Review Pediatric Exercise Science, 2014, 26, 375-383 http://dx.doi.org/10.1123/pes.2014-0066 © 2014 Human Kinetics, Inc.
Exercise in Pediatric Type 1 Diabetes Brian D. Tran and Pietro Galassetti University of California, Irvine The beneficial effects of exercise, including reduction of cardiovascular risk, are especially important in children with type 1 diabetes (T1DM), in whom incidence of lifetime cardiovascular complications remains elevated despite good glycemic control. Being able to exercise safely is therefore a paramount concern. Dysregulated metabolism in T1DM however, causes frequent occurrence of both hypo- and hyperglycemia, the former typically associated with prolonged, moderate exercise, the latter with higher intensity, if shorter, challenges. While very few absolute contraindications to exercising exist in these children, exercise should not be started with glycemia outside the 80–250 mg/dl range. Within this glycemic range, careful adjustments in insulin administration (reduction or infusion rate via insulin pumps, or overall reduction of dosage of multiple injections) should be combined with carbohydrate ingestion before/during exercise, based on prior, individual experience with specific exercise formats. Unfamiliar exercise should always be tackled with exceeding caution, based on known responses to other exercise formats. Finally, gaining a deep understanding of other complex exercise responses, such as the modulation of inflammatory status, which is a major determinant of the cardio-protective effects of exercise, can help determine which exercise formats and which individual metabolic conditions can lead to maximally beneficial health effects. Keywords:glycemic regulation, inflammation, exercise-induced hypoglycemia, hyperglycemia Physical exercise exerts a number of beneficial health effects at all ages. In children, however, these effects may be even more important, as exercise, in addition to cardiovascular risk prevention, weight control and psychological well-being, also modulates physiological growth and development (7). Further, learning to exercise regularly at an early age may establish healthy lifestyle patterns sustaining health later in life. While these concepts apply to the overall population, they may be even more relevant for specific categories of subjects, such as those displaying an elevated risk of cardiovascular disease (CVD). Type 1 diabetes (T1DM) falls within this category as T1DM patients, even when they manage to control their blood glucose within a near-optimal range, still suffer from a 3-fourfold greater risk of macro-vascular complications (coronary artery disease and stroke) than the general population (38). The question then naturally arises: Can children with T1DM exercise as much and as freely as all other children of the same age? The short answer is yes. Having T1DM per se is not only not a contraindication to exercise, but regular participation in a variety of physical activities, including
Tran is with the Institute for Clinical and Translational Science, and Galassetti the Dept. of Pediatrics, University of CaliforniaIrvine, Irvine, CA. Address author correspondence to Brian D. Tran at [email protected].
structured and competitive sports, is strongly encouraged in these children. This being said, the very nature of T1DM, a disease of altered carbohydrate metabolism, implies that a number of factors must be taken into account, and precautions implemented, to ensure that exercise can be performed safely. In T1DM most pancreatic b-cells, the only cells in the human body that secrete insulin, are irreversibly lost during an acute inflammatory event; as a consequence, endogenous insulin production is almost completely suppressed (2). As insulin is key to both disposing of circulating glucose ingested with meals, as well as to controlling endogenous glucose production by the liver, these subjects become completely dependent for glucose homeostasis on exogenous insulin administration, which is normally performed either via multiple daily injection of insulin preparations with differing action kinetics, of via continuous infusion of fastacting insulin with adjustable infusion rates. To optimize control of their blood glucose, subjects also need to learn the carbohydrate content of the food they ingest, and carefully coordinate timing and nutrient content of their meals with insulin administration. As exercise, depending on format, intensity, and duration, physiologically exerts strong effects on mobilization and utilization of carbohydrates, as well as on insulin secretion kinetics and peripheral action (27), severe glycemic fluctuation can occur in T1DM both during and after exercise. With this concise review we aim to provide an overview of the main current recommendations
375
376 Tran and Galassetti
concerning exercise in T1DM, a detailed description of key issues related to the occurrence of both hyperand hypoglycemia in association with exercise, and a review of current concepts on how exercise-mediated cardiovascular protection, via modulations of acute and chronic inflammatory processes, may be altered in T1DM.
Exercise Recommendations in Children with T1DM
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The key recommendations concerning performance of exercise in children with T1DM are summarized in Table 1. These concepts are broadly based on the exercise
section of the Global Guidelines for Diabetes in Childhood and Adolescence, issued jointly by the International Diabetes Federation and the International Society for Pediatric and Adolescent Diabetes (22), and on several excellent recent reviews, to which the authors remand readers for greater detail (28,37). In general, exercise is only contraindicated in T1DM patients with proliferative retinopathy and nephropathy, due to the risk of elevated blood pressure, while patients with advanced diabetic neuropathy should avoid contact sports like soccer and wrestling. These complications, however, arise after many years of very poor glycemic control, and are therefore unlikely to be seen in T1DM children. Otherwise, the recommended total amount of physical activity in T1DM should be the same as in all
Table 1 Summarized Exercise Recommendations in Children with T1DM Access to Information Resources
Glycemic Management Preexercise
Postexercise
Special Cases
Information about diabetes and exercise should be provided to schools and nurseries
Insulin dose may need to be decreased prior to exercise
Sugar-free fluids should be consumed to avoid dehydration
Patients with proliferative retinopathy or nephropathy should avoid exercise likely to result in high arterial blood pressure
Patients and families should be given personalized advice about what and how much carbohydrate to take before, during, and after exercise, as well as advice about insulin adjustments
Hypoglycemia may be anticipated during or after exercise for up to 24 hr due to increased insulin sensitivity
Postexercise nocturnal hypoglycemia risk is high, and care should be taken if bedtime blood glucose < 7.0 mmolM/l (125 mg/dL)
Patients with advanced neuropathy should avoid contact sports like soccer
Patients should have access to a pediatric dietician with diabetes experience
Blood glucose needs to be measured before exercise, and if needed, during exercise
Children engaged in more serious sport should require additional support which should include discussion about the activity and tailoring of advice on insulin and food adjustments according to diary entries with blood glucose results
Performance in sports where a certain amount of cognitive function and precision is necessary may better be performed during normoglycemia
When unaccustomed exercise is anticipated, a significant reduction in the total daily dose of insulin (20-50%) may be necessary to avoid hypoglycemia Exercise should be avoided preexercise blood glucose levels are high (>14 mmol/L, 250 mg/ dL) with ketonuria. Provide 5% of total daily dose of insulin and postpone exercise until ketones have cleared.
