Acute and chronic metabolism changes following exercise: mechanisms and physiological relevance.
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Animals↗
Biomedical subjects
N B Ruderman
Publications and source records attributed to N B Ruderman.
Effects of starvation and exercise on concentrations of citrate, hexose phosphates and glycogen in skeletal muscle and heart. Evidence for selective operation of the glucose-fatty acid cycle.
Concentrations of citrate, hexose phosphates and glycogen were measured in skeletal muscle and heart under conditions in which plasma non-esterified fatty acids and ketone bodies were physiologically increased. The aim was to determine under what conditions the glucose-fatty acid cycle might operative in skeletal muscle in vivo. In keeping with the findings of others, starvation increased the concentrations of glycogen, citrate and the fructose 6-phosphate/fructose 1,6-bisphosphate ratio in heart, indicating that the cycle was operative. In contrast, it decreased glycogen and had no effect on the concentration of citrate or the fructose 6-phosphate/fructose 1,6-bisphosphate ratio in the soleus, a slow-twitch red muscle in which the glucose-fatty acid cycle has been demonstrated in vitro. In fed rats, exercise of moderate intensity caused glycogen depletion in the soleus and red portion of gastrocnemius muscle, but not in heart. In starved rats the same exercise had no effect on the already diminished glycogen contents in skeletal muscle, but it decreased cardiac glycogen by 25-30%. After exercise, citrate and the fructose 6-phosphate/fructose 1,6-bisphosphate ratio were increased in the soleus of the starved rat. Significant changes were not observed in fed rats. The data suggest that in the resting state the glucose-fatty acid cycle operates in the heart, but not in the soleus muscle, of a starved rat. In contrast, the metabolite profile in the soleus was consistent with activation of the glucose-fatty acid cycle in the starved rat during the recovery period after exercise. Whether the cycle operates during exercise itself is unclear.
Animals↗
Insulin increases thermogenesis in rat skeletal muscle following exercise.
Insulin increased O2 consumption in isolated perfused rat muscle for upward of 2 h after a treadmill run. Insulin did not increase O2 consumption in nonexercised rats, nor did prior exercise increase O2 consumption in the absence of added insulin. The stimulation of glycogen synthesis by insulin was also enhanced in muscle of previously exercised rats. The additional energy required for this was not sufficient to account for the increase in O2 consumption, however. The results indicate that insulin increases thermogenesis in skeletal muscle after exercise. They also raise the possibility that in intact organisms the thermogenic effect of foods that increase insulin secretion could be increased by prior exercise.
Animals↗
Muscle alpha-aminoisobutyric acid transport after exercise: enhanced stimulation by insulin.
After exercise the ability of insulin to stimulate glucose transport and glycogen synthesis in rat skeletal muscle is markedly enhanced (25). The present study was designed to determine whether prior exercise augments the stimulation of other processes by insulin and, if so, whether this can be attributed to an increase in insulin binding to its receptor. Toward this end rats were run on a treadmill for 45 min at moderate intensity and the uptake of alpha-aminoisobutyric acid (AIB) by muscle was then assessed using the isolated perfused hindquarter preparation. Approximately 30 min after the cessation of exercise, both the sensitivity and responsiveness of insulin-stimulated AIB uptake were significantly enhanced in the soleus and the red portion of the gastrocnemius. As previously shown for glucose transport and glycogen synthesis, only small effects were observed in the white portion of the gastrocnemius, which unlike the other muscles was not depleted of glycogen during the run. Insulin-stimulated glucose utilization was also enhanced in the incubated soleus muscle of exercised rats; however, insulin binding to the soleus was not altered. These studies indicate that the ability of insulin to stimulate processes other than glucose transport and glycogen synthesis is enhanced in skeletal muscle after exercise and that this is not due to an alteration in insulin binding. The changes in insulin-stimulated AIB uptake and glucose metabolism after exercise are the reverse of those found in denervated and immobilized muscle and in both situations insulin binding is not altered. This suggests that a common factor(s) modulates the increase in insulin effect after exercise and the insulin resistance of disuse.
Aminoisobutyric Acids↗
Studies on the mechanism of improved glucose control during regular exercise in type 2 (non-insulin-dependent) diabetes.
The effects of 6 weeks of thrice weekly training on glycaemic control were assessed in 20 sedentary Type 2 (non-insulin-dependent) diabetic patients and 11 control subjects matched for previous physical activity. Maximal oxygen uptake was lower in the diabetic patients than in control subjects before training (26.2 +/- 1.1 versus 32.6 +-/ 1.7 ml X kg-1 X min-1; p less than 0.001). Glycosylated haemoglobin levels decreased in the diabetic patients during the training programme (12.2 +/- 0.5 to 10.7 +/- 0.4%; p less than 0.02). Oral and intravenous glucose tolerance determined 72 h after the last exercise period showed only minimal improvement. Plasma glucose levels were, however, significantly lower at 12 h than 72 h after exercise in eight subjects tested at both time points. These data suggest than an exercise programme can produce a significant decrease in glycosylated haemoglobin levels in Type 2 diabetic males probably due, in great measure, to the cumulative effect of transient improvements in glucose tolerance which follow each individual period of exercise.
