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Exercise and the Regulation of Blood Glucose

Page history last edited by Robert Rushakoff, MD 11 years, 8 months ago

The Web diabetesmanager




Jack F Youngren, PhD 








The development of type 2 diabetes mellitus (T2D) has both genetic and acquired components. The rapid increase in this disease in the US, and more dramatically worldwide, underscores the important role that lifestyle plays in its development. In the US, over 15 million people have T2D, and its prevalence increased more than 3-fold over the second half of the 20th century (1). Worldwide, it is estimated that 120 million individuals have T2D, and this figure is expected to reach 300 million by 2025 (2). These patterns are tightly associated with the global adoption of a western lifestyle involving changes both in dietary habits and physical activity (3).


The phenotype of T2D includes reductions in both insulin secretion and action. The progression from normal glycemia to impaired glucose tolerance and eventually to fasting hyperglycemia via these impairments is described in chapter 6 . Insulin resistance, more so than impaired insulin secretion, is directly affected by numerous lifestyle factors. Obesity is recognized as one primary independent cause of insulin resistance (4). However, much of the negative effects attributed to obesity are likely the result of other related lifestyle factors such as physical activity level and diet; which both impact the accumulation or loss of body fat stores, and can influence insulin sensitivity independent of changes in adiposity (5;6). In the absence of pharmacological treatments that directly improve insulin sensitivity (see chapter 16 ), as well as the fact that pharmacological treatments are not currently employed to prevent the progression to T2D in at risk individuals, lifestyle modifications are important components in the treatment of T2D. Thus, regular physical activity may be the treatment of choice in reversing insulin resistance in diabetics and non-diabetics alike, and preventing the development of T2D in subjects with impaired glucose tolerance (see below). This chapter will review the relationships between exercise and glucose control.




It is well established that the incidence of T2D is much lower in individuals who regularly engage in physical activity. The two-fold increase in the prevalence of T2D in Japanese living in Hawaii compared to individuals with a similar genetic background living in Hiroshima is correlated with a decreased frequency of occupational physical activity (7). The University of Pennsylvania Alumni Health study demonstrated an inverse relationship between leisure-time energy expenditure during physical activity and the development of T2D. In these male subjects, interviewed 14 years apart, physical activity had a protective effect that decreased T2D risk 6% for each increment of 500 kcal/week energy expended. The protective effect was greatest in the highest risk subgroup, those individuals with obesity, hypertension and a parental history of T2D (8). In a shorter term prospective study of males, a similar protective effect of exercise was reported, with increasing frequency of weekly exercise being associated with decreased T2D risk (9). A protective effect of exercise was demonstrated in women in the Nurses Health Study. In this study, women who regularly engaged in vigorous physical activity demonstrated a significant decrease in the risk of developing T2D during the 8 years of the study (10). Follow up analysis of these subjects indicated that even time spent engaging in non-strenuous walking was associated with reduced T2D risk (11). These epidemiological studies are limited, however, by their ability to fully control for all other factors associated with physical activity that could explain the relationship between exercise and development of T2D.




The causal link between regular physical activity and the prevalence of T2D has been explored further in several interventional studies. Recently, the results of the Diabetes Prevention Program have been released. This multicenter, randomized clinical trial examined the effects of three interventions (intensive diet and exercise, metformin, and placebo) on the relative risk of diabetes development among high-risk individuals with impaired glucose tolerance (12). In this study, lifestyle intervention (13) was significantly more effective then metformin in reducing the rate of progression to T2D over the average follow-up period of 2.8 years. Subjects enrolled in he DPP underwent significant weight loss in addition to undertaking an exercise program equivalent to at least 150 minutes per week similar in intensity to brisk walking. Similar reductions in progression to T2D were obtained in the Finnish Diabetes Prevention Study. In this 4 year study, in which total caloric intake and fat consumption were reduced in the intervention group in addition to the increased physical activity, this intensive lifestyle modification reduced the risk of developing diabetes by 58%, a greater amount than by pharmacological intervention (14). These interventional studies are discussed in greater depth in Chapter 37 .



