That has implications for the nutritional strategies that they need to adapt to those circumstances. Another important factor, which influences glycogen breakdown during exercise is training status.

You can see that both the aerobic and the so-called anaerobic utilization of glycogen is reduced after exercise training. This is a major adaptation, which is thought to contribute to the increased fatigue resistance that you see in well-trained subjects during prolonged strenuous exercise.

If we turn our attention to glucose from the bloodstream, as a source of energy for contracting the muscle, we see again that both exercise intensity and duration impact on the rate of glucose uptake. You can see in this graph, the glucose uptake into contracting leg muscles at three exercise intensities.

So, like this, an increased intensity, an increase in glucose uptake, and you also see that at any given exercise intensity, a progressive increase in glucose uptake.

If the exercise extends for several hours, then over time, what one sees is a slow reduction in glucose uptake as the blood glucose levels decline. This is one of the reasons why ingesting carbohydrate-containing drinks is often used as a strategy by endurance athletes to maintain blood glucose levels and to maintain glucose uptake during prolonged exercise.

In terms of the regulation of glucose uptake into muscle, we need to remember that this process occurs by facilitated diffusion and what that means is that we need a gradient for glucose to move from outside the muscle to inside the muscle.

We need a special transport carrier molecule to help get glucose across the membrane. There are three main sites of regulation for muscle glucose uptake: the supply of glucose, the transport of glucose across, the plasma membrane by a protein that we know as GLUT4, and the intracellular metabolism of glucose, during exercise with a large increase in muscle blood flow we see increase glucose delivery to the muscle.

In the post-exercise period, a very important process is the recovery of muscle glycogen. The re-synthesis of glycogen is the major metabolic fate of glucose that is taken up in the recovery period.

Ingesting carbohydrates during recovery is an important way of maximizing the re-synthesis of glycogen during recovery. The GLUT4 transport protein, which normally resides inside the muscle cell moves quickly to the plasma membrane where it becomes a functioning glucose transporter. Finally, as I said, if you increase the disposal of glucose through glycolytic oxidative pathways that will maintain the diffusion gradient into the contracting skeletal muscle.

We know that the availability of other substrates will influence glucose uptake. If glycogen levels are high in the muscle we tend to see a lower glucose uptake. The availability of glucose in the bloodstream is very important because it sets the arterial glucose concentration for that diffusion gradient.

So, if glucose levels are low during prolonged exercise, in the absence of glucose ingestion, you will tend to see a decrease in glucose uptake, and if you increase the blood glucose level by ingesting a carbohydrate drink and absorbing the glucose from the gut, you will see an increase in glucose uptake.

The effects of free fatty acids on glucose uptake are a little less clear compared with those on muscle glycogen. With some studies suggesting that increased fatty acid availability will slow glucose uptake, other studies have seen no effect.

The important point to make in relation to glucose uptake during exercise is that it occurs independently of insulin. The processes that are involved in glucose uptake during muscle contractions are slightly different from those involved with insulin stimulation.

Another important consideration is that if you are Type I diabetic and you have to inject yourself with insulin. If that occurs in close proximity to exercise because the two stimuli are additive that can often increase the risk of premature hypoglycemia.

Given that the translocation of GLUT4 from inside the muscle cell to the sarcolemma is very important in removing the plasma membrane as a barrier for glucose uptake. You can see in this slide a number of molecules and enzymes that have been implicated in this GLUT4 translocation process.

Most attention has focused on two pretty fundamental changes in muscle. We spoke about those in the adaptations lecture, and that is the increase in calcium, and the change in energy status, which has an impact on a kinase, the ANP activated protein kinase.

So again, local events in the muscle changes in calcium and changes in the energy levels within the muscle serve to stimulate GLUT4 translocation to facilitate glucose uptakes in the contracting muscle during exercise. Just as we saw with muscle glycogen neutralization after training, we also see a reduction in the reliance on glucose.

This study was done using labeled isotopes of glucose, which enable you to measure glucose uptake and also the appearance of the carbon label in the expired breath, so you can measure oxidation. You can see that both glucose uptake and glucose oxidation, are reduced, after endurance training.

