Management of diabetes mellitus in children and adolescents: engaging in physical activity

Introduction

Physical activity has been universally recognized as an important component of a healthy lifestyle in all individuals and this includes children and adolescents with diabetes mellitus as well. In addition to benefits for physical health, participation in regular exercise has been shown to improve school performance, cognition, and enhance quality of life (1). The American Academy of Pediatrics (AAP) recommends that all children, including those with diabetes mellitus engage in at least 60 minutes of daily physical activity starting at 5 years of age (2). Exercise, insulin, and dietary management were described as three components important for management of blood glucose regulation by Joslin as early as the 1950s (3). Regular physical activity has been shown to improve cardiovascular complications (hypertension and dyslipidemia) and improve insulin sensitivity, leading to an improvement in glycemic control in these patients (4-6). Despite these well recognized benefits, multiple studies demonstrate that children and adolescents with diabetes are less active when compared to children without diabetes (7-9). There are multiple factors which lead to limitations of physical activity in these individuals, including, but not limited to concerns for altered glycemic control associated with activity, need for increased and closer monitoring, and fear of being ostracized and feeling “different” while participating in sports with a chronic disease. It is important for families, friends, peers, coaches, and health care providers to identify and address these concerns early to limit sedentary behavior and promote physical activity in children and adolescents with diabetes mellitus.

Definitions and diagnostic criteria

Diabetes Mellitus is a disorder of glucose metabolism and is classified into multiple types based on underlying pathophysiology. The two most common types of diabetes are type 1 and type 2. Type 1 diabetes mellitus (T1DM) is characterized by an absolute deficiency of insulin, and is seen most often in children and adolescents, whereas type 2 diabetes mellitus (T2DM) is caused by insulin resistance, inadequate secretion of insulin and is generally associated with overweight and obesity. As per diagnostic criteria from the American Diabetes Association (ADA), the diagnosis of diabetes mellitus can be made in several ways as summarized in Table 1 (10). It should be noted that unless there is a clear clinical diagnosis, a second confirmatory test is required. Individuals with prediabetes may be diagnosed similarly using criteria listed in Table 1.

Table 1 Diagnostic criteria for diabetes mellitus and pre-diabetes
Full table

Epidemiology

T1DM is the most common type of diabetes in children and adolescents with a prevalence of 20 to 25 per 100,000 in the United States (11). Over the last few decades, with increasing rates of obesity, the prevalence of T2DM has increased to approximately 12 per 100,000 (12). Individuals with T2DM are at a higher risk for developing complications early (13).

Physiology of exercise

An understanding of glucose metabolism and hormonal changes occurring during exercise is important for guiding appropriate management of glycemic control during participation in physical activity in these children and adolescents. The major sources of fuel for the body during exercise are fat and carbohydrates (14,15). Glucose is obtained from carbohydrates in the diet and is stored as glycogen in the liver and skeletal muscle during the resting state (15). Soon after exercise begins, muscle glycogenolysis serves as the primary source of glucose. At about 20–30 minutes into the physical activity, fatty acid breakdown contributes to the energy requirements needed for exercise. During prolonged exercise regimens and sports activities, the energy is derived primarily from free fatty acids (15).

The physiology of muscle contraction is complex and needs consideration as well. Briefly, exercise requires adenosine triphosphate (ATP) production, which occurs in balance with the various energy systems in the body, including the glycolytic pathway, phosphagen system, and aerobic mitochondrial respiration (15). During the initial few seconds of exercise or limited high intensity contractions, ATP is produced through reactions involving creatine kinase and adenylate kinase. Adenylate kinase leads to the production of adenosine monophosphate, which promotes glycolysis through the activation of phosphorylase and phosphofructokinase (15). Adenosine monophosphate production and increase in intracellular calcium and phosphate promote glucose uptake by muscles and glycogen breakdown (15).