Special care should be taken at high altitude where symptoms of hypoglycemia may be confused with hypoxia/altitude sickness
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Exercise in Pediatric Type 1 Diabetes 377
children, ie, according to the U.S. Department of Human Services, 60 min of moderate to vigorous exercise daily (42). It is crucial, however, that children and their parents, as well as school nurses and sports coaches/advisors, have comprehensive access to relevant information in all settings in which exercise is performed. This has to include professional advice on timing and frequency of glucose testing, changes in insulin administration and nutrient intake. The best overall strategy is to exercise under conditions the child is familiar with, as the same exercise format (exercise type, duration, intensity, repetition pattern) is likely (but unfortunately not guaranteed) to induce similar perturbations in glucose control. Ideally, exercise should be initiated with glycemia as close as possible to the euglycemic range, and exercise not be initiated if glycemia is below 80 or above 250 mg/dl, in which case values should be corrected by glucose ingestion or insulin administration. Values closer to euglycemia may be necessary for performance of sports requiring a greater amount of cognitive function and precision. Even if exercise is started during euglycemia, a reduction in insulin administration, possibly associated with ingestion of variable amounts of carbohydrates, is normally required to prevent onset of hypo- or hyperglycemia during exercise. The magnitude of the insulin adjustments, as well as the timing and amount of supplemented carbohydrate, varies with the type and duration of exercise, but even for comparable exercise formats may differ considerably across subjects, rendering personal experience the best reference guideline. If unfamiliar exercise is performed, substantial reductions in insulin administration should be attempted, based on individual response to other exercise formats, and a snack ingested before exercise. It is important to remember that exercise effects on glucose control may last for many hours after exercise has been completed. Again, prior experience often allows one to identify optimal individual patterns of prevention of unwarranted fluctuations of blood glucose (for instance, timing and size of a late-night snack to prevent overnight hypoglycemia after an intense afternoon exercise session); in case of uncertainty, more frequent glucose testing should be performed.
Hyperglycemia and Exercise The hallmark of diabetes being hyperglycemia, a logical concern in diabetes management is understanding the likelihood of hyperglycemia occurring in relation to exercise. In this context (ie, with respect to glycemic regulation), not all exercise formats are the same. While moderate intensity exercise is more likely to result in a drop in blood glucose (BG) of variable severity, intense exercise is known to exert a largely opposite effect. For instance, exercise activities above the lactate threshold (occurring in well controlled T1DM children at roughly similar levels as in healthy controls, ie, at ~60% VO2max or 80–90% maximal heart rate; 3), may result in an overall increase in BG. While exertions at this level of intensity
cannot be sustained for prolonged periods of time, they induce a very strong cardiovascular adaptation, sustained via generalized adrenergic activation. The ensuing levels of catecholamine secretion, therefore, are mainly driven by the increased blood-flow requirements and, from the point of view of their stimulation of endogenous glucose production, exceed the energy needs of the exercising muscle. The consequent transient, moderate hyperglycemia which in a healthy metabolic environment is easily controlled with additional insulin secretion, in individuals with already poor glucose control can develop into serious and prolonged hyperglycemia and possibly ketoacidosis (25). This typically occurs already at the end of the exercise challenge, with glucose levels continuing to rise rapidly after exercise cessation, but may also occur at any time during the first few hours after exercise has been completed. As in most exercise contexts with T1DM, the best strategy in preventing the occurrence of these episodes is being familiar with a particular exercise format and the glycemic response it individually elicits, proactively adjusting insulin administration at critical times. Unfortunately, the complexity of glucose regulation in the delicate metabolic environment of the growing child with T1DM often results in unpredictably different glycemic responses to seemingly identical exercise challenges. When very intense exercise is involved, therefore, while previous patterns of glycemic response can be used as guidelines, great attention should be paid to evolving glycemic profiles which may require rapid changes in insulin administration. The intrinsic hyperglycemic effect of an exercise format with a specific intensity and duration can be substantially altered if performed during an official competition. The psychological anticipatory stress preceding a competitive challenge may in fact result in elevated secretion of key counterregulatory hormones, which in turn increase BG before the metabolic needs in peripheral tissue have even begun to increase. Individuals therefore may find that, for example, while a regular training run of a snowboarding course or a 1,500-m track run leaves them euglycemic, identical exertions under race conditions acutely trigger severe hyperglycemic episodes. This effect is particularly problematic in the case of sport that requires breaks in play. Periods of physical inactivity coupled with elevations in stress hormones may result in high BG temporarily unmatched even by increased peripheral glucose uptake, particularly if an individual has decreased their insulin dosage in anticipation to exercise. In this setting, the use of a real time continuous glucose monitoring device may be useful, where small, carefully timed boluses of fast-acting insulin may be effective in controlling hyperglycemia.