This is the role of the liver during exercise. Informed consent was obtained from all subjects before inclusion in the study. The study was approved by the Regional Committee on Biomedical Research Ethics of Copenhagen approval H-D and was performed according to the ethical standards of the Declaration of Helsinki.

Results are described qualitatively and with descriptive statistics and are reported as means ± SE. Plasma lactate increased from rest to exhaustion in the patient 1. No second wind phenomenon was observed, and the patient did not report any exercise-related symptoms.

Despite this shift in metabolism toward fat use, the oxidation rate of carbohydrates during exercise was high, and plasma lactate levels increased Figure 1 , C and D , indicating a significant glycolytic flux during exercise. In the patient, plasma glucose levels declined during exercise and almost reached hypoglycemic levels Figure 1 E.

Substrate oxidation rates and lactate and glucose concentrations during exercise. This phase was followed by a stepwise increase in workload every other minute until exhaustion, when a final blood sample was drawn. Time of exhaustion was arbitrarily set to 40 minutes.

A, Palmitate oxidation rates ROX. B, Rate of appearance Ra of palmitate. C, Carbohydrate oxidation rates during exercise. D and E, Lactate concentrations D and glucose concentrations E measured during the stable isotope infusion trial.

Plasma lactate levels increased in the patient, but plasma glucose levels declined, even at time of exhaustion 3. These results were in contrast to those of the control subjects, in whom the glucose levels remained stable and finally increased at the time of exhaustion all subjects.

F, Glucose concentrations during the iv glucose infusion trial. Plasma glucose levels declined more rapidly in the patient, and hypoglycemia was barely prevented by the infusion, indicating an increased uptake.

In the patient, the iv glucose infusion caused a reduction in heart rate, which was accompanied by a reduction in ratings of perceived exertion during constant load exercise Figure 2. In contrast, the glucose infusion did not influence exercise tolerance in any of the control subjects.

In further support of a beneficial effect of iv glucose, the patient could exercise longer and reached a higher W peak than with a placebo Figure 2. The plasma glucose concentration tended to drop faster and more during exercise in the patient than in the control subjects, indicating an increased uptake Figure 1 F.

Plasma lactate concentrations were similar in both groups. We examined substrate metabolism and the response to an iv glucose infusion during cycle ergometry exercise in a patient with genetically proven PGM1 deficiency. He had a normal peak work capacity and no second wind phenomenon, suggesting that the condition clinically resembles a number of other glycogen storage diseases such as phosphoglycerate mutase and kinase deficiencies and lactate dehydrogenase deficiency 12 , However, unlike these conditions, iv glucose infusion improved the capacity for work.

This response to glucose infusion has so far only been observed in patients with McArdle disease, pointing to a higher reliance on hepatic glucose to feed contracting muscle to compensate for the mildly affected muscle glycogenolysis 4.

In support of a partially reduced capacity for skeletal muscle glycogenolysis, the PGM1-deficient patient had a shift in metabolism toward an increase in fatty acid oxidation.

This may be compensatory for a reduced capacity for glycogenolysis during exercise and is also seen in McArdle disease Glycogenolysis is partially preserved in PGM1 deficiency.

In addition, in contrast to the effects of McArdle disease, capacity for work was normal and lactate production during exercise was normal. Several mechanisms may explain these differences. One factor is the expression of the PGM2 isoform of phosphoglucomutase in skeletal muscle. Liver glycogenolysis is unaffected in McArdle disease, as a consequence of the expression of different isoforms of glycogen phosphorylase in these two tissues.

Blood glucose levels are maintained above hypoglycemic levels, but, as we found in the PGM1-deficient patient, blood glucose levels may gradually decline during exercise because of the large increase in skeletal muscle uptake and use of blood glucose 4.

The PGM1 isoform of phosphoglucomutase is expressed in both liver and muscle This finding implies that the liver may be affected in PGM1 deficiency, and reduced liver glucose may be a contributing factor to the low blood glucose levels during exercise in this condition.

If the liver is affected in PGM1 deficiency, the risks of fasting and exercise-induced hypoglycemia may be increased. Because the exercise intolerance in PGM1 deficiency is mild and symptoms only are provoked by strenuous physical activity, it is likely that the condition may be overlooked.