Insulin, glucagon, and other counter-regulatory hormones are responsible for maintaining glycemic control during aerobic exercise (15,16). Under normal circumstances, insulin is produced in response to hyperglycemia and acts by promoting glucose uptake by muscle and liver for purposes of metabolism, for storage as glycogen, and also for inhibition of fat and protein breakdown (ketogenesis) (15). Glucagon is released in response to exercise to provide energy by stimulating glycogenolysis and gluconeogenesis to prevent hypoglycemia and maintain homeostasis (15). The complex feedback interactions between insulin, glucagon, and other counter-regulatory hormones (catecholamines, growth hormone, cortisol) maintain a balance between glucose utilization and glucose production (3,16). Glucose metabolism by muscle is also highly regulated. Glucose is delivered to active muscle groups via increases in local blood flow, based on metabolic demand (14). Glucose uptake into muscle cells is then mediated by GLUT4 glucose transporters. GLUT4 gene expression is stimulated during exercise which increases glucose transport into the muscles, and this transport changes with insulin resistance (3,14,17). The mechanisms are complex, but believed to be via intracellular calcium release following muscle contraction (17).

Hormone responses also vary depending on exercise types. With mild to moderate aerobic exercise, glucagon secretion is increased and insulin secretion is decreased, so rate of glucose release is matched to the glucose uptake by muscles (6,16). This is in contrast to more intense exercise, where insulin release first decreases and then increases in opposition of the counter-regulatory hormones (16).

Physiology in type 1 diabetes

Patients with T1DM do not have the typical regulatory insulin response to hyperglycemia. They are therefore more prone to hypoglycemia or hyperglycemia associated with exercise and exogenous insulin administration. Glycemic control can become more predictable over time with regular physical activity and appropriate management of diabetes care during exercise. Individuals with T1DM may not have predictable or adequate endogenous glucose production due to multiple factors. There may be an increased risk of hypoglycemia due to lower glycogen stores, impaired glucagon secretion due to alpha cell dysfunction, and decreased glucagon sensitivity (18). Exercise causes increased blood flow to the muscles, leading to a more local glucose and insulin delivery, which also contributes to hypoglycemia. Exercise leads to mobilization of the glucose transporters which increases glucose uptake by the muscles (16). Patients with T1DM have increased rates of gluconeogenesis, which may help maintain blood glucose levels (18,19). Another difference to note between individuals without diabetes and T1DM patients during physical activity is that glucose production is primarily by glycogenolysis in the former versus gluconeogenesis in the latter (3). Studies have shown that a ten second sprint following physical activity lead to transient increases in counter-regulatory hormones, for which the risk of immediate hypoglycemia may be decreased, although this may not effect delayed hypoglycemia (3). When the amount of insulin in the system is not sufficient for the amount of exercise, or when the individual is exercising during illness, increased counter-regulatory hormone production can lead to hyperglycemia associated with ketone production (3). The presence of ketones can thus be used as an indicator of inadequate insulin effect. Hyperglycemia and ketosis should be monitored closely in the children who are not routinely well controlled and who start exercise, as the counter-regulatory response may be amplified. It has been shown that controlled (and uncomplicated) T1DM does not impair optimal athletic and physical performance (20) and children and adults with good control of diabetes have exercise capacity similar to matched controls (3,15,21). Anaerobic exercise or high intensity activity leads to increase in counter-regulatory hormones and hyperglycemia is expected almost immediately after start of exercise. This is often transient and can eventually lead to hypoglycemia a few hours later. In contrast, aerobic activity increases the risk of hypoglycemia during and after exercise. In general, the aerobic activities which have more muscle involvement have a greater risk of hypoglycemia (3). Resistance training is often associated with steady blood glucose levels, although hyperglycemia should be monitored for in some individuals (6).

Physiology in type 2 diabetes

At baseline, obese adolescents with T1DM or T2DM have decreased aerobic activity when compared to non-obese individuals (15,22). Adolescents with T2DM have impaired exercise capacity even when compared to obese controls without diabetes (23). Insulin resistance in T2DM has been thought to be related to a combination of excess lipid production and mitochondrial dysfunction (24,25). Obesity is associated with the presence of increased free fatty acids, which in turn leads to increased fat storage causing a decrease in insulin sensitivity. Excessive free fatty acid production also leads to an increase in reactive oxygen species, which affects mitochondrial function (24). The presence of reactive oxygen species also effects adequate insulin secretion from the beta-cells from the pancreas (24). Regular physical activity leads to an overall improvement in insulin sensitivity with a reduction in baseline insulin levels (26). Exercise capacity has been shown to improve with regular physical activity in children despite not having any changes in the body mass index (BMI) (26).