Hypoglycemia Before, During, and After Exercise Hypoglycemia, defined as the drop in blood glucose below the normal physiological levels, can occur when
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there is a sufficient imbalance between the energy needs of tissue and circulating glucose, or when circulating insulin levels are higher than required by the prevailing metabolic status. While this broad definition is difficult to translate into exact quantitative terms, a value of plasma glucose < 70 mg/dL has been determined by the American Diabetes Association to be generally applicable in both research and clinical settings (1). Whether caused by a relative excess of insulin or by an acute increase in energy requirements, hypoglycemia triggers compensatory (counterregulatory) mechanisms, including the release of the major counterregulatory hormones (glucagon, epinephrine, norepinephrine, growth hormone, and cortisol) to prevent the onset, or at least limit the severity and duration of the hypoglycemic episode (8). During physical exercise the increased energy substrate requirements of working peripheral muscles determine the acute activation of the same counterregulatory mechanisms even if hypoglycemia has not yet occurred. In T1DM, due to the intrinsic metabolic alterations characteristic of the disease, as well as to inappropriate exogenous insulin administration, these expected response to hypoglycemia and /or exercise may be significantly altered. As regular exercise is recommended to most diabetic individuals for its many beneficial health effects, it is important to consider possible exercise-related situations where individuals with T1DM may put themselves at risk for a hypoglycemic episode.
Predisposition to Exercise-Induced Hypoglycemia In broad terms, two independent settings can predispose an individual with T1DM to hypoglycemia during or following exercise. The first setting involves the improper adjustment of insulin therapy relative to the planned physical activity. Physiologically, less insulin is required during exercise to dispose of the same glucose load, due to an acute increase in insulin sensitivity induced by exercise. In the nondiabetic environment, this is compensated for by a reduction in pancreatic insulin secretion during some exercise formats (typically prolonged, moderate exercise) with plasma insulin levels dropping by as much as 40–50%. In T1DM, the attempt to reproduce this physiological pattern involves individual personal experience with particular formats of exercise and type of insulin therapy. For example, patients using insulin pumps may choose to decrease, or sometimes completely stop, their basal insulin infusion rate, in anticipation to familiar exercise formats. In contrast, patients on multiple insulin injections are unable to reduce the long-acting component of their therapy, and instead can compensate by ingesting an appropriate amount of carbohydrates. Food and insulin adjustments should be based off individual diary entries with blood glucose results recorded during similar prior events. Best results can therefore be expected for familiar exercise types and durations, and considerable caution should be used when patients are challenged with novel exercise formats.
The second setting involves prior stimulation of the hypothalamic-pituitary-adrenal (HPA) axis. While there is still controversy on the precise mechanism of this effect, repeated stress inducing activation of the HPA axis appears to blunt the counterregulatory response that is key to preventing hypoglycemia (6). One study analyzed the effect of prior hypoglycemia on the counterregulatory responses to exercise in T1DM patients. After a few days of documented absence of any hypoglycemic episodes, the glucagon, epinephrine, and other counterregulatory responses to exercise in 16 T1DM patients were indistinguishable from healthy controls. However, when patients were exposed to 4h of hypoglycemia at ~50 mg/dL and later they exercised, the glucagon response to exercise was completely suppressed, and the epinephrine response, as well as endogenous glucose production and lipolysis, were reduced by ~50%. In a subsequent study the depth of prior hypoglycemia was varied (70, 60, and 50 mg/dL), resulting in proportional levels of suppression of the subsequent glucagon response to exercise (40%, 60%, and 95% suppression, respectively), indicating the presence of a clear dose-dependent response. As the prior hypoglycemia was induced on the day before the exercise challenge (which occurred the next morning), this blunting effect was shown to persist for many hours. While no longer-term data are available on this effect, it is believed that, over time, counterregulatory responses will return to normal levels should there be no more continued blunting stimuli, such as recurrent hypoglycemic episodes. In reality, however, in T1DM avoidance of recurrent hypoglycemia is often problematic, particularly among individuals who strive to obtain close-to-normal Hb1Ac values (an index of long-term glucose control) through aggressive insulin therapy (21). Recent evidence indicates that this effect is different between genders. In general, men elicit significantly greater neuroendocrine responses (ie, epinephrine, glucagon) to comparable exercise than women, despite the fact that the overall metabolic effect is similar across genders. When exposed to antecedent hypoglycemia, T1DM men in a recent study displayed substantially blunted exercise responses, whereas in T1DM women exercise responses were only marginally affected (17). While these effects have not been tested in T1DM children, these data suggest that boys may become more susceptible to the effect of prior hypoglycemia during sexual maturation. Before puberty, on the other hand, responses are likely similar between boys and girls, likely paralleling the pattern of loss of sexual dimorphism in metabolic responses between postmenopausal women and age-matched men (35). Interestingly, exercise itself also appears to be a blunting stimulus, likely through pathways parallel to those evoked by hypoglycemia. Repeated exercise bouts, such as with morning and afternoon cycling, appear to significantly impair the body’s ability to maintain euglycemia in healthy subjects (13). This effect was mirrored in a later study with T1DM subjects, where low and moderate intensity exercise (30% and 50% individual
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Exercise in Pediatric Type 1 Diabetes 379
VO2max respectively) resulted in reduced counterregulatory responses during further, subsequent exercise (36). On the same line of thought, it is also likely that psychosocial stress, which is known to activate the HPA axis (23), may act as a prior blunting stimulus. While studies directly testing this effect are currently lacking, it may be reasonable to assume some individuals competing in serious sport may face anticipatory stress before exercise, resulting in the predisposition to hypoglycemia. When these cases are considered altogether, any of the above stimuli can create a time window of increased susceptibility during which additional hypoglycemia may occur more easily. Practically, these stimuli may be at times difficult to avoid, resulting in a vicious cycle of prolonged or chronic hypoglycemia. One bout of hypoglycemia, for example, can feed forward to down regulate counterregulatory responses that would normally counteract hypoglycemia (15).
