Effects of prior exercise on insulin-mediated and noninsulin-mediated glucose uptake in horses during a hyperglycaemic clamp

We have examined the effects of insulin on p38 mitogen-activated protein kinase (MAPK) phosphorylation in human skeletal muscle and the effects of prior exercise hereon. Seven men performed 1-h one-legged knee extensor exercise 3 h before the initiation of a 100-min euglycemic-hyperinsulinemic (600 pmol/l) clamp. Glucose uptake across the legs was measured with the leg balance technique, and muscle biopsies were obtained from the rested and exercised vastus lateralis before and during insulin infusion. Net glucose uptake during the clamp was ∼50% higher ( P< 0.05) in the exercised leg than in the rested leg. Insulin induced a modest sustained 1.2- and 1.3-fold increase ( P < 0.05) in p38 MAPK phosphorylation in the rested and exercised legs, respectively. However, p38 phosphorylation was ∼50% higher ( P < 0.05) in the exercised compared with the rested leg before and during insulin infusion. We conclude that a physiological concentration of insulin causes modest but sustained activation of the p38 MAPK pathway in human skeletal muscle. Furthermore, the stimulatory effect of exercise on p38 phosphorylation is persistent for at least 3 h after exercise and remains evident during subsequent insulin stimulation. Because p38 MAPK has been suggested to play a necessary role in activation of GLUT-4 at the cell surface, the present data may suggest a putative role of p38 MAPK in the increased insulin sensitivity of skeletal muscle after exercise.

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Increased submaximal insulin-stimulated glucose uptake in mouse skeletal muscle after treadmill exercise

Journal of Applied Physiology ◽

10.1152/japplphysiol.00416.2006 ◽

2006 ◽

Vol 101 (5) ◽

pp. 1368-1376 ◽

Cited By ~ 57

Author(s):

Taku Hamada ◽

Edward B. Arias ◽

Gregory D. Cartee

Keyword(s):

Skeletal Muscle ◽

Insulin Sensitivity ◽

Glucose Uptake ◽

Extensor Digitorum Longus ◽

Treadmill Exercise ◽

Genetically Modified ◽

Extensor Digitorum ◽

Exercise Protocol ◽

Mouse Skeletal Muscle ◽

Prior Exercise

The primary purpose of this study was to determine the effect of prior exercise on insulin-stimulated glucose uptake with physiological insulin in isolated muscles of mice. Male C57BL/6 mice completed a 60-min treadmill exercise protocol or were sedentary. Paired epitrochlearis, soleus, and extensor digitorum longus (EDL) muscles were incubated with [3H]-2-deoxyglucose without or with insulin (60 μU/ml) to measure glucose uptake. Insulin-stimulated glucose uptake for paired muscles was calculated by subtracting glucose uptake without insulin from glucose uptake with insulin. Muscles from other mice were assessed for glycogen and AMPK Thr172 phosphorylation. Exercised vs. sedentary mice had decreased glycogen in epitrochlearis (48%, P < 0.001), soleus (51%, P < 0.001), and EDL (41%, P < 0.01) and increased AMPK Thr172 phosphorylation ( P < 0.05) in epitrochlearis (1.7-fold), soleus (2.0-fold), and EDL (1.4-fold). Insulin-independent glucose uptake was increased 30 min postexercise vs. sedentary in the epitrochlearis (1.2-fold, P < 0.001), soleus (1.4-fold, P < 0.05), and EDL (1.3-fold, P < 0.01). Insulin-stimulated glucose uptake was increased ( P < 0.05) ∼85 min after exercise in the epitrochlearis (sedentary: 0.266 ± 0.045 μmol·g−1·15 min−1; exercised: 0.414 ± 0.051) and soleus (sedentary: 0.102 ± 0.049; exercised: 0.347 ± 0.098) but not in the EDL. Akt Ser473 and Akt Thr308 phosphorylation for insulin-stimulated muscles did not differ in exercised vs. sedentary. These results demonstrate enhanced submaximal insulin-stimulated glucose uptake in the epitrochlearis and soleus of mice 85 min postexercise and suggest that it will be feasible to probe the mechanism of enhanced postexercise insulin sensitivity by using genetically modified mice.