Hypoglycemia and hyperglycemia

Physical activity is associated with blood glucose fluctuations leading to hypoglycemia or hyperglycemia. Fear of hypoglycemia appears to be the most common reason to avoid exercise in children and adolescents. Therefore, addressing the appropriate management of insulin regimen and carbohydrate intake is important to avoid these fluctuations in glycemic control for safety and also for reassuring the child/adolescent and families (27,28). Severe hypoglycemia may be related to insulin-dependent and insulin-independent glucose uptake. Early hypoglycemia occurs immediately after exercise and late/delayed or nocturnal hypoglycemia may occur many hours after physical activity even overnight following periods of activity in the afternoon and evening. Delayed hypoglycemia is most often due to an increase in insulin sensitivity post-exercise. It may also be related to decrease in counter-regulatory response or lack of insulin adjustment prior to exercise (29). Close monitoring for glycemic control for sports participation requires increased blood glucose monitoring and this may become a barrier in sports participation. On the other hand, exercise-induced hyperglycemia can be seen due to an increased adrenal response either due to the nature of the physical activity or short intense bouts of anaerobic activity. Mismatch of insulin dose and carbohydrates may also result in hyperglycemia, either from under-insulinization or excessive food or carbohydrate intake prior to or during exercise.

Management of type 1 diabetes with exercise

Importance of a care plan

A proper approach to optimizing glycemic control in the exercise and peri-exercise period involves adequate blood glucose monitoring, timely carbohydrate supplementation and proper insulin adjustments. All of these can be addressed by the development of a comprehensive ‘Diabetes Care Plan’, which involves a team approach to the balancing of carbohydrate intake and insulin administration, in order to achieve stable glycemia during physical activity (or as close to it as possible) (30).

Pre-participation evaluation

It is recommended that children undergo a pre-participation evaluation to identify any risk factors and to decrease risk of medical harm to the individual. It also serves as a chance to provide anticipatory guidance (31). Patients with T1DM should have a similar comprehensive pre-participation evaluation prior to initiation of any new physical activity. Details of history should explore all aspects of an individual’s medical history and should not simply focus on sports-related history. Both in youth with and without diabetes, the cardiovascular history and exam is one of the most important aspects of the pre-participation evaluation. Ensuring regular visits with their local pediatric endocrinologist and regular communication with the diabetes care team are important measures in improving glycemic control. Strategies to avoid exercise related hypoglycemia or hyperglycemia should be discussed, in addition to quarterly assessment of glycosylated Hemoglobin (HbA1c) and glycemic control. Special attention should be given to potential risks of microvascular complication precaution and related concerns including blood pressure and concerns for the presence of hypertension. Exercise may improve hypertension and should be encouraged. Individuals with more advanced complications such as proliferative retinopathy or neuropathy should avoid exercise and activities which can cause sudden increase in blood pressures (3,5). Recommendations for adequate foot care for all athletes should also be in place.

Blood glucose monitoring

Optimal blood glucose monitoring is essential to avoid acute complications related to exercise such as hypoglycemia and hyperglycemia with ketosis. It is recommended that blood glucose levels be checked prior to starting exercise, during, and after exercise. Prior to starting exercise, it is recommended that a patient’s blood glucose be greater than 90 mg/dL (5). If initial blood glucose levels are low, the individual should avoid physical activity at that time and consume sufficient carbohydrates to achieve euglycemia (32). Exercise and physical activity should also be avoided if there is significant hyperglycemia with/without ketones present as this could induce diabetes ketoacidosis (DKA) (3,33). During periods of continuous physical activity, it is recommended that blood glucose levels be monitored about every 30 minutes, and then 15 minutes after completion of exercise, and at bedtime. In addition, more frequent monitoring may be needed over the next 24 hours due to increased risk of delayed hypoglycemia especially until the individual’s glycemic response pattern to exercise is well defined (31,34). Optimal sports performance particularly in activities requiring the highest focus and precision would be expected when glycemic control is in a reasonably normal range as cognitive function and “mental efficiency” have been shown to be relatively lower during periods of hypoglycemia or significant hyperglycemia (35).

