Plasma glucose concentration is commonly observed to fall during prolonged exercise lasting more than 2 h(1,2,21,38,40). While the decrement in glycemia during exercise appears relatively mild for many subjects, severe hypoglycemia of less than 2.5 mM has been reported to occur with some frequency (2,12,39). Ahlborg and Felig(1) reported that 50% of their subjects demonstrated severe hypoglycemia at exhaustion. In a subsequent study designed to specifically address this issue, the same group reported a 37% rate of severe hypoglycemia when exercising to exhaustion at 60-65% of ˙VO2max (21). The onset of hypoglycemia has often been associated with the induction of fatigue for sustained exercise(2,9,14,22,58). When defined as an inability to maintain an established workload, fatigue has been shown to ensue from modest reductions in blood glucose (9). Under these conditions fatigue appears attributable to an insufficient fuel, i.e., carbohydrate supply, for the working muscle. Preventing the onset of hypoglycemia via exogenous glucose supply can significantly delay the onset of fatigue (9). Severe hypoglycemia (2.5 mM) may introduce added complications resulting from neuroglucopenia. Under normal conditions the brain uses blood glucose as its primary source of fuel and is dependent upon a positive gradient between the plasma and CNS compartments(4). A fall in plasma glucose to below 50 mg·dL-1 would be expected to impair both cognitive and motor function; however, impaired neurological function appears to be relatively rare during exercise (2,9,21).
The fall in glycemia during exercise results from an inability of glucose production to match the demands of glucose uptake. At rest in the postabsorptive state, the brain accounts for the majority of glucose utilization with skeletal muscle playing a minor role, i.e., ≈10%-15%(55). However, with the onset of exercise, skeletal muscle glucose uptake is substantially increased. During prolonged exercise skeletal muscle glucose utilization is reported to increase by some 16- to 19-fold (1,2,55). While fat contributes an increasing proportion of the total fuel requirement during the course of prolonged exercise, an apparent requirement for carbohydrates persists even after 4 h (2). As muscle glycogen is depleted during exercise, the carbohydrate requirement is increasingly met by blood glucose(1,2,55). The increase in glucose production during exercise is met by a combination of hepatic glycogenolysis and gluconeogenesis. Glycogenolysis plays the primary role over the first 2 h, with gluconeogenesis contributing an ever increasing proportion of glucose production as exercise is sustained (1,2). It has been proposed that when liver glycogen stores are substantially depleted and the individual must rely on gluconeogenesis, hypoglycemia will begin to ensue rapidly (9).
Endurance training is known to improve one's resistance to exercise-induced hypoglycemia (8,26,37,57,58). Whether endurance training improves glucose homeostasis during exercise via suppressed glucose uptake or increased glucose production has, until recently, been the subject of some speculation(26,36,37,56). Over the past decade the application of tracer techniques to this question has served to greatly enhance our understanding of this phenomena. Evidence has been garnered in support of both mechanisms, i.e., reduced uptake and enhanced production. The objective of this short review is to examine what is known regarding each of these processes with an emphasis on findings from the authors' laboratory. Specifically, data will be introduced supporting the hypothesis that training leads to an enhanced capacity for hepatic gluconeogenesis which can be invoked to combat hypoglycemia during prolonged exercise.
GLUCOSE PRODUCTION AND TRAINING ENHANCED GLUCOSE HOMEOSTASIS
The relative importance of the suppressed glucose uptake versus enhanced glucose production for improved hypoglycemic resistance with training is currently unknown for humans. To date all human studies have been conducted under conditions in which trained and untrained individuals demonstrate comparable glucose homeostasis, essentially maintaining euglycemia for the entire exercise period. Under such conditions, i.e., low to moderate intensity exercise (50-60% of ˙VO2max) with little or no change in glycemia, it has been demonstrated for both humans(10,12,40) and rats (8) that training results in a suppression of whole-body glucose uptake and production. In theory the reduced glucose uptake and sparing of liver glycogen in trained individuals should provide for better glucose homeostasis as exercise continues and hypoglycemia develops in untrained individuals. However, this hypothesis assumes that untrained individuals will maintain their relatively elevated glucose uptakes as hypoglycemia ensues. While glucose production has been shown consistently to increase over the first 2 h of exercise for both trained and untrained individuals(1,12), as exercise progresses beyond 2 h untrained subjects display substantial reductions in glucose uptake and production(1,2,55). Ahlborg and Felig(1) reported a 60% decrease in hepatic glucose production between the second and third hour of moderate exercise, ≈ 65% of˙VO2max. Whether glucose uptake and production also decreases for trained individuals beyond 2 h or continues to climb, reaching or exceeding the rates for untrained individuals, has yet to be tested.