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Prior exercise increases net hepatic glucose uptake during a glucose load

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1999.276.6.e1022 ◽

1999 ◽

Vol 276 (6) ◽

pp. E1022-E1029 ◽

Cited By ~ 8

Author(s):

Pietro Galassetti ◽

Robert H. Coker ◽

Drury B. Lacy ◽

Alan D. Cherrington ◽

David H. Wasserman

Keyword(s):

Portal Vein ◽

Glucose Uptake ◽

Control Period ◽

Vena Cava ◽

Experimental Period ◽

Glucose Infusion ◽

Glucose Load ◽

Prior Exercise ◽

Hepatic Glucose ◽

Hepatic Glucose Uptake

The aim of these studies was to determine whether prior exercise enhances net hepatic glucose uptake (NHGU) during a glucose load. Sampling catheters (carotid artery, portal, hepatic, and iliac veins), infusion catheters (portal vein and vena cava), and Doppler flow probes (portal vein, hepatic and iliac arteries) were implanted. Exercise (150 min; n = 6) or rest ( n = 6) was followed by a 30-min control period and a 100-min experimental period (3.5 mg ⋅ kg−1⋅ min−1of glucose in portal vein and as needed in vena cava to clamp arterial blood glucose at ∼130 mg/dl). Somatostatin was infused, and insulin and glucagon were replaced intraportally at fourfold basal and basal rates, respectively. During experimental period the arterial-portal venous (a-pv) glucose gradient (mg/dl) was −18 ± 1 in sedentary and −19 ± 1 in exercised dogs. Arterial insulin and glucagon were similar in the two groups. Net hepatic glucose balance (mg ⋅ kg−1⋅ min−1) shifted from 1.9 ± 0.2 in control period to −1.8 ± 0.2 (negative rates represent net uptake) during experimental period in sedentary dogs (Δ3.7 ± 0.5); with prior exercise it shifted from 4.1 ± 0.3 ( P < 0.01 vs. sedentary) in control period to −3.2 ± 0.4 ( P < 0.05 vs. sedentary) during experimental period (Δ7.3 ± 0.7, P < 0.01 vs. sedentary). Net hindlimb glucose uptake (mg/min) was 4 ± 1 in sedentary animals in control period and 13 ± 2 during experimental period; in exercised animals it was 7 ± 1 in control period ( P < 0.01 vs. sedentary) and 32 ± 4 ( P < 0.01 vs. sedentary) during experimental period. As the total glucose infusion rate (mg ⋅ kg−1⋅ min−1) was 7 ± 1 in sedentary and 11 ± 1 in exercised dogs, ∼30% of the added glucose infusion due to prior exercise could be accounted for by the greater NHGU. In conclusion, when determinants of hepatic glucose uptake (insulin, glucagon, a-pv glucose gradient, glycemia) are controlled, prior exercise increases NHGU during a glucose load due to an effect that is intrinsic to the liver. Increased glucose disposal in the postexercise state is therefore due to an improved ability of both liver and muscle to take up glucose.

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Role of a negative arterial-portal venous glucose gradient in the postexercise state

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1999.277.6.e1038 ◽

1999 ◽

Vol 277 (6) ◽

pp. E1038-E1045 ◽

Cited By ~ 4

Author(s):

Pietro Galassetti ◽

Yoshiharu Koyama ◽

Robert H. Coker ◽

Drury B. Lacy ◽

Alan D. Cherrington ◽

...

Keyword(s):