Other screenings

It is appropriate to make sure the individual is up to date on surveillance and screening for complications prior to participating in sports, to help identify and manage any complications if present. An individual with diabetes should have thyroid function studies soon after diagnosis and repeated every 1–2 years. Celiac disease screening should be done soon after diagnosis and repeated 2–5 years after diagnosis, or if concerning symptoms arise. Fasting lipid profile should be obtained after 10 years of age. In addition, nephropathy should be screened for with microalbuminuria once the individual has had diabetes for 5 years, and retinopathy and neuropathy after 10 years of age and after the individual has had diabetes for 3–5 years (10).

Adjustment of insulin regimen

Patients with T1DM may need individualization of recommendations based on the type, timing, and duration of physical activity the individual is participating in, with specific adjustments based on their treatment regimen. This will facilitate appropriate guidance for insulin dosing and carbohydrate ingestion. The management of diabetes during physical activity involves balancing of the type and timing of insulin given, the amount and timing of carbohydrate administration, fluid and electrolyte replacement, and management of complications including hypoglycemia, hyperglycemia, and ketones. Attention should be given to additional factors which may affect insulin dosing as well. For example, insulin absorption is increased in the exercising limb due to increased blood flow, and therefore it is recommended that individuals avoid injections in the exercising limb or muscle groups (3). Also, higher temperatures increase insulin absorption while cold weather decreases insulin absorption (3).

Basal-bolus regimen

The use of multiple-dose injections to address the insulin requirements in T1DM is the simplest, yet can be effective. Insulin requirements are covered generally by a once daily injection of long-acting “basal” insulin, in addition to several “short-acting” insulin bolus doses to cover food intake and hyperglycemia through the day. Adjustments of pre-meal short-acting insulin with a reduction of the bolus dose is effective in decreasing the risk of hypoglycemia associated with exercise (33). Adjustment of basal insulin dosing on the day prior to exercise should not be routinely done due to risk of hyperglycemia outside of the physical activity, but may be considered in certain circumstances such as camp (6).

Insulin pump (continuous subcutaneous insulin infusion)

Insulin pumps handle the daily insulin requirement by providing a continuous infusion of short-acting insulin at a low rate to provide the basal insulin requirements, along with bolus doses for the prandial requirements. Disposable Infusion “sets” or “pods” along with an insulin reservoir are changed every 2–3 days, and catheter tubing can then infuse into the subcutaneous space providing the insulin delivery. The use of insulin pumps may be associated with lower rates of early, severe, and delayed hypoglycemia if appropriate insulin rate adjustments are made (29). Early hypoglycemia can be prevented by suspending or decreasing the basal rate during exercise. The risk of nocturnal hypoglycemia can be reduced by decreasing or even suspending basal rate during exercise, followed by a temporary basal rate reduction of at least 20% for the next several hours or overnight (29). A common time for children and adolescents to exercise is after school, although this is often associated with nocturnal hypoglycemia, typically occurring between midnight and 2 AM. Although decreasing basal insulin during and after exercise does significantly decrease the number of hypoglycemic events, it is useful for patients/families to know that it does not eliminate the risk completely. However, hypoglycemia may be less severe and amenable to easy treatment. It is important to remember that there may be additional tendency towards hyperglycemic events as well (33,36). Hyperglycemia following exercise is more commonly associated with high intensity exercise due to increased catecholamine production (3). This may be prevented with a small bolus immediately after completion of the physical activity (3). Post-exercise bolus dosing should be done with caution due to possibility of severe nocturnal hypoglycemia, which has been associated with the fatal “dead-in-bed” syndrome (6,37). It is important to be aware of the types of activities that may lead to hyperglycemia instead of the more common occurrence of hypoglycemia as one learns about the individual’s own unique glucose response during exercise.