While these are very important findings concerning the efficacy of lifestyle intervention in reducing T2D risk, it must be pointed out that the extent to which the benefits of lifestyle intervention are due to the beneficial effects of exercise, separate from diet and weight changes, was not determined in these studies. The DA Qing IGT and Diabetes Study (15) employed three intervention groups in studying progression to T2D in Chinese subjects with IGT, and thus were able to compare dietary intervention with increased physical activity as well as with the additive effects of the two strategies. In this study, the incidence of T2D was similarly reduced in both the diet and exercise intervention groups, and was reduced to a greater degree in the group receiving both interventions.




These protective effects of exercise result from both short term and long term effects of contractile activity on the regulation of glucose metabolism by skeletal muscle. These effects range from the insulin-independent stimulation of glucose transport induced by exercise, to acute and chronic alterations in the biological effectiveness of insulin in muscle. In order to better understand these phenomena, a brief examination of the regulation of glucose transport in required.


The molecular mechanisms whereby insulin stimulates the cellular uptake of glucose is described in chapter 4 . A representation of the key steps in insulin signaling is provided below (Figure 1). The effects of insulin on glucose uptake are mediated via the insulin receptor which, following insulin binding, undergoes autophosphorylation on tyrosine residues activating its tyrosine kinase activity. The activated IR then phosphorylates IRS-1 and other substrates. Tyrosine phosphorylated IRS-1 then serves as a docking protein for PI 3-kinase, which is activated by this interaction. The necessity of PI 3-kinase activation in the insulin effect is demonstrated by the complete ablation of the stimulatory effect of insulin on glucose transport when cells are incubated with specific inhibitors of this serine kinase. The serine phosphorylation cascade initiated by PI 3-kinase involves activation of PI3K-dependent serine/threonine kinases (PDK), and, in turn, Akt and results in the translocation of intracellular GLUT4 to the cell surface. It is the increased amount of GLUT4 on the cell plasma membrane that results in an increased rate of glucose transport into the cell. In muscle cells, stimuli other than insulin can produce a stimulation of the glucose transport system of a similar magnitude, albeit via a separate signaling route.


Figure 1. Insulin signaling pathways involved in stimulating glucose transport. Insulin binding to the IR results in phosphorylation of tyrosine residues (in green) on the receptor and substrates such as IRS-1. Docking of the regulatory subunit of PI3-kinase to phosphotyrosine residues of IRS-1 activates its serine/threonine kinase activity and the phosphorylation cascade involving PDKs and Akt. While these steps are necessary for the recruitment of intracellular pools of insulin-responsive glucose transport to the plasma membrane, the mechanism connecting Akt to cellular trafficking of GLUT4 is not known.




Via its ability to affect various components of the insulin signaling/glucose transport pathway, exercise can regulate blood glucose levels through three distinct mechanisms: acute stimulation of muscle glucose transport; acute enhancement of insulin action, and long term upregulation of the insulin signaling pathway resulting from regular exercise training.


Contractile activity directly increased muscle glucose transport

Skeletal muscle is a unique tissue in that its metabolic rate can increase 200-fold during contractile activity. This metabolic load is met in part by an increased utilization of exogenous glucose. Thus, the cellular machinery of skeletal muscle is equipped to respond to contractile activity with rapid increases in the rate of glucose transport into the cell to match the high glycolytic flux. This effect of contractile activity shares many characteristics with the effect of hypoxia on muscle (16), another condition requiring increased glycolytic rates.

This effect of contractile activity is quite rapid, reaching a maximal increase in the rate of muscle glucose transport within minutes. The magnitude of the exercise effect is roughly equal to the maximal insulin effect, and greater than the effect of more physiological concentrations of insulin (17;18). This enhancement in glucose transport can last up to an hour, as glucose is taken up by previously active muscle for restoration of glycogen stores.