For rats we have assessed the relative importance of glucose uptake and production under exercise conditions in which trained animals actually demonstrate hypoglycemic resistance (18). Following a 30-h fast to deplete liver glycogen stores, untrained animals when run at 20 m·min-1 demonstrated a significant fall in blood glucose by 15 min, which continued reaching a nadir of 2.4 ± 0.4 mM at 60 min(Fig. 1). In contrast trained animals maintained euglycemia over the first 45 min of exercise and demonstrated significantly higher glucose values between 15 and 60 min when compared to their untrained counterparts. With blood glucose falling more rapidly for untrained animals, no differences were observed in glucose disappearance between groups over the first 30 min of exercise. Thereafter, trained animals actually demonstrated higher rates of glucose disappearance, attributable most likely to their higher blood glucose levels, ≈1.4 mM higher. Thus, in this study the improved glucose homeostasis during exercise was ascribed to a significant increase in glucose production following training (Fig. 2). Given that glycogen stores were essentially depleted following the fast, the training induced increase in glucose production must have occurred via gluconeogenesis. That the improved glucose production was derived from gluconeogenesis was supported by an increase in the apparent rate of glucose recycling (an indicator of Cori Cycle activity) in trained rats.
Evidence that training might lead to improved gluconeogenesis under certain physiological conditions was actually forthcoming from some of our earlier studies. In studies designed to examine lactate clearance following training(16,17), we continuously infused trained and untrained rats with equivalent amounts of molar lactate and14 C-lactate. Under these conditions we observed a 25% increase in the incorporation of 14C-lactate into 14C-glucose for trained animals. This occurred despite similar 14C-lactate specific activities and 50% lower circulating lactate levels for trained animals, i.e., the mass of tracer passing through the liver was apparently 50% lower for trained animals. This enhanced incorporation of 14C into glucose from14 C-lactate despite lower circulating lactate concentrations has also been observed during exercise (15). Again the circulating14 C-lactate specific activity was identical for trained and untrained animals running at 30 m·min-1. However, in this case the rate of14 C-lactate delivery (dpm·min-1) to the liver may have been more equivalent owing to the higher sustained hepatic blood flows reported for exercising trained individuals (3,45). This may explain in part the relatively greater impact of training upon14 C incorporation into glucose, i.e., an 88% increase, observed in that study (Fig. 3). That this reflected a true increase in gluconeogenic activity is supported by the fact that trained rats running at this higher speed actually demonstrate slightly greater glucose production rates than untrained rats (8). Again this was associated with improved hypoglycemic resistance on the part of trained animals.
The above findings led us to specifically examine the impact of training upon hepatic gluconeogenesis (51). Using an in situ perfused preparation, rates of glucose production were measured from livers of trained and untrained rats. To assure the gluconeogenic origin of the glucose production in these experiments, animals were fasted for 24 h to reduce liver glycogen (<5 mg·g-1) and the livers perfused without substrate for the first 30 min, a “washout” period, to further reduce liver glycogen (1.07 ± 0.09 mg·g-1). Under these conditions endurance training was observed to induce a 25% increase in the Vmax for hepatic gluconeogenesis at saturating lactate concentrations (Fig. 4). This enhancement in the maximal gluconeogenic rate with training was confirmed by a concomitant 23% elevation in 14C-incorporation into glucose from 14C-lactate. Other indices consistent with this training-induced increase in gluconeogenesis and its associated energy demands were observed. These included similar relative increases for lactate uptake (25%), oxygen consumption (19%), and14 CO2 production (23%) from endurance trained livers. Alternatively, the Km for hepatic gluconeogenesis was unchanged following endurance training. These findings provided the first direct evidence that chronic physical activity results in an elevated capacity for hepatic gluconeogenesis.