Adult↗
Sites of protein conservation and loss during starvation: influence of adiposity.
Previous studies have established that older (16 wk) and more obese rats conserve body protein during prolonged starvation. This adaptation is due in part to a curtailment of muscle proteolysis. To determine whether this response occurs also in younger rats and whether protein is conserved at sites other than muscle, studies were conducted in young 6-wk-old rats previously fed either a chow or a high-fat diet before starvation. Fat feeding caused a marked increase in adipose mass and prolonged survival. Whereas chow-fed rats survived the fast for approximately 5 days, fat-fed rats lived for 10 days and diminished their excretion of nitrogen for at least 6 days, indicative of protein conservation. Despite the ability of fat-fed rats to survive the fast longer, protein was conserved in only a few organs. The timing and magnitude of protein loss from liver, kidney, intestine, and lung was similar to that in chow-fed rats, and little protein was lost during the fast from brain, stomach, skin, and soleus muscle in either group. In fat-fed rats, cardiac and skeletal muscle were the principle tissues in which protein was conserved, and this adaptation was lost when body fat stores were nearing exhaustion. In both groups nitrogen excreted in the urine early in the fast was derived mainly from protein lost from muscle, liver, and to a lesser extent intestine. Later in the fast, the principal source was muscle. These findings indicate that during starvation in the rat the conservation of protein occurs principally in skeletal and cardiac muscle. They also suggest that the ability of the rat to conserve protein is dependent on the size of its lipid stores.
Adipose Tissue↗
Enhanced muscle glucose metabolism after exercise in the rat: the two phases.
Thirty minutes after a treadmill run, glucose utilization and glycogen synthesis in perfused rat skeletal muscle are enhanced due to an increase in insulin sensitivity (Richter et al., J. Clin. Invest. 69: 785-793, 1982). The exercise used in these studies was of moderate intensity, and muscle glycogen was substantially repleted at the time (30 min postexercise) that glucose metabolism was examined. When rats were run at twice the previous rate (36 m/min), muscle glycogen was still substantially diminished 30 min after the run. At this time the previously noted increase in insulin sensitivity was still observed in perfused muscle; however, glucose utilization was also increased in the absence of added insulin (1.5 vs. 4.2 mumol X g-1 X h-1). In contrast 2.5 h after the run, muscle glycogen had returned to near preexercise values, and only the insulin-induced increase in glucose utilization was evident. The data suggest that the restoration of muscle glycogen after exercise occurs in two phases. In phase I, muscle glycogen is depleted and insulin-stimulated glucose utilization and glucose utilization in the absence of added insulin may both be enhanced. In phase II glycogen levels have returned to near base-line values and only the increase in insulin sensitivity persists. It is proposed that phase I corresponds to the period of rapid glycogen repletion that immediately follows exercise and phase II to the period of supercompensation.
Animals↗
Enhanced muscle glucose metabolism after exercise: modulation by local factors.
Studies in the rat suggest that after voluntary exercise there are two phases of glycogen repletion in skeletal muscle (preceding study). In phase I glucose utilization and glycogen synthesis are enhanced both in the presence and absence of insulin, whereas in phase II only the increase in the presence of insulin is found. To determine whether these alterations and in particular those mediated by insulin are due to local or systemic factors, one hindlimb of an anesthetized rat was electrically stimulated, and both hindlimbs were perfused immediately thereafter. Glucose and glycogen metabolism in the stimulated leg closely mimicked that observed previously after voluntary exercise on a treadmill. With no insulin added to the perfusate, glucose incorporation into glycogen was markedly enhanced in muscles that were glycogen depleted as were the uptake of 2-deoxyglucose and 3-O-methylglucose. Likewise, the stimulation of these processes by insulin was enhanced and continued to be so 2 h later when the muscles of the stimulated leg had substantially repleted their glycogen stores. The results suggest that the increases in insulin-mediated glucose utilization and glycogen synthesis in muscle after exercise are modulated by local contraction-induced factors.
Adenosine Triphosphate↗
Diabetes-induced alterations of glucose metabolism in rat cerebral microvessels.