Glucose Uptake ◽

Vena Cava ◽

Experimental Period ◽

Glucose Infusion ◽

Whole Body ◽

Glucose Disposal ◽

Prior Exercise ◽

Basal Period ◽

Hepatic Glucose ◽

Venous Glucose

Prior exercise stimulates muscle and liver glucose uptake. A negative arterial-portal venous glucose gradient (a-pv grad) stimulates resting net hepatic glucose uptake (NHGU) but reduces muscle glucose uptake. This study investigates the effects of a negative a-pv grad during glucose administration after exercise in dogs. Experimental protocol: exercise (−180 to −30 min), transition (−30 to −20 min), basal period (−20 to 0 min), and experimental period (0 to 100 min). In the experimental period, 130 mg/dl arterial hyperglycemia was induced via vena cava (Pe, n = 6) or portal vein (Po, n = 6) glucose infusions. Insulin and glucagon were replaced at fourfold basal and basal rates. During the experimental period, the a-pv grad (mg/dl) was 3 ± 1 in Pe and −10 ± 2 in Po. Arterial insulin and glucagon were similar in the two groups. In Pe, net hepatic glucose balance (mg ⋅ kg−1⋅ min−1, negative = uptake) was 4.2 ± 0.3 (basal period) and −1.2 ± 0.3 (glucose infusion); in Po it was 4.1 ± 0.5 and −3.2 ± 0.4, respectively ( P < 0.005 vs. Pe). Total glucose infusion (mg ⋅ kg−1⋅ min−1) was 11 ± 1 in Po and 8 ± 1 in Pe ( P < 0.05). Net hindlimb and whole body nonhepatic glucose uptakes were similar. Conclusions: the portal signal independently stimulates NHGU after exercise. Conversely, prior exercise eliminates the inhibitory effect of the portal signal on glucose uptake by nonhepatic tissues. The portal signal therefore increases whole body glucose disposal after exercise by an amount equal to the increase in NHGU.

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Enhanced muscle glucose uptake facilitates nitrogen efflux from exercised muscle

Journal of Applied Physiology ◽

10.1152/jappl.1998.84.6.1952 ◽

1998 ◽

Vol 84 (6) ◽

pp. 1952-1959 ◽

Cited By ~ 2

Author(s):

Pietro Galassetti ◽

Fiona K. Gibbons ◽

Katherine S. Hamilton ◽

D. Brooks Lacy ◽

Alan D. Cherrington ◽

...

Keyword(s):

Skeletal Muscle ◽

Glucose Uptake ◽

Prolonged Exercise ◽

Glucose Infusion ◽

Oral Glucose ◽

Glucose Load ◽

Prior Exercise ◽

Glucose Ingestion

The hypothesis that glucose ingestion in the postexercise state enhances the synthesis of glutamine and alanine in the skeletal muscle was tested. Glucose was infused intraduodenally for 150 min (44.5 μmol ⋅ kg−1⋅ min−1) beginning 30 min after a 150-min period of exercise ( n = 7) or an equivalent duration sedentary period ( n = 10) in 18-h-fasted dogs. Prior exercise caused a twofold greater increase in limb glucose uptake during the intraduodenal glucose infusion compared with uptake in sedentary dogs. Arterial glutamine levels fell gradually with the glucose load in both groups. Net hindlimb glutamine efflux increased in response to intraduodenal glucose in exercised but not sedentary dogs ( P < 0.05–0.01). Arterial alanine levels, depleted by 50% with exercise, rose with intraduodenal glucose in exercised but not sedentary dogs ( P < 0.05–0.01). Net hindlimb alanine efflux also rose in exercised dogs in response to intraduodenal glucose ( P < 0.05–0.01), whereas it was not different from baseline in sedentary controls for the first 90 min of glucose infusion. Beyond this point, it, too, rose significantly. We conclude that oral glucose may facilitate recovery of muscle from prolonged exercise by enhancing the removal of nitrogen in the form of glutamine and alanine.

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Muscle glycogen content and glucose uptake during exercise in humans: influence of prior exercise and dietary manipulation

The Journal of Physiology ◽

10.1113/jphysiol.2001.015594 ◽

2002 ◽

Vol 541 (1) ◽

pp. 273-281 ◽

Cited By ~ 42

Author(s):

Adam Steensberg ◽

Gerrit Hall ◽

Charlotte Keller ◽

Takuya Osada ◽

Peter Schjerling ◽

...

Keyword(s):

Glucose Uptake ◽

Muscle Glycogen ◽

Glycogen Content ◽

Dietary Manipulation ◽

Muscle Glycogen Content ◽

Prior Exercise ◽

Exercise In Humans

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Additive effects of prior exercise and insulin on glucose and AIB uptake by rat muscle

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1986.251.1.e21 ◽

1986 ◽

Vol 251 (1) ◽

pp. E21-E26 ◽

Cited By ~ 9

Author(s):

A. Zorzano ◽

T. W. Balon ◽

M. N. Goodman ◽

N. B. Ruderman

Keyword(s):