We have subsequently examined the impact of endurance training uponin situ hepatic gluconeogenesis from a variety of precursors to constrain the specificity and site of adaptation (49). As the Km for lactate was apparently unaffected, we further examined the training enhanced gluconeogenic capacity using saturating concentrations of alanine (10 mM), dihydroxyacetone (20 mM), and glutamine (10 mM) (Fig. 4). For alanine, the primary amino acid precursor for gluconeogenesis during exercise, the effect of training was similar to that observed for lactate. When perfused with 10 mM alanine, trained livers demonstrated significantly higher gluconeogenic rates, 0.51 ± 0.04μmol·min-1·g-1, when compared with controls, 0.40 ± 0.02 μmol·min-1·g-1, a 28% increase. This elevation in glucose production coincided with similar relative elevations in alanine uptake (30%), oxygen consumption (23%),14 CO2 output (30%), and urea output (22%). The gluconeogenic origin of this training-induced increase in glucose production was supported by a concomitant increase in 14C-alanine incorporation into glucose(26%). Unlike lactate and alanine, endurance training did not impact upon gluconeogenesis or any related parameters when either 20 mM dihydroxyacetone or 10 mM glutamine were employed as the precursor. The significantly higher rate of glucose production from dihydroxyacetone (1.75 ± 0.05μmole·min-1·g-1) when compared with all other substrates was consistent with previous observations(27). It further indicated that the site for this training adaptation lies below the level of the triose phosphates. The results for glutamine, while further constraining the site of adaptation, leave open several possibilities regarding the locus for adaptation. If the results for lactate and alanine reflect a common adaptation, the site of adaptation would appear to be localized between the formation of pyruvate and malate. However, training has not been associated with elevations in either pyruvate carboxylase (28) or phosphoenolpyruvate carboxykinase(51,56), traditionally considered primary steps at this level of the gluconeogenic pathway. Alternatively, as the absolute rate for gluconeogenesis from lactate remains ≈2-fold greater than that for alanine following training we cannot ignore the possibility of adaptations specific to these individual precursors. These specific adaptations might include some of the enzymatic adaptations described below.
That the liver undergoes adaptations in response to endurance training, at least some of which may be related to enhanced gluconeogenesis, has been reported by a number of investigators. Bobyleva-Guarriero and Lardy(6) demonstrated significant increases in the gluconeogenic rate for hepatocytes from trained rats following an acute exercise bout, which contrasted with the nonsignificant increase for hepatocytes from untrained animals. They further reported significant exercise-induced increases in the rate of citrulline synthesis in hepatocytes from trained animals (6), comparable with their previous observation of increased state 3 mitochondrial respiration(7). The increased rates of mitochondrial oxidation, gluconeogenesis, and citrulline synthesis, following an acute bout of exercise, suggest a significant training-exercise interaction. In support of this concept, Huston et al. (28) observed a significantly greater exercise-induced increase in hepatic PEPCK activity for trained when compared with untrained animals. Kraus and Kirsten (38) reported significant elevations in hepatic mitochondrial succinate dehydrogenase activity and cytochrome concentration following a chronic program of treadmill running or swimming in rats. Ji et al.(33) reported significantly higher hepatic mitochondrial enzyme activities for malate dehydrogenase and alanine aminotransferase following endurance training. Other training-induced adaptations noted for the liver include, accelerated hepatic elimination of antipyrine and aminopyrine(19), increases in content and activity of microsomal enzymes (38), and significant increases in liver protein content and concentration (5). We have also observed a significant elevation in cytosolic aspartate aminotransferase (AspAT) with training (49). This latter adaptation may be critical for lactate, as lactate carbons are apparently transported to the cytosol as aspartate, rather than malate. Even observed decreases in certain enzymatic activities with training may favor gluconeogenesis. Dohm et al.(14) reported a significant decrease in hepatic phosphodiesterase activity following endurance training which might be expected to prolong the activation of cAMP. The reported decrease in citrate synthase (56) could be expected to suppress citrate synthesis, thereby elevating oxaloacetate (OAA) levels. Given the equilibrium constants for the malate dehydrogenase and aspartate aminotransferase reactions, small elevations in OAA should translate into large elevations in malate and aspartate. Finally, we (50) have observed, as have others (56), that the Vmax for hepatic lactate dehydrogenase (LDH) is depressed following training. However, while training had no impact on the Km when pyruvate was provided as the substrate, it significantly reduced the Km for lactate. To the extent that the fall in lactate dehydrogenase activity might displace this reaction from equilibrium, these adaptations would favor flux towards pyruvate. Thus, training is observed to induce a number of hepatic enzymatic adaptations, some of which may be relevant to our observations of enhanced gluconeogenesis.