Hypoglycemia From Events During Exercise Additional risk for a hypoglycemic episode may be due to unanticipated changes during the performance of exercise. Consider the subcutaneous insulin injection: in addition to displaying accelerated absorption rates during exercise, a well-known issue that may result in hyperinsulinemia in itself (40), a previous injection may also become trapped in a subcutaneous pocket. At exercise onset, this pocket may be acutely mobilized into the bloodstream, particularly if located near working muscle. In turn, this results in a de facto insulin bolus, which may result in transient hyperinsulinemia and possibly facilitate hypoglycemia. Secondly, while it may be obvious in this context, it is also important to note that major alterations to the anticipated exercise format or exercise conditions (eg, humidity, competition) may also result in unwanted glycemic fluctuations. For example, performing low or moderate intensity exercise based off insulin and carbohydrate adjustment for very intense exercise bouts (VO2max >60–70%) may result in hypoglycemia. This is because, in comparison with moderate intensity exercise, intense exercise bouts tend to elicit a strong prohyperglycemic effect, resulting in the need for additional insulin or reduced carbohydrate (3).
Susceptibility to Hypoglycemia Following Exercise Immediately after an exercise bout, insulin sensitivity is increased and the need to replenish exhausted muscle glycogen reserves shifts a large portion of whole body glucose uptake toward skeletal muscle (4), which increases the chance of a hypoglycemic episode. When this is considered with the fact that counterregulatory responses are physiologically attenuated during sleep (20), it is not surprising to see that two peaks in the incidence of hypoglycemia are often observed following exercise: one peak immediately following exercise (particularly with
prolonged, moderate intensity exercise) and one peak during the night following exercise (39), usually seen between midnight and 4 AM. Clarifying this concept, one study focused on hypoglycemia risk following a moderate-intensity exercise bout performed midday (to exclude sleep), and identified that hypoglycemia risk increased for several hours postexercise (10), with no evidence of a biphasic pattern of glucose requirements. Finally, it is important to note that if this initial bout is followed with additional exercise, the bout itself will act as a prior counterregulatory-blunting stimulus, as mentioned above. A novel concept to offset the prohypoglycemic effect of prolonged moderate intensity exercise has been proposed by the Fournier group (5). Intense and brief exercise bouts, which are prohyperglycemic, can be incorporated into the original exercise format. These bouts, which can be as short as 10s within a standard sport training session, can dramatically reduce the incidence of postexercise hypoglycemia, without concomitantly increasing. As was initially suggested, the risk of later hypoglycemia (as documented by no difference in glucose uptake 8 hr after exercise; 9).
Inflammation and Pediatric T1DM— Implications For Exercise Another important set of issues concerns the modulatory effect of exercise on inflammatory processes. As T1DM is itself considered an inflammatory disease, potential alterations in the interaction between exercise and inflammation may result in attenuated health effects of exercise in this condition. It may therefore be useful to understand how T1DM is characterized as an inflammatory disease. The onset of T1DM is typically mediated by an acute, intense inflammatory reaction, which results in lymphocyte-mediated destruction of the pancreatic beta cells. Following this onset, a chronic state of whole body, low-grade inflammation appears to persist, and is periodically exacerbated by hyperglycemic fluctuations and other metabolic perturbations. The elevated levels of molecular inflammatory markers observed in T1DM (12), when combined with coincidentally observed elevated markers of immune cell activation (11) and oxidative stress (41), are also heavily associated with the initiation and progression of atherosclerosis and CVD. Cardiovascular complications of diabetes are typically classified as microvascular (diabetic retinopathy, nephropathy, neuropathy) and macrovascular (coronary artery disease, stroke). Extensive epidemiological studies have observed that individuals with T1DM can substantially reduce, via aggressive glycemic control, the onset and progression of most microvascular complications, while the risks of stroke and acute coronary events remains very high relative to the general population (21). In the pediatric population, while these early vascular alterations may not induce symptoms for decades, they will start the widespread
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380 Tran and Galassetti
process of systemic arterial damage and accelerate the adult age at which cardiovascular symptoms will begin appearing. The exact biochemical details of the interaction between altered inflammatory processes and early endothelial impairment in children with T1DM, however, remain incompletely understood. Current evidence indicates the presence of a distinct, altered inflammatory profile in T1DM children. Several studies in fact reported elevated IL-6 (a cytokine that has both proinflammatory and anti-inflammatory effects; 18), IL-8 (a powerful chemo-attractant for neutrophils (14), and myeloperoxidiase (32; an oxidative stress marker derived from neutrophils, monocytes, and macrophages) in T1DM children as compared with healthy controls. These findings were paralleled by genetic expression experiments in leukocytes from T1DM children, which displayed an exaggerated pattern of expression of inflammatory mediators (CD40L, CD27L, TNFSF9, IL-8, IP-10) following T-cell receptor and Fc receptor stimulation (31). As hyperglycemia itself acutely induces inflammation in healthy and diabetic individuals (16), it is important to delineate the inflammatory contribution of the presence of diabetes per se against the overlapping inflammatory stimulus of periodic hyperglycemic exacerbations, which are common in diabetic individuals with poor glucose control. In a group of T1DM children several inflammatory markers (IL-1α, IL-4, IL-6) were elevated during morning hyperglycemia as compared with normoglycemic T1DM children; importantly, in the hyperglycemic group these cytokines remained elevated for at least 2 hr after hyperglycemia had been corrected with insulin (29). Therefore, unless hyperglycemic episodes are effectively avoided for prolonged periods, this inability to rapidly compensate for proinflammatory activation may de facto transform the acute effect of hyperglycemia into a chronic inflammatory stimulus, and in turn contribute to the development of vascular complications. Along the same line of thought, at any given time the severity of proinflammatory appears to be related, at least in part, to the levels of glycemic control. In a recent, study, in fact, plasma IL-6 was elevated in T1DM children with a very high prior morning plasma glucose (>300 mg/dL), and it progressively decreases with decreasing severity of hyperglycemia (200–300, 150–200, and
