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Diabetes Research in Children Network (DirecNet) Department of Pediatrics Yale Center for Clinical Investigation Yale University School of Medicine New Haven, Connecticut 06520
Address all correspondence and requests for reprints to: William V. Tamborlane, M.D, Department of Pediatrics, Yale Center for Clinical Investigation, Yale University School of Medicine, 333 Cedar Street, New Haven, Connecticut 06520. E-mail: william.tamborlane{at}yale.edu.
For the past 80 yr, exercise, along with insulin and diet, has been one of the cornerstones of management of diabetes, albeit the least well studied. Like many aspects of treatment of children with type 1 diabetes mellitus (T1DM), vigorous physical exercise presents clinicians, parents, and patients with a dilemma. On one hand, regular exercise is encouraged in children to achieve and maintain ideal body weight and body composition and to enhance psychosocial well-being and cardiovascular health. On the other hand, although often thought of as a way to improve metabolic control, acute bouts of exercise actually make regulation of blood glucose levels more difficult. Hypoglycemia during exercise can be dangerous and decreases a young person’s performance during sports or other activities. Conversely, excessive snacking before or during exercise can result in hyperglycemia and negate some of the metabolic and cardiovascular benefits of exercise. These difficulties are compounded by the irregular pattern of physical activity that characterizes most youth who are not participating in organized sports or regimented training programs and by conventional methods of diabetes management that feature fixed basal insulin replacement doses.
Despite the prominent role that sports and physical activity play in the lives of many youngsters with T1DM, research studies that could provide an evidence-based framework to guide management of glycemia during and after exercise have been lacking. However, a number of recent studies have examined factors that contribute to the risk of hypoglycemia during exercise (1, 2, 3, 4, 5, 6). These studies illustrate that there is an almost infinite number of combinations of conditions that need to be considered in understanding development of hypoglycemia during exercise, including the intensity and duration of exercise (e.g. prolonged moderate vs. short bursts of high intensity exercise), glucose concentrations before starting exercise, and the relation of exercise to meals and basal and bolus insulin doses. The role that individual variations in physical fitness, insulin sensitivity, and the adequacy of counterregulatory responses play in exercise-induced hypoglycemia in children are only a few of a host of patient-related factors that have not even been examined. Because of this complexity, trial and error remains the principal method of managing glycemic excursions during exercise in children and adolescents with T1DM.
One of the greatest fears of parents is to be awakened in the middle of the night by the sounds of their child having a hypoglycemic seizure. A number of studies have demonstrated that most severe hypoglycemic events occur at night and suggest that such events are more frequent after days of increased physical activity (7, 8) The Diabetes Control and Complications Trial reported that unusual physical activity was more frequent on days with severe hypoglycemic events than on randomly chosen days, but the difference was not statistically significant (8). In a 2-yr prospective case-finding study involving 300 patients with T1DM, MacDonald (9) reported in 1987 that 16% of subjects had a symptomatic hypoglycemic event, usually during sleep, 6–16 h after strenuous exercise. The impact of daytime exercise on the frequency of asymptomatic, as well as symptomatic, hypoglycemia during the night has not been well studied in children with T1DM, especially during the current era of intensive insulin therapy with widespread use of insulin pumps and long and rapid-acting insulin analogs that may lower the risk of nighttime hypoglycemia (10, 11).
Fortunately, a clearer picture is emerging regarding the risks of and underlying mechanisms that contribute to nocturnal hypoglycemia after days of increased physical activity in youth with T1DM. To examine the impact of exercise on the frequency of nocturnal hypoglycemia, our Diabetes Research in Children Network (DirecNet) studied 50 youth with T1DM (age 11 to 17 yr, glycosylated hemoglobin 7.8 ± 0.8%) in a clinical research center setting on 2 separate days—one with and one without 60 min of moderate aerobic exercise in the late afternoon. On both days, patients received the same basal and bolus doses that they used at home on sedentary days and plasma glucose and counterregulatory hormone concentrations (see below) were measured frequently during the night. Even on sedentary days, 28% of these relatively well-controlled patients had at least one nighttime plasma glucose value that was less than or equal to 60 mg/dl, and the frequency of nocturnal hypoglycemia nearly doubled to 48% of nights after afternoon exercise (12).