However, the tendency to become hypoglycemic during exercise may aid clinicians in the diagnosis of PGM1 deficiency. This case indicates that PGM1 deficiency should be considered in patients experiencing exercise-induced hypoglycemia. This report characterizes PGM1 deficiency as a mild metabolic myopathy with exercise-related symptoms, as seen in patients with McArdle disease, but the patient with PGM1 deficiency did not have a second wind phenomenon.

The lack of a second wind phenomenon is interesting, because the patient had a positive effect of glucose on work capacity. It could be hypothesized that patients with more severe reductions in PGM activity could have a second wind during exercise. The study of the effect of glucose infusion was not randomized, and therefore an order effect cannot be ruled out.

However, the decreases in heart rate and in Borg score that we observed in the patient was not observed in any of the control subjects. These findings support the conclusion that the positive effect of the glucose infusion was due to a physiological effect and not an order effect.

As more cases of PGM1 deficiency are diagnosed, additional research will determine whether the results in this patient can be replicated in other patients. Hypoglycemia may develop during exercise in PGM1 deficiency, as a consequence of increased muscular uptake of blood glucose and a potentially impaired mobilization of glucose from the liver.

This work was funded by the Merchant L. Foght's Fondation, The Family Hede Nielsen's Foundation, the Sara and Ludwig Elsass Foundation, and the A. Møller Foundation for the Advancement of Medical Science. Disclosure Summary: The authors have nothing to disclose that pertains to the present work.

However, the following authors report disclosures unrelated to the present work: N. report having received research support, honoraria, and travel funding from the Genzyme Corporation; P. and J. are members of the Genzyme Pompe Disease Advisory Board; and J.

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Correspondence to Jennifer Wismann. Open Access This article is published under license to BioMed Central Ltd. Reprints and permissions. Wismann, J. Gender Differences in Carbohydrate Metabolism and Carbohydrate Loading.

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Article Google Scholar. Kingsley M, Penas-Reiz C, Terry C, et al. Effects of carbohydrate-hydration strategies on glucose metabolism, sprint performance and hydration during a soccer match simulation in recreational players. J Sci Med Sport. Bendiksen M, Bischoff R, Randers M, et al.

The Copenhagen Soccer Test: physiological response and fatigue development. Roberts S, Stokes K, Trewartha G, et al. Effects of carbohydrate and caffeine ingestion on performance during a rugby union simulation protocol. Nicholas C, Williams C, Boobis L, et al. Effect of ingesting a carbohydrate-electrolyte beverage on muscle glycogen utilisation during high intensity, intermittent shuttle running.

Med Sci Sport Exerc. Saltin B. Metabolic fundamentals of exercise. Bangsbo J, Mohr M, Krustrup P. Physical and metabolic demands of training and match play in the elite player. Sherman W, Costill D, Fink W, et al. Effect of exercise-diet manipulation on muscle glycogen and its subsequent utilization during performance.

Balsom P, Wood K, Olsson P, et al. Carbohydrate intake and multiple sprint sports: with special reference to football soccer. Gregson W, Drust B, Atkinson G, et al. Match-to-match variability of high-speed activities in premier league soccer. Wee S, Williams C, Tsintzas K, et al.

Ingestion of a high-glycemic index meal increases muscle glycogen storage at rest but augments its utilization during subsequent exercise. Chryssanthopoulos C, Williams C, Nowitz A, et al. Skeletal muscle glycogen concentration and metabolic responses following a high glycaemic carbohydrate breakfast.

Wu C-L, Williams C. A low glycemic index meal before exercise improves running capacity in man. CAS Google Scholar. Hulton AT, Gregson W, Maclaren D, et al. Effects of GI meals on intermittent exercise. Bennett CB, Chilibeck PD, Barss T, et al.

Metabolism and performance during extended high-intensity intermittent exercise after consumption of low- and high-glycaemic index pre-exercise meals.

Br J Nutr. Erith S, Williams C, Stevenson E, et al. The effect of high carbohydrate meals with different glycemic indices on recovery of performance during prolonged intermittent high-intensity shuttle running. Richter EA, Hargreaves M. Exercise, GLUT4 and skeletal muscle glucose uptake.

Physiol Rev. Jensen TE, Richter EA. Regulation of glucose and glycogen metabolism during and after exercise. Tsintzas K, Williams C. Human muscle glycogen metabolism during exercise: effect of carbohydrate supplementation.

