Journal of Diabetes & Metabolism

PA: Physical Activity; ATP: Adenosine Triphosphate; T1D: Type 1 Diabetes or Type 1 Diabetes Patient; GLUT 4: Glucose Transporters; HbA1c: A_1c Glycated hemoglobin; HDL-C: High-Density-Lipoprotein-Cholesterol; LDL-C: Low Density Lipoprotein-Cholesterol; PWC₁₇₀: Physical Working Capacity 170; VO₂: Oxygen consumption

Type 1 diabetes (T1D) is a form of diabetes that results from autoimmune destruction of insulin-producing beta cells of the pancreas. This insulin deficiency once quickly caused death in children, but technological advances in insulin therapy and diabetes management tools now allow for a near full life expectancy with dramatically improved patient quality of life. Nonetheless, poor diabetes management can lead to diabetes-related complications and childhood should be a time in which good diabetes control habits should be developed. Since the diagnosis of type 1 diabetes (T1D) often occurs in childhood, age and maturation of that patient brings elevated risk of developing microvacular (diabetic retinopathy, nephropathy, and neuropathy) and macrovascular complications. Therefore, childhood represents a very good timeframe to focus on the prevention of microand macrovascular disease through good diabetes management.

Type 1 diabetes treatment is based on exogenous insulin injection, diet control and regular physical activity. A basal insulin concentration is needed throughout the day, but insulin boluses are also required at mealtimes and for corrections for hyperglycemia. However, other parameters, such as physical activity, illness and stress levels have to be constantly monitored to determine the appropriate insulin dosage. It is generally well accepted that regular activity along with a good diet are helpful in maintaining glycemic control, since very sedentary behavior is associated with poor control [1].

Diet recommendations are relatively straight forward for children and adolescents with T1D, and are similar to the general dietary guidelines for healthy children [2]. When respected, this helps to avoid unbalanced and irregular carbohydrate intake. The aim of regular physical activity for youth with type 1 diabetes is to improve quality of life and to enhance both short-term and long-term health. Due to the possibility of worsening metabolic control during exercise (resulting in either hypoglycemia or hyperglycemia), guidelines regarding metabolic control, blood glucose monitoring and food intake for physical activity must be followed. Some review papers have focused on glycemic variations with exercise and on practical considerations for the clinical management of type 1 diabetes in athletic youth [1,3-7]. Other reviews previously presented exercise training induced benefits on glycemic control in both adulthood and childhood [8,9] but not on different other important health related parameters. The purpose of this review is to focus on the short- and long-term effects of different training models in youth with T1D and to understand which mechanisms are involved. This review will also focus on physical activity rate in young T1D and analyze what would limit their adherence, in order to improve its promotion.

In T1D management, physical activity, glycemic control, insulin treatment and diet control represent the three cornerstones of care. Physical activity by itself induces health-related beneficial effects and improves patient quality of life.

Beneficial effects of regular exercise in young patients with T1D

A number of studies of TD1 children or adolescent have shown that pure endurance or mixed (endurance and strength exercise) training have beneficial effects in type 1 diabetes. After 3 to 9 months, training has beneficial effects on quality of life (assessed using a questionnaire) [10-13], endurance capacity (4 to 34% improvement) [11,14-24], body composition - fat to muscle mass ratio [10,15,16,21,22,25], lipid profile - fraction of ‘good’ (HDL-C) and ‘bad’ cholesterol (LDL-C) [10,21,26,27], tissue insulin sensitivity - insulin receptor efficiency [22], and finally, but not universally observed, glycemic control (as reflected by improvement of long term indicator HbA_1c, or short and middle term indicators such as fructosamine, glycemia/glycosuria) [16,18,20,21,26-30] (Table 1 data included as supplementary). It is worth noting that lipid profile and fructosamine improvement can be observed after only 2 weeks of intensive physical activity in youth with T1D [27].

Importantly, some studies in young patients with T1D report training-induced improvement in bone mineral density [25], vascular function (vasomotricity) [14] and antioxidant capacity [31].

These results from longitudinal studies are in accordance with cross-sectional studies, which underline significant correlations between different health indicators and the amount of physical activity performed as assessed by accelerometer and/or questionnaires [32-44].