Mechanisms of the acute stimulation of muscle glucose transport: Despite the fact that insulin and contractile activity can induce similar increases in muscle glucose transport, these two stimuli act through very different mechanisms. While the end result of contractile activity is an increased content of GLUT4 in the plasma membrane as described above for insulin, this translocation of GLUT4 is achieved via a separate cellular signaling pathway, and appears to involve distinct intracellular pools of sequestered GLUT4 molecules (19;20). The characteristics differentiating these distinct intracellular pools, such as their subcellular localization, their membrane components and the factors regulating their separate recruitment are not well described. These two pools of GLUT4-containing vesicles can be separated by cellular fractionation techniques (20). Both intracellular pools contain the membrane proteins insulin-responsive amino peptidase (IRAP) and vesicle-associated membrane protein-2 (VAMP-2) which are involved in regulating endocytosis/exocytosis (20;21). However, exercise-stimulated GLUT4 translocation apparently does not induce a redistribution of the GTP-binding protein Rab4 as occurs following insulin stimulation (22).


The signaling pathway that regulates recruitment of the exercise-responsive glucose transporters is not known. However, it has been demonstrated that this GLUT4 pool is not recruited by the insulin/PI3kinase mediated pathway. The important components of the insulin signaling cascade (the IR, IRS-1, PI-3kinase) are not phosphorylated or activated by exercise (23-25), and the PI-3kinase inhibitor, wortmanin, does not block the stimulation of glucose transport by contraction as it does the response to insulin (26;27). The existence of separate mechanisms for contractile activity and insulin to stimulate glucose transport provides some, but not full, additivity for the two effects (28). In addition, this effect of contractile activity is not diminished in insulin resistant states where the response of muscle to insulin is impaired (29-32).

The exact cellular mechanisms responsible for activating the glucose transport system in response to contractile activity have yet to be fully detailed. Traditional theories concerning the role of intracellular calcium (released from the sarcoplasmic reticulum to induce the contractile process) have been supplemented by recent studies suggesting a role for 5'AMP-activated protein kinase (AMPK), or nitric oxide (NO) as mediators of the exercise effect (Figure 2).


Figure 2. Potential mechanisms involved in the stimulation of glucose transport by acute exercise. Muscle contractile activity induces a recruitment of a separate pool of intracellular GLUT4 to the plasma membrane and a subsequent increase in glucose transport. This effect does not involve the components of the insulin signaling pathway. Muscle contraction is initiated by a necessary release of calcium to permit cross bridge formation. Intracellular calcium activates PKC serine kinases which have been hypothesized to stimulate GLUT4 recruitment by unknown mechanisms. Contractile activity alters the AMP/ATP ratio leading to the stimulation of AMPK. AMPK activation leads to an increase in glucose transport, possibly through several mechanisms. AMPK can phosphorylate and activate eNOS, and NO production by this enzyme may contribute to exercise stimulated glucose transport. AMPK can also lead to the phosphorylation of p38 MAPK, which may be involved in the GLUT4 translocation response.


The most likely scenario whereby intracellular calcium activates the glucose transport system is via activation of a calcium-dependent signaling protein such as protein kinase C (PKC). The evidence for this mechanism is mostly indirect. Downregulation of PKC activity by preincubation with phorbol esters leads to a diminished glucose transport response to contraction (33). The PKC inhibitor calphostin C inhibits contraction- but not insulin-stimulated glucose transport (34;35).


NO production increases dramatically in contracting skeletal muscle as nitric oxide synthase (NOS) activity is stimulated (36;37). NO thus produced has a profound impact on increasing blood flow to contracting muscle, overriding systemic vasoconstriction by relaxing smooth muscle. In addition, there is evidence that NO acts as a signaling molecule, mediating both immediate and long term adaptive responses of muscle cells to increased activity (38;39). NO stimulates muscle glucose transport in a cGMP-mediated mechanism (40). Like the exercise response, the effect of NO is independent of PI-3 kinase (41), and inhibition of NO production can block the ability of exercise to stimulate glucose transport in rats (42). However, NOS inhibition has also been shown to have no effect on the ability of contractile activity to stimulate glucose transport in isolated muscle (41;43), and two studies on exercising humans have produced conflicting reports on the effects of NOS inhibition on glucose transport (44).