Glucose Uptake ◽

Moderate Intensity ◽

Additive Effects ◽

Absolute Rate ◽

Intense Exercise ◽

Rat Muscle ◽

Prior Exercise ◽

Ad Libitum ◽

Insulin Responsiveness ◽

Parallel Fashion

After exercise of moderate intensity the ability of insulin to stimulate the uptake of glucose and alpha-aminoisobutyric acid (AIB) in perfused rat muscle is enhanced in a parallel fashion. The present study was designed to examine the effect of intense exercise on the subsequent uptake of these substrates. For this purpose, rats fed ad libitum were run on a treadmill for 50 min at high intensity and glucose and AIB uptake by muscle were then assessed in the isolated perfused hindquarter preparation. In confirmation of previous studies, 30 min after such exercise the absolute rate of glucose uptake in the presence of 20,000 microU/ml of insulin was greater due to additive effects of insulin and prior exercise. A novel finding was that 150 min postexercise the rate of glucose uptake was still increased in the presence of a supramaximal concentration of insulin, but entirely due to an increase in insulin responsiveness. The uptake of AIB and its response to insulin in general paralleled that of glucose. The results indicate that both glucose and AIB uptake by skeletal muscle in the presence of a supramaximal concentration of insulin are increased after intense exercise. They suggest that this is initially due to an additive effect of insulin and exercise and later due to an increase in insulin responsiveness. The findings are compatible with the notion that after exercise insulin is able to recruit or activate glucose (and possibly AIB) transporters in muscle, that it does not affect in the resting state.

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Prolonged Exercise-Induced Stimulation of Skeletal Muscle Glucose Uptake Is due to Sustained Increases in Tissue Perfusion and Fractional Glucose Extraction

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2010-1801 ◽

2011 ◽

Vol 96 (4) ◽

pp. 1085-1092 ◽

Cited By ~ 5

Author(s):

K. Hamrin ◽

V. Qvisth ◽

E. Hagström-Toft ◽

S. Enoksson ◽

J. Henriksson ◽

...

Keyword(s):

Skeletal Muscle ◽

Glucose Uptake ◽

Glucose Concentration ◽

Time Course ◽

Tissue Perfusion ◽

Acute Bout ◽

Positive Effects ◽

Prior Exercise ◽

Interstitial Glucose ◽

Skeletal Muscle Glucose Uptake

Abstract Context: The mechanisms behind the positive effects of physical activity on glucose metabolism in skeletal muscle and the time course of the effects need to be more elucidated. Objective: The aim was to examine the prolonged effects of an acute bout of one-legged exercise on local skeletal muscle glucose utilization and tissue perfusion. Design and Setting: Interstitial glucose concentration, local tissue perfusion, glucose uptake, and effects of insulin infusion were studied 12 h after an acute bout of exercise and without prior exercise. Participants: Ten healthy subjects, five women and five men, participated in the study. Intervention: Microdialysis measurements, 133Xe clearance, and a 2-h hyperinsulinemic euglycemic clamp were performed on two occasions. Main Outcome Measures: We measured interstitial glucose concentration and tissue perfusion in the quadriceps femoris muscle of both legs. Results: Tissue perfusion (3.3 ± 0.6 ml × 100 g−1 × min−1vs. 1.4 ± 0.2 ml × 100 g−1 × min−1; P = 0.007) and basal glucose uptake (2.3 ± 0.5 μmol × 100 g−1 × min−1vs. 0.9 ± 0.2 μmol × 100 g−1 × min−1; P = 0.006) were increased in the leg that had exercised compared to the resting leg; the findings in the resting leg were comparable to those in the control experiment without prior exercise. The relative effect of insulin on fractional skeletal muscle glucose uptake was the same in all experimental settings, and insulin did not affect tissue perfusion. Conclusions: The prolonged stimulatory effect of physical exercise on skeletal muscle glucose uptake was mediated via vascular effects combined with an increase in basal glucose transport independent of enhancement of insulin responses.

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Effects of insulin and prior exercise on prostaglandin release from perfused rat muscle Evidence that prostaglandins do not mediate changes in glucose uptake

Biochemical Journal ◽

10.1042/bj2400437 ◽

1986 ◽

Vol 240 (2) ◽

pp. 437-443 ◽

Cited By ~ 10

Author(s):

A Zorzano ◽

T W Balon ◽

J A Jakubowski ◽

M N Goodman ◽

D Deykin ◽

...