Shi X, Gisolfi C. Fluid intake and intermittent exercise. Nicholas C, Williams C, Lakomy H, et al. Influence of ingesting a carbohydrate-electrolyte solution on endurance capacity during intermittent, high intensity shuttle running. Davis J, Welsh R, Alderson N. Effects of carbohydrate and chromium ingestion during intermittent high-intensity exercise to fatigue.

Chryssanthopoulos C, Hennessy L, Williams C. The influence of pre-exercise glucose ingestion on endurance running capacity. Phillips SM, Turner AP, Sanderson MF, et al.

Beverage carbohydrate concentration influences the intermittent endurance capacity of adolescent team games players during prolonged intermittent running. Foskett A, Williams C, Boobis L, et al.

Carbohydrate availability and muscle energy metabolism during intermittent running. Matsui T, Soya S, Okamoto M, et al. Brain glycogen decreases during prolonged exercise. PubMed Central CAS PubMed Google Scholar. Nybo L, Moller K, Pedersen B, et al. Association between fatigue and failure to preserve cerebral energy turnover during prolonged exercise.

Leiper J, Broad N, Maughan R. Effect of intermittent high intensity exercise on gastric emptying in man. Leiper J, Prentice A, Wrightson C, et al. Gastric emptying of a carbohydrate-electrolyte drink during a soccer match. Leiper J, Nicholas C, Ali A, et al.

The effect of intermittent high intensity running on gastric emptying of fluids in man. Patterson S, Gray S. Carbohydrate-gel supplementation and endurance performance during intermittent high-intensity shuttle running.

Carbohydrate gel ingestion significantly improves the intermittent endurance capacity, but not sprint performance, of adolescent team games players during a simulated team games protocol. Pfeiffer B, Stellingwerff T, Zaltas E, et al. CHO oxidation from a CHO gel compared with a drink during exercise.

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Mohr M, Mujika I, Santisteban J, et al. Examination of fatigue development in elite soccer in a hot environment: a multi-experimental approach.

Morris J, Nevill M, Lakomy H, et al. Effect of a hot environment on performance of prolonged, intermittent, high intensity shuttle running. Morris J, Nevill M, Boobis L, et al. Muscle metabolism, temperature, and function during prolonged intermittent high intensity running in air temperatures of 33 °C and 17 °C.

J Sport Med. Shirreffs S. Hydration: special issues for playing football in warm and hot environments. Morris J, Nevill M, Thompson D, et al. The influence of a 6. Clarke N, Maclaren D, Reilly T, et al. Carbohydrate ingestion and pre-cooling improves exercise capacity following soccer-specific intermittent exercise performed in the heat.

Cunningham D, Faulkner J. The effect of training on aerobic and anaerobic metabolism during a short exhaustive run. Ivy J. Glycogen resynthesis after exercise: effect of carbohydrate intake.

Nicholas C, Green P, Hawkins R, et al. Carbohydrate intake and recovery of intermittent running capacity. Int J Sport Nutr. Price T, Laurent D, Petersen K, et al. Glycogen loading alters muscle glycogen resynthesis after exercise.

Naperalsky M, Ruby B, Slivka D. Environmental temperature and glycogen resynthesis. Slivka D, Heesch M, Dumke C, et al. Effects of post-exercise recovery in a cold environment on muscle glycogen, PGC-1alpha, and downstream transcription factors. Tucker TJ, Slivka DR, Cuddy JS, et al. Effect of local cold application on glycogen recovery.

J Sports Med Phys Fit. Zawadzki K, Yaspelkis B III, Ivy J. Carbohydrate-protein complex increases the rate of muscle glycogen storage after exercise. Ivy J, Goforth H Jr, Damon B, et al. Early post-exercise muscle glycogen recovery is enhanced with a carbohydrate-protein supplement.

Betts J, Williams C. Short-term recovery from prolonged exercise: exploring the potential for protein ingestion to accentuate the benefits of carbohydrate supplements. Gunnarsson T, Bendiksen M, Bischoff R, et al.

Effect of whey protein-and carbohydrate-enriched diet on glycogen resynthesis during the first 48 h after a soccer game. Phillips S. Exercise and protein nutrition: The science of muscle hypertrophy: making dietary protein count.