Exercise in Pediatric Type 1 Diabetes Brian D. Tran and Pietro Galassetti University of California, Irvine The beneficial effects of exercise, including reduction of cardiovascular risk, are especially important in children with type 1 diabetes (T1DM), in whom incidence of lifetime cardiovascular complications remains elevated despite good glycemic control. Being able to exercise safely is therefore a paramount concern. Dysregulated metabolism in T1DM however, causes frequent occurrence of both hypo- and hyperglycemia, the former typically associated with prolonged, moderate exercise, the latter with higher intensity, if shorter, challenges. While very few absolute contraindications to exercising exist in these children, exercise should not be started with glycemia outside the 80–250 mg/dl range. Within this glycemic range, careful adjustments in insulin administration (reduction or infusion rate via insulin pumps, or overall reduction of dosage of multiple injections) should be combined with carbohydrate ingestion before/during exercise, based on prior, individual experience with specific exercise formats. Unfamiliar exercise should always be tackled with exceeding caution, based on known responses to other exercise formats. Finally, gaining a deep understanding of other complex exercise responses, such as the modulation of inflammatory status, which is a major determinant of the cardio-protective effects of exercise, can help determine which exercise formats and which individual metabolic conditions can lead to maximally beneficial health effects. Keywords:glycemic regulation, inflammation, exercise-induced hypoglycemia, hyperglycemia Physical exercise exerts a number of beneficial health effects at all ages. In children, however, these effects may be even more important, as exercise, in addition to cardiovascular risk prevention, weight control and psychological well-being, also modulates physiological growth and development (7). Further, learning to exercise regularly at an early age may establish healthy lifestyle patterns sustaining health later in life. While these concepts apply to the overall population, they may be even more relevant for specific categories of subjects, such as those displaying an elevated risk of cardiovascular disease (CVD). Type 1 diabetes (T1DM) falls within this category as T1DM patients, even when they manage to control their blood glucose within a near-optimal range, still suffer from a 3-fourfold greater risk of macro-vascular complications (coronary artery disease and stroke) than the general population (38). The question then naturally arises: Can children with T1DM exercise as much and as freely as all other children of the same age? The short answer is yes. Having T1DM per se is not only not a contraindication to exercise, but regular participation in a variety of physical activities, including
Tran is with the Institute for Clinical and Translational Science, and Galassetti the Dept. of Pediatrics, University of CaliforniaIrvine, Irvine, CA. Address author correspondence to Brian D. Tran at [email protected].
structured and competitive sports, is strongly encouraged in these children. This being said, the very nature of T1DM, a disease of altered carbohydrate metabolism, implies that a number of factors must be taken into account, and precautions implemented, to ensure that exercise can be performed safely. In T1DM most pancreatic b-cells, the only cells in the human body that secrete insulin, are irreversibly lost during an acute inflammatory event; as a consequence, endogenous insulin production is almost completely suppressed (2). As insulin is key to both disposing of circulating glucose ingested with meals, as well as to controlling endogenous glucose production by the liver, these subjects become completely dependent for glucose homeostasis on exogenous insulin administration, which is normally performed either via multiple daily injection of insulin preparations with differing action kinetics, of via continuous infusion of fastacting insulin with adjustable infusion rates. To optimize control of their blood glucose, subjects also need to learn the carbohydrate content of the food they ingest, and carefully coordinate timing and nutrient content of their meals with insulin administration. As exercise, depending on format, intensity, and duration, physiologically exerts strong effects on mobilization and utilization of carbohydrates, as well as on insulin secretion kinetics and peripheral action (27), severe glycemic fluctuation can occur in T1DM both during and after exercise. With this concise review we aim to provide an overview of the main current recommendations
375
376 Tran and Galassetti
concerning exercise in T1DM, a detailed description of key issues related to the occurrence of both hyperand hypoglycemia in association with exercise, and a review of current concepts on how exercise-mediated cardiovascular protection, via modulations of acute and chronic inflammatory processes, may be altered in T1DM.
Exercise Recommendations in Children with T1DM
Downloaded by Northern Illinois University on 09/20/16, Volume 26, Article Number 4
The key recommendations concerning performance of exercise in children with T1DM are summarized in Table 1. These concepts are broadly based on the exercise
section of the Global Guidelines for Diabetes in Childhood and Adolescence, issued jointly by the International Diabetes Federation and the International Society for Pediatric and Adolescent Diabetes (22), and on several excellent recent reviews, to which the authors remand readers for greater detail (28,37). In general, exercise is only contraindicated in T1DM patients with proliferative retinopathy and nephropathy, due to the risk of elevated blood pressure, while patients with advanced diabetic neuropathy should avoid contact sports like soccer and wrestling. These complications, however, arise after many years of very poor glycemic control, and are therefore unlikely to be seen in T1DM children. Otherwise, the recommended total amount of physical activity in T1DM should be the same as in all
Table 1 Summarized Exercise Recommendations in Children with T1DM Access to Information Resources
Glycemic Management Preexercise
Postexercise
Special Cases
Information about diabetes and exercise should be provided to schools and nurseries
Insulin dose may need to be decreased prior to exercise
Sugar-free fluids should be consumed to avoid dehydration
Patients with proliferative retinopathy or nephropathy should avoid exercise likely to result in high arterial blood pressure
Patients and families should be given personalized advice about what and how much carbohydrate to take before, during, and after exercise, as well as advice about insulin adjustments
Hypoglycemia may be anticipated during or after exercise for up to 24 hr due to increased insulin sensitivity
Postexercise nocturnal hypoglycemia risk is high, and care should be taken if bedtime blood glucose < 7.0 mmolM/l (125 mg/dL)
Patients with advanced neuropathy should avoid contact sports like soccer
Patients should have access to a pediatric dietician with diabetes experience
Blood glucose needs to be measured before exercise, and if needed, during exercise
Children engaged in more serious sport should require additional support which should include discussion about the activity and tailoring of advice on insulin and food adjustments according to diary entries with blood glucose results
Performance in sports where a certain amount of cognitive function and precision is necessary may better be performed during normoglycemia
When unaccustomed exercise is anticipated, a significant reduction in the total daily dose of insulin (20-50%) may be necessary to avoid hypoglycemia Exercise should be avoided preexercise blood glucose levels are high (>14 mmol/L, 250 mg/ dL) with ketonuria. Provide 5% of total daily dose of insulin and postpone exercise until ketones have cleared.