Continuous glucose monitoring (CGM) technology

CGM offers closer monitoring and can help decrease glycemic excursions and prevent dangerous hypoglycemia or hyperglycemia by early warning, whether used along with multiple daily injections or insulin pumps. While persons using multiple-injection regimens can certainly still benefit from CGM, additional technology offers the pump users greater flexibility and added functionality. For example, CGM linked to an insulin pump (sometimes called Sensor-Augmented Pump therapy) is now available with automated algorithm processors to suspend basal insulin delivery automatically if blood glucose drops below specified set thresholds (sometimes called “low glucose threshold suspend”), and can be very effective in reducing hypoglycemia (38). Various strategies may be used to fine-tune insulin dosing to mitigate exercise-associated dysglycemia (39).

Approach to pre-exercise period

In the preparation phase for the sports activity/physical activity participation, it is recommended to have a well-balanced meal containing carbohydrates (CHO), protein and fat about 3–4 hours prior to exercise (40). At the same time, one should avoid exercise during peak insulin action. Additionally, in T1DM patients, about an hour prior to starting, about 1–2 grams of carbohydrates/kilogram body weight (g CHO/kg) consumption without insulin coverage should occur for longer duration planned activities (40). A pre-exercise blood glucose check is essential, as it can guide pre-exercise carbohydrate dosing and insulin dose adjustments. Pre-exercise blood glucose targets are generally recommended to be in the 90–250 mg/dL range (5). Below this threshold blood glucose of 90 mg/dL, a pre-exercise carbohydrate snack is recommended and intense physical activity should be avoided (39). Within this target range, exercise can be initiated, with regular consumption of carbohydrates depending on intensity and type of exercise and the amount of active insulin present. And if glucose levels are greater than 250 mg/dL, ketones should be checked and if present, exercise should be held, with conservative insulin correction given if significant hyperglycemia (39). Severe hypoglycemia, defined by blood glucose is less than 50 mg/dL or hypoglycemia requiring assistance, if within the previous 24 hours, should also be a relative contraindication to exercise (6). If the sports participant is in the euglycemic range noted above and no compensatory insulin adjustments have been made in the period before the activity, it is important to add a carbohydrate snack prior to starting physical activity to prevent risk of hypoglycemia. Adult guidelines have recommended consuming 10–15 gram of carbohydrates prior to starting exercise, although with children the amount of carbohydrates consumed depend greatly on blood glucose level prior to start of activity, duration and intensity of physical activity (36). Maintaining hydration is an extremely important factor in this broader context not directly related to insulin and carbohydrates. Adequate fluid intake should be maintained in the pre, intra, and post activity periods to prevent dehydration (6).

Approach during exercise

Regular monitoring of blood glucose should be performed, and carbohydrate and/or insulin doses be considered with the goal to maintain blood glucose in the 120–180 mg/dL range though an individualized approach is always best (20). For more strenuous and prolonged activities, additional carbohydrate supplementation is typically required to replete stores. The amount of carbohydrate intake should equal the amount of carbohydrates being consumed, or about 0.5–1.5 g CHO/kg for each hour of strenuous activity (5,40), and on the higher end of the range (1–1.5 g CHO/kg) if pre-exercise insulin doses have not been reduced.

Approach post-exercise

One should consider replacing carbohydrates immediately following exercise. Due to the delayed hypoglycemia effect, blood glucose monitoring hourly and overnight (if the activity is in the afternoon or evening) is prudent. Changes in insulin sensitivity post-exercise is believed to be one of many mechanisms causing late or delayed hypoglycemia, and this effect is seen particularly following intermittent high-intensity exercising (10). Please refer to guidelines listed in Table 2 for key points regarding exercise safety.