AMPK is activated during exercise by changes in the AMP/ATP and creatine/phosphocreatine ratios resulting from alterations in the fuel status of the muscle cell with increased fuel utilization. Thus, exercise has been demonstrated to activate muscle AMPK in vivo (45), and the enzyme is activated in isolated hindlimb muscle stimulated to contract (46). Other factors which lead to activation of AMPK are hypoxia and inhibition of glycolysis (47). AMPK is hypothesized to act as a fuel sensor within the cell (47). It is a homologue of the yeast protein kinase SNF-1, which plays a role in adaptation to nutrient stress (47). In mammalian cells, AMPK inhibits acetyl-CoA carboxylase, which leads to increased fat oxidation (46;48). AMPK also can phosphorylate NOS, and this action may be responsible for increased NO production during exercise (49;50). Pharmacological activation of AMPK can be achieved by employing 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) which is metabolized into the AMP mimic, ZMP. AICAR treatment stimulates glucose transport in isolated muscle independently of PI3-kinase (51). Similarly to contraction, the effects of AICAR and exercise are partly additive (51). However, there is no additive effect of AICAR and contractile activity (51). While the correlative evidence favors some role for AMPK in generating the increased glucose transport with contractile activity the causal link has not been firmly established.


Recently it has been suggested that the mitogen activated protein kinase (MAPK) p38, part of the MAP family of serine/threonine kinases plays a role in the metabolic response of muscle to contractile activity. Several components of the MAP kinase pathway are activated by exercise and contribute to the various cellular responses to exercise (reviewed in (52)). In muscle from exercising humans and rodents (53-55), as well as in isolated muscles stretched (56) or stimulated to contract (57), p38 is phosphorylated and activated.



Clinical significance of the actue stimulation of muscle glucose transport

In normal subjects, blood glucose levels are maintained in the face of dramatic increases in glucose disposal into muscle during exercise due to counter-regulatory mechanisms (increased gluconeogenesis and hepatic glucose release) (58;59). However, in T2D patients, exercise can effectively reduce hyperglycemia (58;59). When obese T2D subjects and both lean and obese control subjects were studied in the post-absorptive state, glucose production was similar in T2D and control subjects during exercise. However the greater glucose utilization in the diabetic patients resulted in a fall in blood glucose levels that was not observed in normoglycemic individuals (59). The effectiveness of exercise to increase glucose clearance in T2D patients is consistent with laboratory studies demonstrating full exercise stimulation of glucose transport in insulin resistant muscle (29-32). Insulin levels are not reduced in T2D patients during moderate exercise in the post-absorptive state (59). When moderate to mild exercise is performed post-prandially by patients with T2D, glucose levels are reduced as well (60).


These acute effects of exercise can therefore be exploited by individuals with T2D to reduce blood glucose levels. This exercise effect also works in concert with standard pharmacological therapies to further improve glycemia in T2D patients. In a study comparing the effects of exercise with the sulfonylurea glibenclamide, both interventions produced similar reductions in blood glucose (61). Subjects who combined moderate exercise with earlier administration of glibenclamide obtained a further reduction in blood glucose levels. The increased insulin levels resulting from glibenclamide treatment did not alter glucose clearance during the exercise session, but produced a significant decrease in hepatic glucose production facilitating the reduced glucose levels (61). Treatment of T2D patients with rosiglitazone, but not metformin, has been shown to enhance exercise-stimulated glucose transport (62).


In contrast, acute strenuous exercise can actually lead to an increase in blood glucose levels in individuals with T2D (63). However, this effect appears to be related to the nutrient status of the subject. When T2D patients perform intense exercise in the postprandial state instead, there is a transient decrease in blood glucose levels compared to fed, non-exercised T2D subjects (64).