However, since the beneficial effects of exercise training are not systematically observed (Table 1 data included as supplementary), it seems relevant to examine further the underlying mechanisms involved in order to adapt and optimize the training prescription.

Physical fitness improvement and underlying mechanism: All studies except two, show that aerobic fitness, evaluated with maximal oxygen uptake (VO_2max) or PWC₁₇₀ (power output corresponding to 170 bpm during an incremental test), is improved when the training lasts for at least 3 months and is supervised [28,45]. The aerobic capacity improvement could be linked to different parameters like heart volume [19] and muscle mass improvement [10] following training. The increase of muscle aerobic enzyme maximal activity could also be involved, but to date, data are just available in the adult T1D population [46-48].

Insulin sensitivity and underlying mechanisms: Only a few papers have focused on the effects of regular exercise on tissue insulin sensitivity in T1D children, but results are encouraging [22,24]. Training-induced improvements in insulin sensitivity may be particularly important in children and adolescents, since puberty is known to increase insulin resistance, especially in girls [49,50]. The stimulating effect of insulin on glucose metabolism, measured during hyperinsulinemic euglycemic clamp, is reduced by 33 to 42% in T1D adolescent compared to prepubescent and adult T1D [49]. It is also worth noting that in T1D, 2 weeks of intense activity decreases circulating ghrelin levels [51], while more prolonged training (6 month) attenuates the puberty induced increase in leptin levels [10]. Ghrelin and leptin are both insulin resistance indicators/factors.

There are likely multiple underlying mechanisms for training induced improvements in insulin sensitivity in youth with T1D. A first explanation could be the training-induced improvement in body composition. The training-induced lean mass gain observed in youth with T1D [10,21,22,25] is likely representative of muscle mass gain, which may be linked to improvement in peripheral insulin sensitivity. Indeed, skeletal muscle represents the main insulin stimulated glucose utilization site, even at rest (consumption of 54.4 kJ/kg/j vs. 18.8 kJ/ kg/j for adipose tissue) [52-54]. In addition, muscle is quantitatively the main tissue involved in lipid metabolism [55,56]. Muscle energy expenditure during each training session could lead to fat mass decrease [57], that has already been observed in a few studies of youth with T1D [15,21] (Table 1 data included as supplementary). The fat mass decrease could induce improvement in insulin resistance since when adipose tissue mass is in excess, it secretes more molecules (adipocytokines) like leptin, that increases insulin resistance [58]. A 6-month combined training (aerobic and muscle strength) was able to limit fat mass increase, and also leptin levels, in T1D adolescents who were in their later stages of puberty [10]. In this context, it seems reasonable to combine different training models that would at the same time, also help to avoid monotony and keep young T1D patients motivated. As such, the exercise prescription could be as follows:

Muscle strength training activities [10,21], such as weight bearing, weight activities, like jumping, push-up and sit-ups, step climbing machines, rope climbing, and rock climbing [10,25] are all favorable for muscle mass gain [59], which should promote increased insulin sensitivity.

Aerobic exercise activities like running or swimming [15], which promote increased energy expenditure, increase aerobic fitness and increase lipid oxidation - they can be planed as continuous and moderate intensity (example : 30min at 50% VO₂ peak), or as high intensity intermittent exercise (example : 30sec at 100% VO₂ peak/30sec recovery). This kind of intermittent activity has been shown to improve insulin sensitivity in healthy subjects [60]. Moreover, intermittent exercise is comparable to continuous exercise (at the same total mechanic work) according to the total energy expenditure during exercise and lipid oxidation level during recovery [61]. Intermittent exercise also tends to represent the type of activities that children prefer according to Bailey et al. [62].

Training induced structural and functional skeletal muscle adaptations could be responsible for the enhancement of peripheral insulin sensitivity. For example, it has been shown in healthy adults and in adults with Type 2 diabetes that physical training improves glucose delivery to muscle via an enhanced muscle vascularization (increased muscle capillaries number, and increased local blood flow) [63]. It also has been shown that maximal capacity for glucose utilization is improved via increased glucose transporter (GLUT4) number [63] and/or maximal activity of the enzymes involved in blood glucose catabolism (i.e. hexokinase), or muscle glucose disposal (i.e. glycogen synthase) [63]. In T1D adult, the same improvement is observed for muscle capillarization [46,47] and maximal activity of enzymes involved in aerobic glucose disposal (citrate synthase) [46,48] (Succinate dehydrogenase) [47,48] after 2 to 4 months of aerobic training.