The effect of diabetes on the metabolism of glucose and lactate was examined in isolated rat cerebral microvessels. In rats with diabetes induced with streptozotocin, glucose oxidation to CO2 by the microvessels was decreased by 54-83% and its conversion to lactate by 21-61%. Insulin therapy for several days or starvation for 48 h both lowered blood glucose levels in the diabetic rats and restored microvessel glucose metabolism to normal. Cerebral microvessels consist principally of the capillaries that constitute the blood-brain barrier. Direct assessment of the blood-brain barrier in vivo using the brain uptake index (BUI) technique revealed a close parallel to the findings in the microvessels. Thus, hexose transport was diminished in diabetic rats and restored to normal by both insulin therapy and starvation. The oxidation of [1-14C]lactate to CO2 like that of glucose was depressed in microvessels of diabetic rats. In contrast to glucose, however, the transport of lactate across the blood-brain barrier in vivo was not altered. These findings suggest that diabetes suppresses glucose metabolism in rat cerebral microvessels and downregulates glucose transport across the blood-brain barrier. They also suggest that both of these processes are regulated by chronic alterations in blood glucose concentration rather than by insulin per se.
Animals↗
Glucose uptake and insulin sensitivity in rat muscle: changes during 3-96 weeks of age.
It has been demonstrated that aging diminishes the rate of glucose utilization by rat skeletal muscle. To determine the basis for this occurrence as well as its temporal sequence, glucose utilization was examined in isolated hindquarters of 3-, 5-, 8-, 16-, 24-, 48-, and 96-wk-old male Sprague-Dawley rats. Glucose utilization diminished progressively during early development (3-5 wk) and adolescence (5-16 wk) in hindquarters perfused in the absence of added insulin. At the same time there was a progressive shift of the insulin dose-response curve to the right, indicating diminished insulin sensitivity and a marked decrease in maximum insulin responsiveness. In contrast, between 24 and 96 wk of age, insulin sensitivity and the rate of glucose utilization in the absence of added insulin did not decrease, and there was only a small decrease in maximum responsiveness. The rate-limiting step in glucose utilization under all conditions was glucose transport. Even at high insulin concentrations, free glucose was not detected in the muscle cells of young or old rats, the uptake of 2-deoxyglucose diminished in parallel with that of glucose, and there was no evidence of a defect in glucose metabolism. These findings indicate that in the Sprague-Dawley rat glucose transport into skeletal muscle and in particular its sensitivity and responsiveness to insulin diminish progressively during early development and adolescence. No further marked changes occurred up to at least 96 wk of age. To what extent these early age-associated changes are due to insulin binding and to what extent to alterations in the glucose transport system per se remains to be determined.
Aging↗
Alpha and beta adrenergic effects on metabolism in contracting, perfused muscle.
The role of alpha- and beta-adrenergic receptor stimulation for the effect of epinephrine on muscle glycogenolysis, glucose- and oxygen uptake and muscle performance was studied in the perfused rat hindquarter at rest and during electrical stimulation (60 contractions/min). Adrenergic stimulation was obtained by epinephrine in a physiological concentration (2.4 X 10(-8) M) and alpha- and beta-adrenergic blockade by 10(-5) M phentolamine and propranolol, respectively. Epinephrine enhanced net glycogenolysis during contractions most markedly in slow-twitch red fibers. In these fibers the effect was mediated by alpha- as well as by beta-adrenergic stimulation, the latter involving production of cAMP, phosphorylase activation and synthase inactivation. In contrast, in fast-twitch fibers only beta-adrenergic mechanisms were involved in the glycogenolytic effect of epinephrine. Moreover, inactivation of synthase was less in these fibers. Epinephrine also increased the net release of lactate from the hindquarter, an effect abolished by combined alpha- and beta-adrenergic blockade but by neither alpha- nor beta-adrenergic blockade alone. Epinephrine increased uptake of oxygen and glucose by stimulation of alpha-adrenergic receptors and had a positive inotropic effect during contractions which was abolished by alpha- as well as by beta-adrenergic blockade. The results indicate that epinephrine has profound effects on contracting muscle, and that these effects are elicited through different combinations of alpha- and beta-adrenergic receptor stimulation.
Adrenergic alpha-Agonists↗
Muscle glycogenolysis during exercise: dual control by epinephrine and contractions.
The interaction of epinephrine and contractions on muscle metabolism was studied in the isolated perfused rat hindquarter. Subtetanic contractions (180/min) through 20 min elicited glycogenolysis and increased phosphorylase a activity. In the soleus, a slow-twitch red muscle, these effects were transient, but when epinephrine at a physiological concentration (2.4 X 10(-8) M) was added to the perfusate, glycogenolysis and phosphorylase activity were sustained throughout contractions. At this high frequency of contractions, the effect of epinephrine was much smaller in the fast-twitch red fibers and not significant in the fast-twitch white fibers of the gastrocnemius muscle. However, during less frequent contractions (30/min) epinephrine increased glycogenolysis and phosphorylase a activity in fast-twitch muscle. The data suggest that epinephrine and muscle contractions exert a dual control of muscle glycogenolysis during exercise: contractions principally stimulate glycogenolysis early in exercise, and a direct effect of epinephrine on muscle is needed for continued glycogenolysis. In addition, epinephrine increased oxygen consumption and glucose uptake in both resting and electrically stimulated hindquarters and, under some conditions, it had a positive inotropic effect on contracting muscle.