There has been a tendency to downplay the importance of glucose production in the training enhanced glucose homeostasis during exercise(26,56). This position is predicated on the training induced changes in glucoregulatory hormones and gluconeogenic precursors observed during exercise. In particular, the higher insulin, lower glucagon, and the lower concentrations of lactate and glycerol in trained individuals have been cited as evidence against improved hepatic glucose output (10,56). However, Turcotte and Brooks(52) have demonstrated that when gluconeogenesis is inhibited with mercaptopicolinate (MPA), not only is glucose homeostasis and exercise performance compromised, but the improvement in these parameters following training is eliminated. One possible explanation for this apparent paradox is that training may lead to significant alterations in hormonal sensitivity and/or responsiveness. Evidence for such an enhancement has been forthcoming from the recent work of Podolin et al.(43,44) in which liver slices from trained animals demonstrated substantially greater rates of gluconeogenesis in the presence of several counter-regulatory hormones. Additionally, Duan and Winder(20) demonstrated similar fructose-2,6-bisphosphate levels in livers from trained and control rats following exercise, despite lower glucagon, higher insulin, and lower cAMP concentrations for the trained animals. This latter finding suggests significant alterations in post-receptor cell signaling with endurance training.
GLUCOSE UPTAKE AND TRAINING ENHANCED GLUCOSE HOMEOSTASIS
Beyond the question of the quantitative contribution of reduced glucose uptake to training improved glucose homeostasis, there is the issue of the site at which this occurs. Traditionally the training-induced suppression in glucose utilization has been attributed to adaptations occurring at the level of the skeletal muscle. Over 25 years ago it was hypothesized that training led to the sparing of carbohydrates, both skeletal muscle glycogen and blood glucose, through an enhancement of the “glucose-fatty acid cycle”(41). The glucose-fatty acid cycle purports to explain how an elevation in fatty acid oxidation will lead aspects to a suppression of carbohydrate catabolism. Essential aspects of the cycle include the inhibition of pyruvate dehydrogenase via acetyl-CoA and phosphofrucktokinase via citrate with a subsequent rise in glucose-6-phosphate (G6P) levels. That training might enhance the glucose-fatty acid cycle during exercise was originally predicated on two well known observations for the trained state, i.e., the suppressed respiratory quotient and reduced skeletal muscle glycogen depletion. Additional support appeared to be garnered from the studies of Holloszy et al. (25,26) demonstrating training induced elevations in skeletal muscle palmityl oxidase activity,β-Ketothiolase, and palmityl carnitine transferase. However, Coggan et al. (12) have shown that despite suppressed RQs trained individuals demonstrated no change in skeletal muscle citrate levels. Further, training has been shown to actually lead to a suppression in glucose-6-phosphate levels during exercise (12) and muscular contraction (13). These recent findings cast strong doubt on the putative role of the glucose-fatty acid cycle in the observed metabolic events following endurance training.