Keyword(s):

Glucose Uptake ◽

Blood Cells ◽

Treadmill Exercise ◽

Prostaglandin Synthesis ◽

Metabolic Effects ◽

Aminoisobutyric Acid ◽

Rat Muscle ◽

Prior Exercise ◽

Prostaglandin Release ◽

Stimulation Of

Prostaglandin generation and its inter-relation to the metabolic effects of insulin and prior exercise were examined in perfused muscle of fed rats. During a 60 min perfusion of the rat hindquarter, a substantial release of the prostaglandins PGF2 alpha, PGE2 and 6-oxoPGF1 alpha was observed. Blood cells present in the perfusate released these substances in negligible amounts indicating the prostaglandins were produced by the hindquarter. Addition of insulin to the perfusate increased both glucose uptake and the generation of PGE2 and 6-oxoPGF1 alpha. At 30 min after intense treadmill exercise, glucose and alpha-aminoisobutyric acid (AIB) uptake by the hindquarter were increased in the absence of added insulin, but prostaglandin release was not increased. Insulin further increased glucose and AIB uptake; however, in contrast with its effects in non-exercised rats, insulin no longer stimulated prostaglandin generation. Indomethacin (10 microM) added to the perfusate inhibited the release of PGF2 alpha and PGE2 by 90% and the release of 6-oxoPGF1 alpha by 54%. It had no effect on the stimulation of glucose uptake by either insulin or prior exercise. The data indicate that insulin increases prostaglandin synthesis by perfused rat muscle, and that prior exercise blocks this effect. They suggest that under the conditions studied prostaglandins do not mediate the effects of insulin or prior exercise on glucose uptake.

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Two isoprenylated flavonoids from Dorstenia psilurus activate AMPK, stimulate glucose uptake, inhibit glucose production and lower glycemia

Biochemical Journal ◽

10.1042/bcj20190326 ◽

2019 ◽

Vol 476 (24) ◽

pp. 3687-3704 ◽

Cited By ~ 2

Author(s):

Aphrodite T. Choumessi ◽

Manuel Johanns ◽

Claire Beaufay ◽

Marie-France Herent ◽

Vincent Stroobant ◽

...

Keyword(s):

Glucose Uptake ◽

Human Cancer ◽

Glucose Production ◽

Liver Mitochondria ◽

New Drugs ◽

Structural Isomer ◽

Rat Liver Mitochondria ◽

Ionization Mass ◽

Ampk Activation ◽

Starting Point

Root extracts of a Cameroon medicinal plant, Dorstenia psilurus, were purified by screening for AMP-activated protein kinase (AMPK) activation in incubated mouse embryo fibroblasts (MEFs). Two isoprenylated flavones that activated AMPK were isolated. Compound 1 was identified as artelasticin by high-resolution electrospray ionization mass spectrometry and 2D-NMR while its structural isomer, compound 2, was isolated for the first time and differed only by the position of one double bond on one isoprenyl substituent. Treatment of MEFs with purified compound 1 or compound 2 led to rapid and robust AMPK activation at low micromolar concentrations and increased the intracellular AMP:ATP ratio. In oxygen consumption experiments on isolated rat liver mitochondria, compound 1 and compound 2 inhibited complex II of the electron transport chain and in freeze–thawed mitochondria succinate dehydrogenase was inhibited. In incubated rat skeletal muscles, both compounds activated AMPK and stimulated glucose uptake. Moreover, these effects were lost in muscles pre-incubated with AMPK inhibitor SBI-0206965, suggesting AMPK dependency. Incubation of mouse hepatocytes with compound 1 or compound 2 led to AMPK activation, but glucose production was decreased in hepatocytes from both wild-type and AMPKβ1−/− mice, suggesting that this effect was not AMPK-dependent. However, when administered intraperitoneally to high-fat diet-induced insulin-resistant mice, compound 1 and compound 2 had blood glucose-lowering effects. In addition, compound 1 and compound 2 reduced the viability of several human cancer cells in culture. The flavonoids we have identified could be a starting point for the development of new drugs to treat type 2 diabetes.

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