Table 2 Key points: exercise and safety
Full table

Exercise management in T2DM

Management of children and adolescents with T2DM is unique in that it combines behavioral, dietary, and physical activity components of an individual’s lifestyle in addition to possible pharmaceutical interventions for appropriate management. There is also the added opportunity for managing individuals at risk for developing T2DM if they are identified early enough with a diagnosis of impaired glucose tolerance or pre-diabetes. Puberty is a time of relative physiologic reduction in insulin sensitivity and of the added behavioral component of physical inactivity which can both increase the risk of obesity and tendency towards developing T2DM (29). The optimal time to intervene in at-risk children is in childhood prior to starting of puberty. Studies have shown that lifestyle intervention has been associated with improved glycemic control in adolescents who have impaired glucose tolerance. Experimental studies support this, showing improved glycemic control along with improvement in fasting insulin levels (29,41,42). The management of exercise in patients with T2DM is focused primarily on behavioral aspects by establishing routines that promote regular physical activity and reduce sedentary activity. This may be particularly challenging in individuals and families with established sedentary and unhealthy lifestyles (3,29). It is recommended that patients with T2DM participate in at least 60 minutes of moderate to vigorous exercise daily (43).

The management of T2DM is typically healthy lifestyle modification, metformin, and in many cases insulin depending on the presentation and level of glycemia. There are other less commonly used drugs which are not FDA approved in the pediatric population.

Metformin is the first line pharmacologic agent used for T2DM in the pediatric population, and works by improving insulin sensitivity (43). Common side effects include abdominal discomfort and diarrhea, but can sometimes be mitigated by taking with food. Other medications commonly used in T2DM, but are not currently FDA approved for use in children, include sulfonylureas, thiazolidinediones, alpha-glucosidase inhibitors. If being used off-label, side effects should be closely monitored.

With presence of some residual beta cell function and insulin resistance and less effects on the counter-regulatory mechanisms (3), the risk of hypoglycemia is decreased in patients with T2DM. Despite this, insulin combined with physical activity may still lead to hypoglycemia and should be monitored closely for possible adjustments with insulin regimen, as elaborated in the discussion above.

Additional considerations

• Controlled and uncomplicated T1DM does not (and should not) impair optimal athletic and physical performance, so young people with T1DM should be strongly encouraged to pursue sports interests;
• Fear of hypoglycemia is very common and may drive many people with diabetes to keep blood glucoses higher than needed. Hypoglycemia is more troublesome in interfering with exercise and activities than is mild hyperglycemia, so strategies to mitigate hypoglycemia must be emphasized;
• While general targets and guidance can be provided (as described above), empirically derived and individualized goals and targets should always supersede any general “protocol”.

Acknowledgements

None.

Footnote

Conflicts of Interest: The authors have no conflicts of interest to declare.