Exercise-induced hypoglycemia is a serious concern for patients with type 1 diabetes due to these insulin-mimetic effects of insulin. For T1D patients, increased physical activity will necessitate a reduction in the insulin dose. In a study of T1D patients receiving continuous subcutaneous insulin infusion, the subjects attempted to complete a 60 minute exercise session 90 minutes following an insulin bolus and a standard breakfast (65). Exercise-induced hypoglycemia could not be prevented even if insulin infusion was discontinued during the exercise period. It required a 50% reduction in the pre-meal insulin bolus in addition to discontinuing the continuous insulin infusion to prevent hypoglycemia during exercise. In order to avoid hypoglycemia in the post-exercise period, the insulin bolus had to be reduced to 25% of the normal pre-meal dose (65).

The hyperglycemic effects of strenuous exercise are also observed in patients with T1D. However, this phenomenon is especially dramatic in T1D patients with poor glycemic control (66). Following a short exercise bout at 80% VO2 max, subjects with initial fasting glucose levels averaging 149 mg/dl had these levels rise progressively over a 2 hour recovery period to over 220 mg/dl.


It is therefore a challenge for the diabetic subject to appropriately adjust insulin, and potentially food intake, as well as to be aware of their degree of glycemic control in order to accommodate the effects of exercise.

Of benefit to the diabetic patient is the fact that the prolonged enhancement of glucose transport in the face of suppressed insulin secretion during and immediately following exercise means that foods with a high glycemic index that would ordinarily result in larger excursions in postprandial glucose can be handled effectively for insulin resistant subjects.


Contractile activity produces a short term increase in insulin sensitivity

Beyond the transient, insulin-independent stimulation of glucose transport that results from contractile activity, a single bout of exercise can markedly enhance insulin sensitivity in the post-exercise period in both normal and insulin resistant subjects (67-69). This effect is quite dramatic and lasts for several hours. Under certain conditions, insulin stimulation of muscle glucose transport remains elevated for up to 48 hours (70). One factor that appears to regulate the duration of the post exercise effect is the replenishment of muscle glycogen stores. It can be argued that the primary function of enhanced insulin stimulation of glucose transport following exercise is the replenishment of cellular glycogen stores. During this period glycogen synthase activity is elevated and glucose oxidation is suppressed compared to the non-exercised state (reviewed in (44)). Consuming sufficient carbohydrates to regenerate muscle glycogen stores following exercise is associated with a return of insulin sensitivity to basal levels, whereas maintained glycogen depletion prolongs the enhanced effectiveness of insulin (71;72). Additionally, glucose uptake in this period is proportional to glycogen used during the preceding exercise bout (73;74). However, experimental manipulation of glycogen repletion has demonstrated that this is certainly not the only factor regulating the time course of post-exercise insulin sensitivity, as these variables are not always tightly coupled (72).


Mechanisms of the post-exercise increase in insulin sensitivity

The cellular mechanisms underlying the post-exercise enhancement of insulin action are unknown (Figure 3). Following exercise, insulin stimulated phosphorylation and activation of the insulin receptor is not different from the non-exercised state. Paradoxically, it has been reported that insulin stimulation of IRS-1 phosphorylation and PI3kinase activity are decreased while insulin action is enhanced following exercise (75). The post exercise increase in insulin action is observed equally in insulin resistant and insulin sensitive subjects, further implicating mechanisms outside the insulin signaling pathway (76;77). As mentioned above cellular glycogen stores appear to play some role in mediating the increased insulin sensitivity post-exercise. However, the mechanism(s) linking glycogen levels to insulin action is unknown. A possible role for AMPK in mediating this response has been suggested. Incubation of isolated muscles with the AMPK activator AICAR produced enhanced insulin-stimulated glucose transport 3.5 hours later, as did contractile activity (78). However, a direct relationship between enhanced insulin sensitivity and activation of AMPK or any other potential mediator has not been established.


