activation by various stimuli

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1990.258.2.e390 ◽

1990 ◽

Vol 258 (2) ◽

pp. E390-E393 ◽

Cited By ~ 33

Author(s):

G. D. Cartee ◽

J. O. Holloszy

Keyword(s):

Insulin Sensitivity ◽

Glucose Transport ◽

Sugar Transport ◽

Insulin Binding ◽

Insulin Mimetic ◽

Increased Sensitivity ◽

Muscle Glucose Transport ◽

Glucose Analogue ◽

Stimulation Of

The insulin sensitivity of glucose transport in skeletal muscle is enhanced after exercise. In this study, stimulation of transport of the nonmetabolizable glucose analogue 3-O-methylglucose by the insulin-mimetic agents vanadate and H2O2 was markedly enhanced in rat epitrochlearis muscles 18 h after a bout of swimming. This increase in susceptibility of the glucose transport process in muscle to stimulation by insulin-mimetic agents that act beyond the insulin-binding step provides evidence that the increased insulin sensitivity results from an effect of exercise on a later step in the activation of glucose transport. Hypoxia and insulin appear to stimulate glucose transport by different pathways in muscle as evidenced by an additivity of their maximal effects. The effect of a submaximal hypoxic stimulus on muscle sugar transport was greatly amplified 3 h after exercise. This increase in susceptibility of glucose transport to stimulation by hypoxia after exercise suggests that the increased sensitivity is not limited to the insulin sensitive pathway. In contrast to exercise (i.e., swimming), in vitro muscle contractions did not result in an increase in sensitivity of muscle glucose transport to insulin, raising the possibility that a humoral factor is necessary for this effect.

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Activation of AMP kinase enhances sensitivity of muscle glucose transport to insulin

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.2002.282.1.e18 ◽

2002 ◽

Vol 282 (1) ◽

pp. E18-E23 ◽

Cited By ~ 186

Author(s):

Jonathan S. Fisher ◽

Jiaping Gao ◽

Dong-Ho Han ◽

John O. Holloszy ◽

Lorraine A. Nolte

Keyword(s):

Insulin Sensitivity ◽

Glucose Transport ◽

Fold Increase ◽

Amp Kinase ◽

Major Purpose ◽

Acute Increase ◽

Exercise Induced ◽

Muscle Glucose Transport ◽

Pkb Phosphorylation

Evidence has accumulated that activation of AMP kinase (AMPK) mediates the acute increase in glucose transport induced by exercise. As the exercise-induced, insulin-independent increase in glucose transport wears off, it is followed by an increase in muscle insulin sensitivity. The major purpose of this study was to determine whether hypoxia and 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAR), which also activate AMPK and stimulate glucose transport, also induce an increase in insulin sensitivity. We found that the increase in glucose transport in response to 30 μU/ml insulin was about twofold greater in rat epitrochlearis muscles that had been made hypoxic or treated with AICAR 3.5 h previously than in untreated control muscles. This increase in insulin sensitivity was similar to that induced by a 2-h bout of swimming or 10 min of in vitro electrically stimulated contractions. Neither phosphatidylinositol 3-kinase activity nor protein kinase B (PKB) phosphorylation in response to 30 μU/ml insulin was enhanced by prior exercise or AICAR treatment that increased insulin sensitivity of glucose transport. Inhibition of protein synthesis by inclusion of cycloheximide in the incubation medium for 3.5 h after exercise did not prevent the increase in insulin sensitivity. Contractions, hypoxia, and treatment with AICAR all caused a two- to three-fold increase in AMPK activity over the resting level. These results provide evidence that the increase in insulin sensitivity of muscle glucose transport that follows exercise is mediated by activation of AMPK and involves a step beyond PKB in the pathway by which insulin stimulates glucose transport.

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Dietary conjugated linoleic acid isomers (cis-9, trans-11 and trans-10, cis-12) modulate insulin-dependent and independent skeletal muscle glucose transport in vitro

Canadian Journal of Diabetes ◽

10.1016/s1499-2671(09)33093-2 ◽

2009 ◽

Vol 33 (3) ◽

pp. 219

Author(s):

S. Mohankumar ◽

C. Taylor ◽

P. Zahradka

Keyword(s):

Skeletal Muscle ◽

Linoleic Acid ◽

Conjugated Linoleic Acid ◽

Glucose Transport ◽

Dietary Conjugated Linoleic Acid ◽

Insulin Dependent ◽

Muscle Glucose Transport

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Insulin resistance of muscle glucose transport in male and female rats fed a high-sucrose diet

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1999.276.3.r665 ◽

1999 ◽

Vol 276 (3) ◽

pp. R665-R672 ◽

Cited By ~ 14

Author(s):

Jong-Yeon Kim ◽

Lorraine A. Nolte ◽

Polly A. Hansen ◽

Dong-Ho Han ◽

Kentaro Kawanaka ◽

...