References

1. Michaud I, Henderson M, Legault L, et al. Physical activity and sedentary behavior levels in children and adolescents with type 1 diabetes using insulin pump or injection therapy – The importance of parental activity profile. J Diabetes Complications 2017;31:381-6. [Crossref] [PubMed]
2. Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents. National Heart, Lung, and Blood Institute. Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents: Summary Report. Pediatrics 2011;128:S213-S256. [Crossref] [PubMed]
3. Robertson K, Riddell MC, Guinhouya BC, et al. Exercise in children and adolescents with diabetes. Pediatr Diabetes 2014;15 Suppl 20:203-23. [Crossref] [PubMed]
4. Herbst A, Kordonouri O, Schwab KO, et al. Impact of physical activity on cardiovascular risk factors in children with type 1 diabetes: a multicenter study of 23,251 patients. Diabetes Care 2007;30:2098-100. [Crossref] [PubMed]
5. Colberg SR, Sigar RJ, Yardley JE, et al. Physical Activity/Exercise and Diabetes: A Position Statement of the American Diabetes Association. Diabetes Care 2016;39:2065-79. [Crossref] [PubMed]
6. Riddell MC, Gallen IW, Smart CE, et al. Exercise management in type 1 diabetes: a consensus statement. Lancet Diabetes Endocrinol 2017;5:377-90. [Crossref] [PubMed]
7. Mohammed J, Deda L, Clarson CL, et al. Assessment of habitual physical activity in adolescents with type 1 diabetes. Can J Diabetes 2014;38:250-5. [Crossref] [PubMed]
8. Trigona B, Aggoun Y, Maggio A, et al. Preclinical noninvasive markers of atherosclerosis in children and adolescents with type 1 diabetes are influenced by physical activity. J Pediatr 2010;157:533-9. [Crossref] [PubMed]
9. Maggio AB, Hofer MF, Martin XE, et al. Reduced physical activity level and cardiorespiratory fitness in children with chronic diseases. Eur J Pediatr 2010;169:1187-93. [Crossref] [PubMed]
10. Marathe PH, Gao HX, Close KL. American Diabetes Association Standards of Medical Care in Diabetes 2017. J Diabetes 2017;9:320-4. [Crossref] [PubMed]
11. Sperling, Mark A. Pediatric Endocrinology. 4th ed. Philadelphia: Elsevier Saunders, 2014.
12. Reinehr T. Type 2 diabetes mellitus in children and adolescents. World J Diabetes. 2013;4:270-81. [Crossref] [PubMed]
13. ISPAD Clinical Practice Consensus Guidelines 2014 Compendium: Type 2 diabetes in the child and adolescent. Pediatr Diabetes 2015;16:392. [Crossref] [PubMed]
14. Sylow L, Kleinert M, Richter EA, et al. Exercise-stimulated glucose uptake – regulation and impications for glycaemic control. Nat Rev Endocrinol 2017;13:133-48. [Crossref] [PubMed]
15. Miller MD, Thompson SR. DeLee & Drez’s Orthopaedic Sports Medicine, 4th ed. Philadelphia: Elsevier Saunders, 2015.
16. Riddell MC, Zaharieva DP, Yavelberg L, et al. Exercise and the Development of the Artificial Pancreas: One of the More Difficult Series of the Hurdles. J Diabetes Sci Technol 2015;9:1217-26. [Crossref] [PubMed]
17. Bally L, Laimer M, Stettler C. Exercise-associated glucose metabolism in individuals with type 1 diabetes mellitus. Curr Opin Clin Nutr Metab Care 2015;18:428-33. [Crossref] [PubMed]
18. Basu R, Johnson ML, Kudva YC, et al. Exercise, hypoglycemia and type 1 diabetes. Diabetes Technol Ther 2014;16:331-7. [Crossref] [PubMed]
19. Petersen KF, Price TB, Bergeron R. Regulation of net hepatic glycogenolysis and gluconeogenesis during exercise: impact of type 1 diabetes. J Clin Endocrinol Metab 2004;89:4656-64. [Crossref] [PubMed]
20. Horton WB, Subauste JS. Care of the Athlete With Type 1 Diabetes Mellitus: A Clinical Review. Int J Endocrinol Metab 2016;14:e36091. [PubMed]
21. Heyman E, Briard D, Gratas-Delamarche A. Normal physical working capacity in prepubertal children with type 1 diabetes compared with healthy controls. Acta Paediatr 2005;94:1389-94. [Crossref] [PubMed]
22. Gusso S, Hofman P, Lalande S, et al. Impaired stroke volume and aerobic capacity in female adolescents with type 1 and type 2 diabetes mellitus. Diabetologia 2008;51:1317-20. [Crossref] [PubMed]