While the mechanism remains elusive, skeletal muscle continues to be identified as the locus for the training-induced reduction in whole-body glucose uptake during exercise(10-12,40). This position appears largely based upon the assumption that skeletal muscle accounts for the majority of glucose uptake during exercise, a result of earlier arterial-venous studies across exercising limbs(1,2,55). However, application of the same arterial-venous technique has uniformly failed to demonstrate any effect of endurance training upon skeletal muscle glucose uptake during exercise(24,35,46). Only in studies of athletes versus nonathletes has there been any indication of reduced muscle glucose uptake during exercise (32,53). Such cross-sectional studies do not distinguish the impact of training per se, nor have they been particularly convincing in identifying skeletal muscle as the exclusive site of adaptation responsible for suppressed whole-body glucose uptake. Jansson and Kaijser (32) observed significantly lower glucose uptake for athletes at only one time point, while Turcotte et al. (53) noted suppressed glucose uptake in athletes only after 2 h of exercise. This latter finding is in marked contrast to the consistent observations for whole body glucose kinetics. Coggan et al. (10,11) have convincingly demonstrated that whole body glucose uptake is significantly suppressed as early as 15 min into exercise for trained humans and this suppression is maintained for the duration of the exercise bout, i.e., 120 min. Thus, at present the site(s) responsible for the suppressed whole-body glucose uptake in humans during exercise subsequent to training remains to be resolved.
In a recent study (48) we tested the hypothesis that endurance training suppresses skeletal muscle glucose uptake during exercise using the nonmetabolized glucose analogue 2-[1,2-3H]-deoxyglucose as proposed by James et al. (31). For this study we employed the rat (a widely studied animal model) which demonstrates many endurance training adaptations similar to those of humans including a reduced exercise respiratory quotient (8,15), increased skeletal muscle mitochondrial content (23,25), and reduced muscle and liver glycogen utilization during exercise(18,48,56-58). Chronically cannulated endurance trained and untrained animals were run on a treadmill at 20 m·min-1 for 55 min. Ten minutes into the run a bolus injection of 2-3H-deoxyglucose was administered via the jugular vein, followed by frequent arterial sampling to establish the plasma 2-3H-deoxyglucose decay curve over the ensuing 45 min of exercise. At the end of exercise animals were sacrificed and five hindlimb muscles, the heart, diaphragm, and lung were rapidly excised and freeze clamped. These tissues were subsequently analyzed for their concentration of phosphorylated 2-3H-deoxyglucose, an index of glucose uptake, i.e., the “glucose metabolic index,” when corrected for the integrated plasma 2-3H-deoxyglucose concentration over time. While exercise led to a significant increase in the glucose metabolic index for several muscles, no significant differences were observed between trained and control animals(Fig. 5). Thus, despite a significant reduction in skeletal muscle glycogenolysis during exercise, training failed to impact upon skeletal muscle glucose uptake.
The results we obtained in vivo with 2-3H-deoxyglucose are not surprising given previous observations for endurance trained skeletal muscle. These include in vitro and in situ demonstrations of unchanged or enhanced glucose uptake under resting(29,30), insulin stimulated(31), and contraction stimulated(30,42) conditions. Slentz et al.(47) have further demonstrated increased quantities of GLUT 4 protein in muscles taken from trained rats. Our findings for rats using 2-3H-deoxyglucose are entirely consistent with the findings for humans using the arterial-venous technique, i.e., that training does not suppress skeletal muscle glucose uptake during exercise(24,35,46).
For trained animals it is clear that their improved resistance to exercise-induced hypoglycemia stems primarily from enhanced glucose production. The source of this improved glucose production appear primarily gluconeogenic in origin. Specific hepatic adaptations for hepatic gluconeogenesis have now been elucidated for lactate and alanine, the primaryin vivo precursors. In addition, evidence has been forthcoming in support of enhanced hepatic hormonal sensitivity/responsiveness following endurance training (20,43,44). The latter findings help to explain the apparent paradox for trained animals of suppressed glucoregulatory responses and elevated gluconeogenesis during exercise. The contribution of reduced glucose uptake towards resistance to exercise-induced hypoglycemia in trained individuals remains unclear. This suppression has only been observed over the first 2 h of exercise while both trained and untrained individuals essentially maintain glucose homeostasis. Whether trained individuals maintain relatively lower glucose production rates during the latter stages of exercise, when untrained subjects become substantially hypoglycemic and demonstrate reductions in hepatic glucose output, is unknown. However, to the extent that the suppression in glucose production over the first 2 h of exercise “spares” liver glycogen, this should improve glucose production for trained individuals during the latter stages of exercise.
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Keywords:©1997The American College of Sports Medicine
LIVER; HYPOGLYCEMIA; GLUCOSE UPTAKE; GLUCOSE PRODUCTION; ENDURANCE TRAINING