Keyword(s):

Insulin Resistance ◽

Glucose Transport ◽

Visceral Fat ◽

High Fat Diets ◽

Sucrose Diet ◽

High Sucrose Diet ◽

Fat Diets ◽

Muscle Glucose Transport ◽

High Sucrose

It has been reported that, unlike high-fat diets, high-sucrose diets cause insulin resistance in the absence of an increase in visceral fat and that the insulin resistance develops only in male rats. This study was done to 1) determine if isolated muscles of rats fed a high-sucrose diet are resistant to stimulation of glucose transport when studied in vitro and 2) obtain information regarding how the effects of high-sucrose and high-fat diets on muscle insulin resistance differ. We found that, compared with rat chow, semipurified high-sucrose and high-starch diets both caused increased visceral fat accumulation and insulin resistance of skeletal muscle glucose transport. Insulin responsiveness of 2-deoxyglucose (2-DG) transport measured in epitrochlearis and soleus muscles in vitro was decreased ∼40% ( P < 0.01) in both male and female rats fed a high-sucrose compared with a chow diet. The high-sucrose diet also caused resistance of muscle glucose transport to stimulation by contractions. There was a highly significant negative correlation between stimulated muscle 2-DG transport and visceral fat mass. In view of these results, the differences in insulin action in vivo observed by others in rats fed isocaloric high-sucrose and high-starch diets must be due to additional, specific effects of sucrose that do not carry over in muscles studied in vitro. We conclude that, compared with rat chow, semipurified high-sucrose and high-cornstarch diets, like high-fat diets, cause increased visceral fat accumulation and severe resistance of skeletal muscle glucose transport to stimulation by insulin and contractions.

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Increased expression of GLUT-4 and hexokinase in rat epitrochlearis muscles exposed to AICAR in vitro

Journal of Applied Physiology ◽

10.1152/jappl.2000.88.3.1072 ◽

2000 ◽

Vol 88 (3) ◽

pp. 1072-1075 ◽

Cited By ~ 107

Author(s):

Edward O. Ojuka ◽

Lorraine A. Nolte ◽

John O. Holloszy

Keyword(s):

Protein Kinase ◽

Glucose Uptake ◽

Glucose Transport ◽

Strong Evidence ◽

Culture Medium ◽

Glut 4 ◽

Muscle Glucose Transport ◽

Stimulation Of

Exercise acutely stimulates muscle glucose transport and also brings about an adaptive increase in the capacity of muscle for glucose uptake by inducing increases in GLUT-4 and hexokinase.1 Recent studies have provided evidence that activation of AMP protein kinase (AMPK) is involved in the stimulation of glucose transport by exercise. The purpose of this study was to determine whether activation of AMPK is also involved in mediating the adaptive increases in GLUT-4 and hexokinase. To this end, we examined the effect of incubating rat epitrochlearis muscles in culture medium for 18 h in the presence or absence of 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR), which enters cells and is converted to the AMP analog ZMP, thus activating AMPK. Exposure of muscles to 0.5 mM AICAR in vitro for 18 h resulted in an ∼50% increase in GLUT-4 protein and an ∼80% increase in hexokinase. This finding provides strong evidence in support of the hypothesis that the activation of AMPK that occurs in muscle during exercise is involved in mediating the adaptive increases in GLUT-4 and hexokinase.

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Effect of AMPK activation on muscle glucose metabolism in conscious rats

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1999.276.5.e938 ◽

1999 ◽

Vol 276 (5) ◽

pp. E938-E944 ◽

Cited By ~ 88

Author(s):

Raynald Bergeron ◽

Raymond R. Russell ◽

Lawrence H. Young ◽

Jian-Ming Ren ◽

Melissa Marcucci ◽

...

Keyword(s):

Skeletal Muscle ◽

Glucose Metabolism ◽

Glucose Uptake ◽

Glucose Transport ◽

Additive Effect ◽

Medial Gastrocnemius ◽

Ampk Activation ◽

Transport Activity ◽

Muscle Glucose Transport

The effect of AMP-activated protein kinase (AMPK) activation on skeletal muscle glucose metabolism was examined in awake rats by infusing them with 5-aminoimidazole-4-carboxamide 1-β-d-ribofuranoside (AICAR; 40 mg/kg bolus and 7.5 mg ⋅ kg−1 ⋅ min−1constant infusion) along with a variable infusion of glucose (49.1 ± 2.4 μmol ⋅ kg−1 ⋅ min−1) to maintain euglycemia. Activation of AMPK by AICAR caused 2-deoxy-d-[1,2-3H]glucose (2-DG) uptake to increase more than twofold in the soleus and the lateral and medial gastrocnemius compared with saline infusion and occurred without phosphatidylinositol 3-kinase activation. Glucose uptake was also assessed in vitro by use of the epitrochlearis muscle incubated either with AICAR (0.5 mM) or insulin (20 mU/ml) or both in the presence or absence of wortmannin (1.0 μM). AICAR and insulin increased muscle 2-DG uptake rates by ∼2- and 2.7-fold, respectively, compared with basal rates. Combining AICAR and insulin led to a fully additive effect on muscle glucose transport activity. Wortmannin inhibited insulin-stimulated glucose uptake. However, neither wortmannin nor 8-(p-sulfophenyl)-theophylline (10 μM), an adenosine receptor antagonist, inhibited the AICAR-induced activation of glucose uptake. Electrical stimulation led to an about threefold increase in glucose uptake over basal rates, whereas no additive effect was found when AICAR and contractions were combined. In conclusion, the activation of AMPK by AICAR increases skeletal muscle glucose transport activity both in vivo and in vitro. This cellular pathway may play an important role in exercise-induced increase in glucose transport activity.

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