Proc Nutr Soc. Download references. This article was published in a supplement supported by the Gatorade Sports Science Institute GSSI. The supplement was guest edited by Lawrence L.

Spriet, who attended a meeting of the GSSI expert panel XP in March and received honoraria from the GSSI for his participation in the meeting. He received no honoraria for guest editing the supplement.

Spriet selected peer reviewers for each paper and managed the process. Clyde Williams, PhD also attended the GSSI XP meeting in March and received honoraria from the GSSI, a division of PepsiCo, Inc. Ian Rollo is an employee of the Gatorade Sports Science Institute, a division of PepsiCo, Inc.

The views expressed in this manuscript are those of the authors and do not necessarily reflect the position or policy of PepsiCo Inc. School of Sport, Exercise and Health Sciences, Loughborough University, Loughborough, Leicestershire, England, LE11 3TU, UK.

You can also search for this author in PubMed Google Scholar. Correspondence to Clyde Williams. Open Access This article is distributed under the terms of the Creative Commons Attribution 4. Reprints and permissions. Williams, C. Carbohydrate Nutrition and Team Sport Performance.

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FormalPara Key Points Repeated brief periods of variable speed running lower muscle glycogen stores. Lowered muscle glycogen stores reduces performance during subsequent variable speed running.

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Article PubMed Google Scholar Rollo I, Homewood G, Williams, C, Carter J, Goosey-Tolfrey V. He presented with recurrent cramps evoked by strenuous exercise and had a history suggesting rhabdomyolysis after strenuous physical activity.

The patient underwent exercise tests on 3 consecutive days, and the responses were compared with those of 6 healthy age- and body mass index—matched, sedentary subjects ranging in age from 19 to 61 years mean 37 years. An incremental cycle ergometer test to exhaustion was performed to determine peak oxygen consumption VO 2peak and peak workload W peak.

Plasma lactate concentration was measured at rest and exhaustion. The subjects exercised at a constant workload for 32 minutes, after which the workload was increased in a stepwise manner every other minute until exhaustion.

Blood samples were drawn as shown in Figure 2. The tracer methodology has been described in detail elsewhere 8 , Heart rate and ratings of perceived exertion during exercise.

Open symbols are results from the iv glucose infusion trial, and closed symbols are results from the placebo infusion trial stable isotope infusion. Error bars are the SE. This phase was followed by a stepwise increase in workload until exhaustion.

A and B, heart rate during exercise in the patient and the controls. C and D, ratings of perceived exertion RPE Borg scale. The patient rated exercise at being easier while receiving the iv glucose infusion, whereas none of the controls did. An iv glucose infusion was given before and during exercise, as described in detail elsewhere Stable isotopes were not infused on this day.

The workload and blood sampling protocol was kept the same as that during the stable isotope trial on the previous day.

The principle behind the use of stable isotopes to trace metabolism is infusion of minute amounts of isotopes that do not affect basal metabolism, and hence the trial on day 2 was used as a placebo test to assess the effect of the glucose infusion. Informed consent was obtained from all subjects before inclusion in the study.

The study was approved by the Regional Committee on Biomedical Research Ethics of Copenhagen approval H-D and was performed according to the ethical standards of the Declaration of Helsinki. Results are described qualitatively and with descriptive statistics and are reported as means ± SE.

Plasma lactate increased from rest to exhaustion in the patient 1. No second wind phenomenon was observed, and the patient did not report any exercise-related symptoms. Despite this shift in metabolism toward fat use, the oxidation rate of carbohydrates during exercise was high, and plasma lactate levels increased Figure 1 , C and D , indicating a significant glycolytic flux during exercise.

In the patient, plasma glucose levels declined during exercise and almost reached hypoglycemic levels Figure 1 E.

Substrate oxidation rates and lactate and glucose concentrations during exercise. This phase was followed by a stepwise increase in workload every other minute until exhaustion, when a final blood sample was drawn. Time of exhaustion was arbitrarily set to 40 minutes.

A, Palmitate oxidation rates ROX. B, Rate of appearance Ra of palmitate. C, Carbohydrate oxidation rates during exercise. D and E, Lactate concentrations D and glucose concentrations E measured during the stable isotope infusion trial.