Glycemic control improvement and underlying mechanisms: In general, regular exercise improves insulin sensitivity in youth with T1D. However, it should be noted that the putative improvement in exercise-induced peripheral insulin sensitivity in young patients with T1D [22,24] is not always coincidental with the improvement of the following parameters (usually linked to improved insulin sensitivity) : daily insulin dose decrease [10,11,22,24,51,64] and glycemic control improvement [10-12,17,22-24,31,51,64,65] (Table 1 data included as supplementary). This could be linked to a difficult management of exercise glycemic variations influenced by multiple factors (delay between last meal and insulin injection, insulin absorption, initial glycemia, time of the day, etc.) [1]. Because of these glycemic variations and the fear of hypoglycemia, patients might consume carbohydrates in excess [66] or they may decrease their insulin dose far too aggressively, thereby eliminating the potential improvements in glucose disposal. This can explain why several studies show significant decrements in total daily insulin dose but no improvement in glycemic control [13,45]. This behavior might induce hyperglycemia, and hence even impair glycemic control [17,45].

On the contrary, when young patients with T1D benefit from recommendations about diet control, insulin therapy and glucose monitoring in addition to the training program, glycemic control (HbA_1c or fructosamine) can significantly improve [20] and this even after only two weeks of high intensity physical activity [27,29].

The effects of chronic exercise on glycemic control in patients (age from 8 to 48 years old) with T1D have been recently studied in a meta-analysis by Tonoli [8]. In prepubescent children (average age 12.1 years old) [17,65], this meta-analysis does not highlight any glycemic improvement with aerobic training. However, chronic aerobic exercise significantly decreased HbA_1c levels in a group of 61 adolescents (average age 13.8 years old) with a poor glycemic control (from studies : [16,20,28-30]). Combined training (aerobic and muscle strength exercise) (based on [10,13,21,67]) slightly decreased HbA_1c levels (Best improvement: from 7.72 to 6.76) in T1D adolescents (average age 17.2 years old). When both young and adult T1D results were analyzed together, beneficial effects were found: exercise traininginduced glycemic control improvement could be observed when training lasted at least 3 months, including 1 to 3 sessions a week, and when diet control and insulin therapy recommendations were added. Glycemic control improved more after training when initial glycemic control was poor (HbA_1c ≥ 8%).

Lipid profile improvement and underlying mechanisms: According to the studies in table 1 (Data included as supplementary), lipid profile (especially HDL-C / LDL-C ratio) improves more when training session frequency is increased [26], and when the glycemic control is improved at the same time [21,26,27]. When glycemic control is not improved with training, most studies [10,24,31,45,64], except one [68], do not detect any improvement in LDL-C and/or HDL-C. This result is in accordance with the fact that glycemic control and lipid profile are often highly correlated health parameters in T1D [69-74]. The link between lipid profile and glycemic control, and their parallel improvement induced by exercise training, could be explained by the negative impact of insulin deficiency and excessive glycosylation (observed in case of high HbA1c level) on LDL degradation and removal, hence increasing LDL-C levels [75]. Moreover, lipolysis, also accentuated in case of insulin deficiency and insulin resistance, increases free fatty acid and serum glycerol, which could in turn impair glucose metabolism through the Randle cycle [2].

Training induced beneficial effects on lipid profile and glycemic control, could eventually diminish the chances to develop vascular complications. According to Kriska et al. [76], an improved spontaneous physical activity between 14 and 17 years old lowers nephropathy and neuropathy prevalence in adults T1D.

Finally, and perhaps most importantly, physical exercise is also very important for enhancing the quality of life (QOL) in young T1D [10-13], especially during psychological instable periods such as puberty.

Adherence and limits to physical activity in young patients with T1D

Because of the numerous beneficial effects on physical and psychological health (see section 1), exercise is clearly highly recommended in young T1D. Nonetheless, some evidence exists to suggest that participation in exercise and physical activity is often suboptimal.