Special care should be taken at high altitude where symptoms of hypoglycemia may be confused with hypoxia/altitude sickness
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Exercise in Pediatric Type 1 Diabetes 377
children, ie, according to the U.S. Department of Human Services, 60 min of moderate to vigorous exercise daily (42). It is crucial, however, that children and their parents, as well as school nurses and sports coaches/advisors, have comprehensive access to relevant information in all settings in which exercise is performed. This has to include professional advice on timing and frequency of glucose testing, changes in insulin administration and nutrient intake. The best overall strategy is to exercise under conditions the child is familiar with, as the same exercise format (exercise type, duration, intensity, repetition pattern) is likely (but unfortunately not guaranteed) to induce similar perturbations in glucose control. Ideally, exercise should be initiated with glycemia as close as possible to the euglycemic range, and exercise not be initiated if glycemia is below 80 or above 250 mg/dl, in which case values should be corrected by glucose ingestion or insulin administration. Values closer to euglycemia may be necessary for performance of sports requiring a greater amount of cognitive function and precision. Even if exercise is started during euglycemia, a reduction in insulin administration, possibly associated with ingestion of variable amounts of carbohydrates, is normally required to prevent onset of hypo- or hyperglycemia during exercise. The magnitude of the insulin adjustments, as well as the timing and amount of supplemented carbohydrate, varies with the type and duration of exercise, but even for comparable exercise formats may differ considerably across subjects, rendering personal experience the best reference guideline. If unfamiliar exercise is performed, substantial reductions in insulin administration should be attempted, based on individual response to other exercise formats, and a snack ingested before exercise. It is important to remember that exercise effects on glucose control may last for many hours after exercise has been completed. Again, prior experience often allows one to identify optimal individual patterns of prevention of unwarranted fluctuations of blood glucose (for instance, timing and size of a late-night snack to prevent overnight hypoglycemia after an intense afternoon exercise session); in case of uncertainty, more frequent glucose testing should be performed.
Hyperglycemia and Exercise The hallmark of diabetes being hyperglycemia, a logical concern in diabetes management is understanding the likelihood of hyperglycemia occurring in relation to exercise. In this context (ie, with respect to glycemic regulation), not all exercise formats are the same. While moderate intensity exercise is more likely to result in a drop in blood glucose (BG) of variable severity, intense exercise is known to exert a largely opposite effect. For instance, exercise activities above the lactate threshold (occurring in well controlled T1DM children at roughly similar levels as in healthy controls, ie, at ~60% VO2max or 80–90% maximal heart rate; 3), may result in an overall increase in BG. While exertions at this level of intensity
cannot be sustained for prolonged periods of time, they induce a very strong cardiovascular adaptation, sustained via generalized adrenergic activation. The ensuing levels of catecholamine secretion, therefore, are mainly driven by the increased blood-flow requirements and, from the point of view of their stimulation of endogenous glucose production, exceed the energy needs of the exercising muscle. The consequent transient, moderate hyperglycemia which in a healthy metabolic environment is easily controlled with additional insulin secretion, in individuals with already poor glucose control can develop into serious and prolonged hyperglycemia and possibly ketoacidosis (25). This typically occurs already at the end of the exercise challenge, with glucose levels continuing to rise rapidly after exercise cessation, but may also occur at any time during the first few hours after exercise has been completed. As in most exercise contexts with T1DM, the best strategy in preventing the occurrence of these episodes is being familiar with a particular exercise format and the glycemic response it individually elicits, proactively adjusting insulin administration at critical times. Unfortunately, the complexity of glucose regulation in the delicate metabolic environment of the growing child with T1DM often results in unpredictably different glycemic responses to seemingly identical exercise challenges. When very intense exercise is involved, therefore, while previous patterns of glycemic response can be used as guidelines, great attention should be paid to evolving glycemic profiles which may require rapid changes in insulin administration. The intrinsic hyperglycemic effect of an exercise format with a specific intensity and duration can be substantially altered if performed during an official competition. The psychological anticipatory stress preceding a competitive challenge may in fact result in elevated secretion of key counterregulatory hormones, which in turn increase BG before the metabolic needs in peripheral tissue have even begun to increase. Individuals therefore may find that, for example, while a regular training run of a snowboarding course or a 1,500-m track run leaves them euglycemic, identical exertions under race conditions acutely trigger severe hyperglycemic episodes. This effect is particularly problematic in the case of sport that requires breaks in play. Periods of physical inactivity coupled with elevations in stress hormones may result in high BG temporarily unmatched even by increased peripheral glucose uptake, particularly if an individual has decreased their insulin dosage in anticipation to exercise. In this setting, the use of a real time continuous glucose monitoring device may be useful, where small, carefully timed boluses of fast-acting insulin may be effective in controlling hyperglycemia.