Figure 3. Potential mechanisms involved in the post-exercise increase in insulin sensitivity. Following an acute bout of exercise, insulin stimulation of glucose transport in muscle is greatly enhanced. This is not due to increased activation of the components of the insulin signaling pathway. The increased translocation of GLUT4 to the plasma membrane in response to insulin appears to be related to the reduced glycogen stores following exercise, but the mechanisms are unknown. It is possible that increased AMPK activity is related to this post-exercise effect.


Clinical significance of the post-exercise increase in insulin sensitivity

Given that insulin sensitivity can be enhanced for close to 24 hours following a single bout of vigorous exercise, it is this effect, rather than the insulin-independent increase in glucose transport during exercise or any long term adaptive response, that will impact subjects who exercise daily. In a study of insulin resistant offspring of diabetic parents, he effects of the final bout of exercise apparently accounted for the majority of the difference in insulin action before and after a 6 week exercise training program (67). The prolonged increase in insulin sensitivity therefore acts in concert with the insulin-independent exercise stimulation of glucose transport to effectively lower blood glucose levels in T2D patients.


For diabetic subjects taking insulin, post-exercise administration of insulin must be adjusted, as the post-exercise risk of hypoglycemia persists well beyond the 1 hour period of enhanced glucose transport (65).


Regular exercise training increases insulin sensitivity

The cumulative effects of exercise training to enhance insulin sensitivity are markedly different, however, from the effect of a single bout of exercise to enhance insulin sensitivity. First, the enhanced insulin sensitivity following acute exercise is rapidly lost, and is typically not observed when insulin action is measured 24 hours following the final exercise bout. Second, the increased glucose uptake in response to a given insulin concentration resulting from chronic exercise is associated with enhanced activation of the insulin signaling pathway, while the effects of acute exercise are separate from insulin signaling pathway (74). To avoid confounding the effects of training with residual effects of the last bout of exercise, measurements of insulin action in trained subjects are typically performed 24-48 hours following the final training session. At that time point the effects of the final bout of exercise should have been eliminated, while the training effects have been shown to last well past this period (79), even up to 2 weeks in one study (80). Thus, the timing of insulin sensitivity measurements is critical when studying the long term adaptations to an exercise training program. Evidence for the beneficial effect of a regular exercise training program comes from: studies of trained athletes (81-83); cross sectional studies correlating insulin sensitivity with degree of physical fitness (84-87); and longitudinal studies of previously sedentary subjects undergoing an exercise training regimen (67;79;88-93). Studies comparing endurance-trained individuals as well as young and master athletes to matched sedentary controls have shown that a long-term exercise program is associated with improved insulin action at the whole body and tissue level (81-83). A positive correlation between maximal aerobic capacity and whole body insulin action in has been documented in several different populations, and this relationship is independent of factors such as obesity and age (84;86;87).


Training intervention studies have reported improvements in insulin-stimulated glucose disposal in normal subjects (91), and in subjects with insulin resistance related to aging (92), obesity (88), and type 2 diabetes (93). In addition, the cessation of regular exercise by highly trained individuals results in a dramatic and rapid deterioration in insulin stimulated glucose disposal (91) and glucose tolerance (83). In longitudinal aerobic exercise training studies, previously sedentary volunteers typically show improvements of insulin action of 10-40% (5;67;88;90;94). Studies have not demonstrated additional benefits of increased exercise intensity (94) or of training programs lasting significantly longer than the standard 12-14 weeks (88). It also has been demonstrated that exercise training significantly improved muscle glucose transport in a small group of lean, insulin-resistant first degree relatives of type 2 diabetes patients (67).