23. Nadeau KJ, Zeitler PS, Bauer TA, et al. Insulin resistance in adolescents with type 2 diabetes is associated with impaired exercise capacity. J Clin Endocrinol Metab 2009;94:3687-95. [Crossref] [PubMed]
24. Cree-Green M, Triolo TM, Nadeau KJ. Etiology of Insulin Resistance in youth with type 2 diabetes. Curr Diab Rep 2013;13:81-8. [Crossref] [PubMed]
25. Cree-Green M, Gupta A, Coe GV, et al. Insulin resistance in type 2 diabetes youth relates to serum free fatty acids and muscle mitochondrial dysfunction. J Diabetes Complications. 2017;31:141-8. [Crossref] [PubMed]
26. Bell LM, Watts K, Siafarikas A, et al. Exercise alone reduces insulin resistance in obese children independent of changes in body composition. J Clin Endocrinol Metab 2007;92:4230-5. [Crossref] [PubMed]
27. Tully C, Aronow L, Mackey E. Physical Activity in Youth with Type 1 Diabetes: A Review. Curr Diab Rep 2016;16:85. [Crossref] [PubMed]
28. Jabbour G, Henderson M, Mathieu ME. Barriers to Active Lifestyles in Children with Type 1 Diabetes. Can J Diabetes 2016;40:170-2. [Crossref] [PubMed]
29. Pivovarov JA, Taplin CE, Riddell MC. Current perspectives on physical activity and exercise for youth with diabetes. Pediatr Diabetes 2015;16:242-55. [Crossref] [PubMed]
30. Jimenez CC, Corcoran MH, Crawley JT, et al. National athletic trainers association position statement: management of the athlete with type 1 diabetes mellitus. J Athl Train 2007;42:536-45. [PubMed]
31. Peterson AR, Bernhardt DT. The preparticipation sports evaluation. Pediatr Rev 2011;32:e53-65. [Crossref] [PubMed]
32. Beck JK, Cogen FR. Outpatient Management of Pediatric Type 1 Diabetes. J Pediatr Pharmacol Ther 2015;20:344-57. [PubMed]
33. Diabetes Research in Children Network (DirecNet) Study Group. Tsalikian E, Kollman C, et al. Prevention of hypoglycemia during exercise in children with type 1 diabetes by suspending basal insulin. Diabetes Care 2006;29:2200-4. [Crossref] [PubMed]
34. Rice SG. American Academy of Pediatrics Council on Sports Medicine and Fitness. Medical Conditions affecting sports participation. Pediatrics 2008;121:841-8. [Crossref] [PubMed]
35. Gonder-Frederick LA, Zrebiec JF, Bauchowitz AU, et al. Cognitive function is disrupted by both hypo- and hyperglycemia in school-aged children with type 1 diabetes: a field study. Diabetes Care 2009;32:1001-6. [Crossref] [PubMed]
36. Younk LM, Mikeladze M, Tate D, et al. Exercise-related hypoglycemia in diabetes mellitus. Expert Rev Endocrinol Metab 2011;6:93-108. [Crossref] [PubMed]
37. Tanenberg RJ, Newton CA, Drake AJ. Confirmation of hypoglycemia in the “dead-in-bed” syndrome, as captured by a retrospective continuous glucose monitoring system. Endocr Pract 2010;16:244-48. [Crossref] [PubMed]
38. Bergenstal RM, Klonoff DC, Garg SK, et al. Threshold-based insulin-pump interruption for reduction of hypoglycemia. N Engl J Med 2013;369:224-32. [Crossref] [PubMed]
39. Zaharieva DP, Riddell MC. Prevention of exercise-associated dysglycemia: a case study-based approach. Diabetes Spectr 2015;28:55-62. [Crossref] [PubMed]
40. Robertson K, Adolfsson P, Scheiner G. Exercise in children and adolescents with diabetes. Pediatr Diabetes 2009;10:154-68. [Crossref] [PubMed]
41. Savoye M, Caprio S, Dziura J, et al. Reversal of early abnormalities in glucose metabolism in obese youth: results of an intensive lifestyle randomized controlled trial. Diabetes Care 2014;37:317-24. [Crossref] [PubMed]
42. Grøntved A, Ried-Larsen M, Ekelund U, et al. Independent and combined association of muscle strength and cardiorespiratory fitness in youth with insulin resistance and β-cell function in young adulthood: the European Youth Heart Study. Diabetes Care 2013;36:2575-81. [Crossref] [PubMed]
43. Copeland KC, Silverstein J, Moore KR, et al. Management of newly diagnosed type 2 diabetes mellitus (T2DM) in children and adolescents. Pediatrics 2013;131:364-82. [Crossref] [PubMed]