The Pediatric Diabetes group in Perth led by Timothy Jones has made a number of important contributions to our understanding of the underlying pathophysiological mechanism that makes children and adolescents with T1DM so vulnerable to hypoglycemia on nights either with or without antecedent exercise (13, 14). In their study in this issue of JCEM, McMahon et al. (13) used the euglycemic glucose clamp technique to quantify and compare the amount of glucose that was required to prevent an exercise-induced fall in glucose levels during and on nights after afternoon exercise vs. sedentary days in a group of adolescents with T1DM (glycosylated hemoglobin 7.8 ± 0.8%). Throughout both studies, insulin was infused iv at a rate based on the subject’s basal insulin dose, and plasma insulin concentrations were nearly identical. The glucose infusion rates to maintain stable glucose levels showed a biphasic response on the day of the exercise study: they were elevated during and shortly after exercise and again from 7–11 h after exercise (i.e. 2400 to 0400 h). This secondary rise in glucose infusion rates appears to be due to an increase in nonoxidative glucose disposal during sleep, which may serve to support repletion of muscle glycogen stores (13).
Jones and colleagues had previously used the hypoglycemic clamp to demonstrate that catecholamine and cortisol responses to hypoglycemia in children with T1DM were markedly blunted relatively early in the night at the onset of deep sleep in comparison to the same hypoglycemic stimulus when the subjects were awake during the day or at the same time of the night (14). The impairments in counterregulatory hormone responses during deep sleep were identical in nondiabetic and diabetic children, indicating that they were due to the sleep-state itself. We observed the same blunting of counterregulatory hormone responses to nocturnal hypoglycemia in our DirecNet study (12, 15). The DirecNet findings extend Jones’ original observations because hypoglycemia spontaneously occurred throughout the entire overnight period and at presumably different levels of sleep. It is also noteworthy that counterregulatory hormone responses to hypoglycemia were blunted on nights with or without antecedent exercise, again indicating that sleep itself was the main culprit (15). Thus, children with T1DM on fixed insulin doses are at "triple jeopardy" for hypoglycemia on nights following exercise: peripheral glucose utilization is increased by exercise, counterregulatory hormone responses are impaired by sleep, and insulin concentrations are unchanged because of the treatment regimen.
Advances in insulin pump and glucose sensor technologies may provide means to substantially reduce the risks of exercise-induced hypoglycemia in children and adolescents with T1DM. In a follow-up study, DirecNet showed that the frequency of hypoglycemia during late afternoon exercise could be reduced by more than 60% in insulin pump-treated patients simply by temporarily suspending the basal insulin infusion rate just before starting exercise (16). In addition, with newer, "smart" insulin pumps, patients can preprogram lower overnight basal rate profiles that can be used on nights with antecedent exercise to lower the risk of nocturnal hypoglycemia. The flexibility provided by insulin pumps to adjust basal infusion doses during and after exercise is not so easily achievable with multiple daily injection regimens that use long-acting insulin analogs.
With real-time continuous glucose sensors, patients are able to monitor glucose levels on a minute-to-minute basis during exercise, and hypoglycemia alarms can be set to alert patients and parents to unexpected drops in glucose levels during the night. However, the utilization of continuous glucose sensors requires the user to be actively engaged in interpretation of data and in insulin dosage determinations, both of which are subject to human error. With respect to prevention of overnight hypoglycemia after very active days, the teenager with T1DM still has to remember to activate the pump’s alternate basal rate and respond appropriately to the nighttime alarm (e.g. just shutting it off and going back to sleep is not appropriate). Thus, the development of an external "closed-loop" system, in which currently available real-time glucose sensors and insulin pumps are linked automatically, may hold the best hope for sharply reducing or eliminating the risk of nocturnal hypoglycemia in children with T1DM in the foreseeable future (17).
Footnotes
Abbreviation: T1DM, Type 1 diabetes mellitus.
Received January 4, 2007.
Accepted January 8, 2007.
References
This article has been cited by other articles:
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  The Highs and Lows of Exercise and Diabetes Journal Watch Pediatrics and Adolescent Medicine, April 18, 2007; 2007(418): 3 - 3. [Full Text]
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