It can be unclear when analyzing long term training studies whether the beneficial effects of exercise on whole body insulin action occur via an indirect effect (e.g. reduced visceral obesity) or result from a direct effect on muscle itself. There is strong evidence that improvements in insulin action in muscle with exercise training result from specific adaptations in resulting from increased activity levels rather than general systemic effects. Studies employing one-legged exercise training have demonstrated improved insulin-stimulated glucose uptake in trained, but not untrained, contralateral muscles (95). Additionally, several short term training studies have documented a clear beneficial effect of just 7 days of intense physical training on insulin sensitivity (96-98). These studies have demonstrated both that the effects of exercise training can occur independently of any changes in adiposity and that specific biochemical adaptations can occur in muscle relatively quickly in response to increased activity levels (see below).

Mechanisms of the effects of regular exercise training on insulin sensitivity:


It is not fully understood how chronic exercise training improves insulin effectiveness in muscle (Figure 4). Muscle levels of GLUT4 (the insulin-responsive glucose transport protein), as well as the activity of glycogen synthase, are elevated in athletes compared to sedentary controls (99). Muscle GLUT4 content has been shown to increase with exercise training in various subject groups (90;94). However while GLUT 4 is critical in meditating muscle glucose transport, increases in GLUT4 associated with exercise training may not be the only mechanism responsible for the increased insulin action in muscle (91;100). For instance during detraining, insulin sensitivity decreases at a significantly faster rate than GLUT4 levels (80).


Figure 4. Mechanisms of increased insulin action resulting from adaptations of skeletal muscle to chronic exercise training. Insulin stimulation of glucose transport in muscle is greatly enhanced following exercise training. This adaptive response of muscle involves enhanced signaling through the insulin second messenger pathway. IR autophosphorylation and tyrosine kinase activity are increased in trained muscle with a resultant increase in activation of PI3-kinase and Akt. This enhanced signal transduction, and perhaps the increased cellular GLUT4 content that results from training are responsible for the increased insulin-stimulated translocation of GLUT4 to the plasma membrane in the trained state.


The increased GLUT4 expression in muscle following exercise training is likely due to the fact that many genes involved in carbohydrate metabolism (hexokinase, GLUT-4) appear to be jointly upregulated with mitochondrial enzymes in response to increased contractile activity (101). GLUT4 levels are higher in the highly oxidative slow twitch fibers than the less mitochondrially dense fast twitch fibers.


We have recently demonstrated that 7 days of intense exercise training can increase insulin-stimulated IR signaling in muscle in young, healthy subjects (5). However, these results may not be demonstrable in all experimental designs. A subsequent study of older, insulin resistant subjects did not produce significant increases in IR function following 6 months of lower intensity exercise. Other training studies of muscle IR function in human and animals have produced conflicting results (102-104).

Our finding that the relationship between improvements in autophosphorylation capacity and increased content of mitochondrial enzymes suggests that the improved IR function after exercise training might be related to the increased oxidative capacity of muscle. Thus it is possible that some gene(s) involved in regulating IR function are under similar coordinate regulation with GLUT4 and other metabolic regulators.


Insulin-stimulated activation of downstream components of insulin signaling has received even less attention on humans. 7 days of exercise training significantly improved insulin stimulation of muscle PI 3-kinase activity (98). A recent study of swim-trained rats demonstrated that five consecutive days of swim-training resulted in a significant increase in insulin stimulation of muscle IR autophosphorylation and activation of downstream, second messenger enzymes PI 3-kinase and Akt (104).

Two recent studies have examined the effects of increased physical activity on muscle expression of key genes involved in the insulin signaling pathway. Yu et al. (105) examined muscle biopsies from endurance trained individuals and sedentary controls. Surprisingly, levels of IR, IRS-1, and IRS-2 proteins were all significantly decreased in the trained subjects. Akt protein levels were unchanged in the trained subjects, and GLUT4 levels were increased 2-fold. Wadley et al. (106) studied the effects of a single bout of exercise on subjects before and after undergoing a 9 week exercise training program. This short term training program had no effect on expression of mRNA for the IR, IRS-1, IRS-2 or the p85 regulatory subunit of PI 3-kinase. However, IRS-2 and p85 mRNA levels were increased significantly 3 hours following a single acute bout of exercise (106).