Hypoglycemia Before, During, and After Exercise Hypoglycemia, defined as the drop in blood glucose below the normal physiological levels, can occur when
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there is a sufficient imbalance between the energy needs of tissue and circulating glucose, or when circulating insulin levels are higher than required by the prevailing metabolic status. While this broad definition is difficult to translate into exact quantitative terms, a value of plasma glucose < 70 mg/dL has been determined by the American Diabetes Association to be generally applicable in both research and clinical settings (1). Whether caused by a relative excess of insulin or by an acute increase in energy requirements, hypoglycemia triggers compensatory (counterregulatory) mechanisms, including the release of the major counterregulatory hormones (glucagon, epinephrine, norepinephrine, growth hormone, and cortisol) to prevent the onset, or at least limit the severity and duration of the hypoglycemic episode (8). During physical exercise the increased energy substrate requirements of working peripheral muscles determine the acute activation of the same counterregulatory mechanisms even if hypoglycemia has not yet occurred. In T1DM, due to the intrinsic metabolic alterations characteristic of the disease, as well as to inappropriate exogenous insulin administration, these expected response to hypoglycemia and /or exercise may be significantly altered. As regular exercise is recommended to most diabetic individuals for its many beneficial health effects, it is important to consider possible exercise-related situations where individuals with T1DM may put themselves at risk for a hypoglycemic episode.
Predisposition to Exercise-Induced Hypoglycemia In broad terms, two independent settings can predispose an individual with T1DM to hypoglycemia during or following exercise. The first setting involves the improper adjustment of insulin therapy relative to the planned physical activity. Physiologically, less insulin is required during exercise to dispose of the same glucose load, due to an acute increase in insulin sensitivity induced by exercise. In the nondiabetic environment, this is compensated for by a reduction in pancreatic insulin secretion during some exercise formats (typically prolonged, moderate exercise) with plasma insulin levels dropping by as much as 40–50%. In T1DM, the attempt to reproduce this physiological pattern involves individual personal experience with particular formats of exercise and type of insulin therapy. For example, patients using insulin pumps may choose to decrease, or sometimes completely stop, their basal insulin infusion rate, in anticipation to familiar exercise formats. In contrast, patients on multiple insulin injections are unable to reduce the long-acting component of their therapy, and instead can compensate by ingesting an appropriate amount of carbohydrates. Food and insulin adjustments should be based off individual diary entries with blood glucose results recorded during similar prior events. Best results can therefore be expected for familiar exercise types and durations, and considerable caution should be used when patients are challenged with novel exercise formats.
The second setting involves prior stimulation of the hypothalamic-pituitary-adrenal (HPA) axis. While there is still controversy on the precise mechanism of this effect, repeated stress inducing activation of the HPA axis appears to blunt the counterregulatory response that is key to preventing hypoglycemia (6). One study analyzed the effect of prior hypoglycemia on the counterregulatory responses to exercise in T1DM patients. After a few days of documented absence of any hypoglycemic episodes, the glucagon, epinephrine, and other counterregulatory responses to exercise in 16 T1DM patients were indistinguishable from healthy controls. However, when patients were exposed to 4h of hypoglycemia at ~50 mg/dL and later they exercised, the glucagon response to exercise was completely suppressed, and the epinephrine response, as well as endogenous glucose production and lipolysis, were reduced by ~50%. In a subsequent study the depth of prior hypoglycemia was varied (70, 60, and 50 mg/dL), resulting in proportional levels of suppression of the subsequent glucagon response to exercise (40%, 60%, and 95% suppression, respectively), indicating the presence of a clear dose-dependent response. As the prior hypoglycemia was induced on the day before the exercise challenge (which occurred the next morning), this blunting effect was shown to persist for many hours. While no longer-term data are available on this effect, it is believed that, over time, counterregulatory responses will return to normal levels should there be no more continued blunting stimuli, such as recurrent hypoglycemic episodes. In reality, however, in T1DM avoidance of recurrent hypoglycemia is often problematic, particularly among individuals who strive to obtain close-to-normal Hb1Ac values (an index of long-term glucose control) through aggressive insulin therapy (21). Recent evidence indicates that this effect is different between genders. In general, men elicit significantly greater neuroendocrine responses (ie, epinephrine, glucagon) to comparable exercise than women, despite the fact that the overall metabolic effect is similar across genders. When exposed to antecedent hypoglycemia, T1DM men in a recent study displayed substantially blunted exercise responses, whereas in T1DM women exercise responses were only marginally affected (17). While these effects have not been tested in T1DM children, these data suggest that boys may become more susceptible to the effect of prior hypoglycemia during sexual maturation. Before puberty, on the other hand, responses are likely similar between boys and girls, likely paralleling the pattern of loss of sexual dimorphism in metabolic responses between postmenopausal women and age-matched men (35). Interestingly, exercise itself also appears to be a blunting stimulus, likely through pathways parallel to those evoked by hypoglycemia. Repeated exercise bouts, such as with morning and afternoon cycling, appear to significantly impair the body’s ability to maintain euglycemia in healthy subjects (13). This effect was mirrored in a later study with T1DM subjects, where low and moderate intensity exercise (30% and 50% individual
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VO2max respectively) resulted in reduced counterregulatory responses during further, subsequent exercise (36). On the same line of thought, it is also likely that psychosocial stress, which is known to activate the HPA axis (23), may act as a prior blunting stimulus. While studies directly testing this effect are currently lacking, it may be reasonable to assume some individuals competing in serious sport may face anticipatory stress before exercise, resulting in the predisposition to hypoglycemia. When these cases are considered altogether, any of the above stimuli can create a time window of increased susceptibility during which additional hypoglycemia may occur more easily. Practically, these stimuli may be at times difficult to avoid, resulting in a vicious cycle of prolonged or chronic hypoglycemia. One bout of hypoglycemia, for example, can feed forward to down regulate counterregulatory responses that would normally counteract hypoglycemia (15).