Plasma lactate levels increased in the patient, but plasma glucose levels declined, even at time of exhaustion 3. These results were in contrast to those of the control subjects, in whom the glucose levels remained stable and finally increased at the time of exhaustion all subjects.

F, Glucose concentrations during the iv glucose infusion trial. Plasma glucose levels declined more rapidly in the patient, and hypoglycemia was barely prevented by the infusion, indicating an increased uptake. In the patient, the iv glucose infusion caused a reduction in heart rate, which was accompanied by a reduction in ratings of perceived exertion during constant load exercise Figure 2.

In contrast, the glucose infusion did not influence exercise tolerance in any of the control subjects. In further support of a beneficial effect of iv glucose, the patient could exercise longer and reached a higher W peak than with a placebo Figure 2.

The plasma glucose concentration tended to drop faster and more during exercise in the patient than in the control subjects, indicating an increased uptake Figure 1 F. Plasma lactate concentrations were similar in both groups.

We examined substrate metabolism and the response to an iv glucose infusion during cycle ergometry exercise in a patient with genetically proven PGM1 deficiency. He had a normal peak work capacity and no second wind phenomenon, suggesting that the condition clinically resembles a number of other glycogen storage diseases such as phosphoglycerate mutase and kinase deficiencies and lactate dehydrogenase deficiency 12 , However, unlike these conditions, iv glucose infusion improved the capacity for work.

This response to glucose infusion has so far only been observed in patients with McArdle disease, pointing to a higher reliance on hepatic glucose to feed contracting muscle to compensate for the mildly affected muscle glycogenolysis 4.

In support of a partially reduced capacity for skeletal muscle glycogenolysis, the PGM1-deficient patient had a shift in metabolism toward an increase in fatty acid oxidation. This may be compensatory for a reduced capacity for glycogenolysis during exercise and is also seen in McArdle disease Glycogenolysis is partially preserved in PGM1 deficiency.

In addition, in contrast to the effects of McArdle disease, capacity for work was normal and lactate production during exercise was normal. Several mechanisms may explain these differences. One factor is the expression of the PGM2 isoform of phosphoglucomutase in skeletal muscle.

Liver glycogenolysis is unaffected in McArdle disease, as a consequence of the expression of different isoforms of glycogen phosphorylase in these two tissues. Blood glucose levels are maintained above hypoglycemic levels, but, as we found in the PGM1-deficient patient, blood glucose levels may gradually decline during exercise because of the large increase in skeletal muscle uptake and use of blood glucose 4.

The PGM1 isoform of phosphoglucomutase is expressed in both liver and muscle This finding implies that the liver may be affected in PGM1 deficiency, and reduced liver glucose may be a contributing factor to the low blood glucose levels during exercise in this condition.

If the liver is affected in PGM1 deficiency, the risks of fasting and exercise-induced hypoglycemia may be increased. Because the exercise intolerance in PGM1 deficiency is mild and symptoms only are provoked by strenuous physical activity, it is likely that the condition may be overlooked.

However, the tendency to become hypoglycemic during exercise may aid clinicians in the diagnosis of PGM1 deficiency. This case indicates that PGM1 deficiency should be considered in patients experiencing exercise-induced hypoglycemia.

This report characterizes PGM1 deficiency as a mild metabolic myopathy with exercise-related symptoms, as seen in patients with McArdle disease, but the patient with PGM1 deficiency did not have a second wind phenomenon. The lack of a second wind phenomenon is interesting, because the patient had a positive effect of glucose on work capacity.

It could be hypothesized that patients with more severe reductions in PGM activity could have a second wind during exercise. The study of the effect of glucose infusion was not randomized, and therefore an order effect cannot be ruled out.

However, the decreases in heart rate and in Borg score that we observed in the patient was not observed in any of the control subjects. These findings support the conclusion that the positive effect of the glucose infusion was due to a physiological effect and not an order effect. As more cases of PGM1 deficiency are diagnosed, additional research will determine whether the results in this patient can be replicated in other patients.

Hypoglycemia may develop during exercise in PGM1 deficiency, as a consequence of increased muscular uptake of blood glucose and a potentially impaired mobilization of glucose from the liver.

This work was funded by the Merchant L. Foght's Fondation, The Family Hede Nielsen's Foundation, the Sara and Ludwig Elsass Foundation, and the A.