Adenosine Triphosphate↗
Muscle glucose metabolism following exercise in the rat: increased sensitivity to insulin.
Muscle glycogen stores are depleted during exercise and are rapidly repleted during the recovery period. To investigate the mechanism for this phenomenon, untrained male rats were run for 45 min on a motor-driven treadmill and the ability of their muscles to utilize glucose was then assessed during perfusion of their isolated hindquarters. Glucose utilization by the hindquarter was the same in exercised and control rats perfused in the absence of added insulin; however, when insulin (30-40,000 muU/ml) was added to the perfusate, glucose utilization was greater after exercise. Prior exercise lowered both, the concentration of insulin that half-maximally stimulated glucose utilization (exercise, 150 muU/ml; control, 480 muU/ml) and modestly increased its maximum effect. The increase in insulin sensitivity persisted for 4 h following exercise, but was not present after 24 h. The rate-limiting step in glucose utilization enhanced by prior exercise appeared to be glucose transport across the cell membrane, as in neither control nor exercised rats did free glucose accumulate in the muscle cell. Following exercise, the ability of insulin to stimulate the release of lactate into the perfusate was unaltered; however its ability to stimulate the incorporation of [(14)C]glucose into glycogen in certain muscles was enhanced. Thus at a concentration of 75 muU/ml insulin stimulated glycogen synthesis eightfold more in the fast-twitch red fibers of the red gastrocnemius than it did in the same muscle of nonexercised rats. In contrast, insulin only minimally increased glycogen synthesis in the fast-twitch white fibers of the gastrocnemius, which were not glycogen-depleted. The uptake of 2-deoxyglucose by these muscles followed a similar pattern suggesting that glucose transport was also differentially enhanced. Prior exercise did not enhance the ability of insulin to convert glycogen synthase from its glucose-6-phosphate-dependent (D) to its glucose-6-phosphate-independent (1) form. On the other hand, following exercise, insulin prevented a marked decrease in muscle glucose-6-phosphate, which could have diminished synthase activity in situ. The possibility that exercise enhanced the ability of insulin to convert glycogen synthase D to an intermediate form of the enzyme, more sensitive to glucose-6-phosphate, remains to be explored. These results suggest that following exercise, glucose transport and glycogen synthesis in skeletal muscle are enhanced due at least in part to an increase in insulin sensitivity. They also suggest that this increase in insulin sensitivity occurs predominantly in muscle fibers that are deglycogenated during exercise.
Animals↗
Partial characterization of an insulin-dependent serum factor that regulates ornithine decarboxylase in skeletal muscle.
We have previously shown that a factor(s) in rat serum induces ornithine decarboxylase (ODC) in incubated muscle and that its activity is diminished in sera from diabetic rats. To characterize this factor further, we have studied some of its physicochemical and biologic properties. As judged from its ability to induce ODC in the incubated rat soleus muscle, the factor is protease-sensitive and both heat- and acid-stable. In untreated whole serum its activity is associated with a high-molecular-weight fraction whereas after boiling at pH 5.5, activity is principally in a fraction with a molecular weight between 3500 and 12,000 daltons. The activity of the factor is diminished in hypophysectomized, starved, and aged as well as diabetic rats. In diabetic rat serum it is restored to normal by the addition of a purified somatomedin, multiplication-stimulating activity. These findings suggest that the "ODC inducing factor" is a low-molecular-weight peptide and that it has many of the characteristics of a somatomedin.
Animals↗
Obesity-associated disorders in normal-weight individuals: some speculations.
A number of disorders including maturity-onset (Type II) diabetes, hypertension and hypertriglyceridemia are frequently associated with adult-onset obesity and improve with energy restriction. It is the premise of this brief review that there are patients with these disorders who are not obese according to standard criteria; but who would also respond favorably to energy restriction. It is proposed that these 'metabolically-obese, normal weight' individuals might be characterized by hyperinsulinism and possibly an increase in fat cell size, compared to patients of similar age, height and weight and/or to themselves at an earlier time. It is also proposed that in some of these individuals inactivity and diet composition might be important contributing factors, and that for them, the appropriate therapy would include exercise and altered diet composition.
Adult↗
Influence of muscle use on amino acid metabolism.
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Alanine↗
Physical training and cardiovascular disease in the diabetic.
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Animals↗