Hypoglycemia From Events During Exercise Additional risk for a hypoglycemic episode may be due to unanticipated changes during the performance of exercise. Consider the subcutaneous insulin injection: in addition to displaying accelerated absorption rates during exercise, a well-known issue that may result in hyperinsulinemia in itself (40), a previous injection may also become trapped in a subcutaneous pocket. At exercise onset, this pocket may be acutely mobilized into the bloodstream, particularly if located near working muscle. In turn, this results in a de facto insulin bolus, which may result in transient hyperinsulinemia and possibly facilitate hypoglycemia. Secondly, while it may be obvious in this context, it is also important to note that major alterations to the anticipated exercise format or exercise conditions (eg, humidity, competition) may also result in unwanted glycemic fluctuations. For example, performing low or moderate intensity exercise based off insulin and carbohydrate adjustment for very intense exercise bouts (VO2max >60–70%) may result in hypoglycemia. This is because, in comparison with moderate intensity exercise, intense exercise bouts tend to elicit a strong prohyperglycemic effect, resulting in the need for additional insulin or reduced carbohydrate (3).
Susceptibility to Hypoglycemia Following Exercise Immediately after an exercise bout, insulin sensitivity is increased and the need to replenish exhausted muscle glycogen reserves shifts a large portion of whole body glucose uptake toward skeletal muscle (4), which increases the chance of a hypoglycemic episode. When this is considered with the fact that counterregulatory responses are physiologically attenuated during sleep (20), it is not surprising to see that two peaks in the incidence of hypoglycemia are often observed following exercise: one peak immediately following exercise (particularly with
prolonged, moderate intensity exercise) and one peak during the night following exercise (39), usually seen between midnight and 4 AM. Clarifying this concept, one study focused on hypoglycemia risk following a moderate-intensity exercise bout performed midday (to exclude sleep), and identified that hypoglycemia risk increased for several hours postexercise (10), with no evidence of a biphasic pattern of glucose requirements. Finally, it is important to note that if this initial bout is followed with additional exercise, the bout itself will act as a prior counterregulatory-blunting stimulus, as mentioned above. A novel concept to offset the prohypoglycemic effect of prolonged moderate intensity exercise has been proposed by the Fournier group (5). Intense and brief exercise bouts, which are prohyperglycemic, can be incorporated into the original exercise format. These bouts, which can be as short as 10s within a standard sport training session, can dramatically reduce the incidence of postexercise hypoglycemia, without concomitantly increasing. As was initially suggested, the risk of later hypoglycemia (as documented by no difference in glucose uptake 8 hr after exercise; 9).
Inflammation and Pediatric T1DM— Implications For Exercise Another important set of issues concerns the modulatory effect of exercise on inflammatory processes. As T1DM is itself considered an inflammatory disease, potential alterations in the interaction between exercise and inflammation may result in attenuated health effects of exercise in this condition. It may therefore be useful to understand how T1DM is characterized as an inflammatory disease. The onset of T1DM is typically mediated by an acute, intense inflammatory reaction, which results in lymphocyte-mediated destruction of the pancreatic beta cells. Following this onset, a chronic state of whole body, low-grade inflammation appears to persist, and is periodically exacerbated by hyperglycemic fluctuations and other metabolic perturbations. The elevated levels of molecular inflammatory markers observed in T1DM (12), when combined with coincidentally observed elevated markers of immune cell activation (11) and oxidative stress (41), are also heavily associated with the initiation and progression of atherosclerosis and CVD. Cardiovascular complications of diabetes are typically classified as microvascular (diabetic retinopathy, nephropathy, neuropathy) and macrovascular (coronary artery disease, stroke). Extensive epidemiological studies have observed that individuals with T1DM can substantially reduce, via aggressive glycemic control, the onset and progression of most microvascular complications, while the risks of stroke and acute coronary events remains very high relative to the general population (21). In the pediatric population, while these early vascular alterations may not induce symptoms for decades, they will start the widespread
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process of systemic arterial damage and accelerate the adult age at which cardiovascular symptoms will begin appearing. The exact biochemical details of the interaction between altered inflammatory processes and early endothelial impairment in children with T1DM, however, remain incompletely understood. Current evidence indicates the presence of a distinct, altered inflammatory profile in T1DM children. Several studies in fact reported elevated IL-6 (a cytokine that has both proinflammatory and anti-inflammatory effects; 18), IL-8 (a powerful chemo-attractant for neutrophils (14), and myeloperoxidiase (32; an oxidative stress marker derived from neutrophils, monocytes, and macrophages) in T1DM children as compared with healthy controls. These findings were paralleled by genetic expression experiments in leukocytes from T1DM children, which displayed an exaggerated pattern of expression of inflammatory mediators (CD40L, CD27L, TNFSF9, IL-8, IP-10) following T-cell receptor and Fc receptor stimulation (31). As hyperglycemia itself acutely induces inflammation in healthy and diabetic individuals (16), it is important to delineate the inflammatory contribution of the presence of diabetes per se against the overlapping inflammatory stimulus of periodic hyperglycemic exacerbations, which are common in diabetic individuals with poor glucose control. In a group of T1DM children several inflammatory markers (IL-1α, IL-4, IL-6) were elevated during morning hyperglycemia as compared with normoglycemic T1DM children; importantly, in the hyperglycemic group these cytokines remained elevated for at least 2 hr after hyperglycemia had been corrected with insulin (29). Therefore, unless hyperglycemic episodes are effectively avoided for prolonged periods, this inability to rapidly compensate for proinflammatory activation may de facto transform the acute effect of hyperglycemia into a chronic inflammatory stimulus, and in turn contribute to the development of vascular complications. Along the same line of thought, at any given time the severity of proinflammatory appears to be related, at least in part, to the levels of glycemic control. In a recent, study, in fact, plasma IL-6 was elevated in T1DM children with a very high prior morning plasma glucose (>300 mg/dL), and it progressively decreases with decreasing severity of hyperglycemia (200–300, 150–200, and