Møller Foundation for the Advancement of Medical Science. Disclosure Summary: The authors have nothing to disclose that pertains to the present work. In terms of the regulation of glucose uptake into muscle, we need to remember that this process occurs by facilitated diffusion and what that means is that we need a gradient for glucose to move from outside the muscle to inside the muscle.

We need a special transport carrier molecule to help get glucose across the membrane. There are three main sites of regulation for muscle glucose uptake: the supply of glucose, the transport of glucose across, the plasma membrane by a protein that we know as GLUT4, and the intracellular metabolism of glucose, during exercise with a large increase in muscle blood flow we see increase glucose delivery to the muscle.

In the post-exercise period, a very important process is the recovery of muscle glycogen. The re-synthesis of glycogen is the major metabolic fate of glucose that is taken up in the recovery period. Ingesting carbohydrates during recovery is an important way of maximizing the re-synthesis of glycogen during recovery.

The GLUT4 transport protein, which normally resides inside the muscle cell moves quickly to the plasma membrane where it becomes a functioning glucose transporter. Finally, as I said, if you increase the disposal of glucose through glycolytic oxidative pathways that will maintain the diffusion gradient into the contracting skeletal muscle.

We know that the availability of other substrates will influence glucose uptake. If glycogen levels are high in the muscle we tend to see a lower glucose uptake. The availability of glucose in the bloodstream is very important because it sets the arterial glucose concentration for that diffusion gradient.

So, if glucose levels are low during prolonged exercise, in the absence of glucose ingestion, you will tend to see a decrease in glucose uptake, and if you increase the blood glucose level by ingesting a carbohydrate drink and absorbing the glucose from the gut, you will see an increase in glucose uptake.

The effects of free fatty acids on glucose uptake are a little less clear compared with those on muscle glycogen. With some studies suggesting that increased fatty acid availability will slow glucose uptake, other studies have seen no effect.

The important point to make in relation to glucose uptake during exercise is that it occurs independently of insulin. The processes that are involved in glucose uptake during muscle contractions are slightly different from those involved with insulin stimulation.

Another important consideration is that if you are Type I diabetic and you have to inject yourself with insulin. If that occurs in close proximity to exercise because the two stimuli are additive that can often increase the risk of premature hypoglycemia. Given that the translocation of GLUT4 from inside the muscle cell to the sarcolemma is very important in removing the plasma membrane as a barrier for glucose uptake.

You can see in this slide a number of molecules and enzymes that have been implicated in this GLUT4 translocation process. Most attention has focused on two pretty fundamental changes in muscle.

We spoke about those in the adaptations lecture, and that is the increase in calcium, and the change in energy status, which has an impact on a kinase, the ANP activated protein kinase.

So again, local events in the muscle changes in calcium and changes in the energy levels within the muscle serve to stimulate GLUT4 translocation to facilitate glucose uptakes in the contracting muscle during exercise.

Just as we saw with muscle glycogen neutralization after training, we also see a reduction in the reliance on glucose. This study was done using labeled isotopes of glucose, which enable you to measure glucose uptake and also the appearance of the carbon label in the expired breath, so you can measure oxidation.

You can see that both glucose uptake and glucose oxidation, are reduced, after endurance training. This is the role of the liver during exercise.

You can see here that the curves for liver glucose output are very similar to those with muscle glucose uptake.

With an increase in exercise intensity and an increase in exercise, the duration will increase liver glucose output. You will note at the lower intensities here were the exercise duration is extended that eventually the liver is unable to maintain the same rate of glucose output and it starts to decline.

We see both feeds forward and feedback mechanisms. There are changes in the pancreatic hormones during exercise, insulin levels tend to go down and glucagon levels tend to go up and restored these two signals playing the important role in allowing the liver to increase its glucose output during exercise.

Circulating adrenaline can also act on the liver glycogen stores, which are then broken down to liberate glucose. The sympathetic nerves are thought to play a role although there have been some interesting experiments in patients who have had liver transplants and therefore the nerves to the liver have been cut.

So, I think this demonstrates if you like the redundancy and usually when there are multiple mechanisms controlling a process, it means that that process is quite important. And we often see that in physiology with a number of regulatory control systems.