Clinical significance of the enhanced insulin sensitivity with exercise training

The clinical benefits of improved insulin sensitivity resulting from long term adaptations to chronic exercise training can be difficult to discern. In diabetic subjects, improved glycemic control observed over the course of period of regular exercise will result from the combined effects of glucose lowering during exercise, enhanced insulin sensitivity post-exercise, and the general increase in insulin sensitivity resulting from training adaptations. Additionally, improved insulin action and glucose tolerance in subjects exercising regularly can also be a function of systemic benefits of exercise such as weight loss, reduced free fatty acids or other factors. Thus, it is impossible to attribute clinical benefits of exercise training solely to adaptations in the insulin signaling pathway in muscle due to repeated bouts of exercise.


Some benefits of regular exercise in preventing the development of T2D in the general population, or the progression to this disease in at risk individuals have already been presented. It is likely that, in these non-diabetic subjects, the protective effects of exercise against T2D result from the improved insulin sensitivity resulting from training adaptations (14;15). While exercise can reduce the requirement for insulin in T1D and can acutely lower blood glucose and chronically improve insulin sensitivity in T2D patients, the data on whether total glycemic control is improved in diabetic patients by a program of regular exercise is somewhat controversial.


The effects of long term exercise training programs on glucose control in subjects with T2D have been studied in several small studies that have produced somewhat conflicting results. Recently, Boulé et al. (107) performed a meta-analysis of these studies in order to provide some definitive answers concerning the benefits of regular exercise. Their analysis involved 14 trials, 10 of which examined the effects of exercise alone without concurrent dietary intervention. By pooling results involving 154 exercise-trained T2D subjects and 156 controls the authors were able to demonstrate a significant effect of exercise on lowering glycosylated hemoglobin (HbA1c) levels. These improvements were corrected for and independent of weight changes incurred in the studies. Overall, the authors concluded that the exercise training interventions were not successful at producing weight loss in the subjects with T2D (107).


The meta-analysis of Boulé et al. (107) included two studies of resistance training in addition to the studies of aerobic exercise. While the authors concluded that resistance exercise was equally effective at reducing HbA1c levels in T2D subjects, analysis of the two cited studies suggests that this topic likely requires further study. One study did not report any significant effect on HbA1c levels (108), but the 8 week trial may not have been long enough to adequately discern a major effect on glycemic control. In a 5-month study of T2D subjects, the beneficial effect of resistance training on glycemic control resulted from the fact that HbA1c levels increased in the control group and did not change in the training group (109). Other reports of resistance training that in T2D subjects not included in the meta-analysis have reported a significant decrease in HbA1c levels in T2D subjects (110) or no effect (111). Thus, despite the reports that weight or resistance exercise training can improve insulin sensitivity and glucose tolerance as effectively as aerobic exercise (112-114) whether this type of exercise intervention can improve long term glycemic control in patients with T2D requires further study.

Long term exercise training reduces the insulin requirements of T1D patients (115;116). It does not, however, appear to improve chronic glycemic control in these subjects (115-119). Improvements in HbA1c with exercise training have been reported, however (120).



The dramatic increase in the prevalence of T2D is due in part to decreased levels of physical activity. Higher levels of habitual physical activity, as well as exercise training intervention, reduces the incidence of T2D. Regular exercise can also improve insulin action and glucose tolerance in subjects with impaired glucose tolerance and T2D. These beneficial effects of exercise are due largely to 3 separate effects of contractile activity on skeletal muscle, an acute stimulation of muscle glucose transport independent of the effects of insulin, an enhanced insulin response during the post-exercise period independent of the insulin signaling pathway, and longer term adaptations in the components of the insulin signaling system in skeletal muscle as a result of regular exercise training. These factors are all separate from other beneficial systemic adaptations to exercise including weight loss, and improved blood lipids.



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