Physical activity engagement in young patients with T1D

As shown in table 2, T1D adolescents often do not achieve the recommended physical activity level (often set at 60 min a day and including moderate to high intensity exercise) and they are often even less active than their non-diabetic healthy peers. This relative inactivity is especially observed in girls and this gender difference is observed in early childhood (i.e. as early as 6-7 years of age [77].

Table 2: Physical activity level in young T1D.

In order to motivate patients who are not involved in physical activity, it is important to know why they choose not to participate in regular activity. A study by Faulkner et al. [12] showed that adolescents with T1D exercising more than 10 min a day don’t have any negative or limiting feelings about physical activity (PA) (evaluated with Diabetes Social Support Questionnaire-Family Version, DSSQ-Family). Also, the frequency of exercise sessions, longer than 30 min, is correlated to the feeling of important family support [12,78].

A Canadian investigation from Quebec [79] conducted in 100 T1D adults showed that the 4 main limitations for exercising were : fear of hypoglycemia (the highest barrier), work schedule, loss of control over diabetes and low levels of fitness. However, further studies are needed in large samples of children and adolescents with T1D in order to determine what are the main barriers to physical activity participation in this age group. It is possible that, like in adults, a fear of hypoglycemia and low levels of fitness could represent strong barriers.

Two possible barriers to physical activity in youth with T1D: Exercise-induced hypoglycemia and low fitness levels

Exercise induced hypoglycemia: Most studies about T1D children and adolescents acknowledge the fact that blood glucose levels decrease during moderate intensity continuous exercise (Table 3). Thus, the fear of hypoglycemia could become a major barrier to physical activity participation in this population. However, when T1D children and adolescents stop their insulin pump basal rate altogether [80], or decrease it by 20% [81] or 50% [82] during a moderate intensity continuous exercise, hypoglycemia occurrence risk is lowered during the activity [80], but also during the following night [81]. Importantly, if exercise is performed at the same time as peak insulin (fast acting) action or during insulin bolus action, it is recommended to anticipate the activity and to decrease the insulin dose at the meal before exercise from 30 to 100%, depending on the duration and intensity of the activity [83,84]. However, the reduction in basal insulin delivery could also enhance hyperglycemia events in early recovery [80] and during the subsequent evening [81] (Table 3). The timing of basal insulin reduction should be about 60-90 minutes before the start of exercise to allow for circulating insulin levels to already be diminished by the time exercise starts [85].

Table 3: Evolution of blood and plasma glucose concentration in T1D according to different exercise type.

An alternative to insulin modification, to prevent hypoglycemia, is to vary the type of exercise performed (duration, intensity, modality). It has been shown in T1D adults that the addition of sprints before (45 min muscle strength exercise [86]), during (sprint: 4 sec every 2 min [87,88], or 15 sec every 2 min [89]) or after (10 sec once [90]) moderate intensity endurance exercise (40 to 60 % of maximal aerobic power during 20 to 45 min) attenuates the drop in blood glucose, or the occurrence of subsequent hypoglycemia, compared to when just moderate intensity exercise is performed. In young patients with T1D, only one study compared the effects of high intensity intermittent exercise (6 times 3 min at 70% of maximal aerobic power with 1.5 min recovery) with moderate intensity exercise (60 min at 40% of maximal aerobic power) [91]. The authors found that the former exercise protects against late-onset hypoglycemia (Table 3). This positive effect of adding sprints or high-intensity exercise might be the result of increased stress hormones secreted (epinephrine or cortisol) [91].

It is important to note that hypoglycemia is not the only concern with exercise for patients with T1D. Indeed, hyperglycemia can occur, particularly if blood insulin levels are insufficient during the activity, or if very high intensity exercise is performed [82,92,93].

Physical fitness impairment in young T1D: It has recently been shown in 304 young T1D that physical activity level and self-perceived physical fitness are significantly related [94]. In addition, literature suggests that aerobic fitness (measured or estimated with maximal incremental test or submaximal test respectively) decreases with age in young T1D. So in T1D prepubescent boys, aerobic fitness is reported to be preserved [95,96] whereas it might already be declined in girls at the same age [96].

In adolescents, aerobic fitness is often impaired in boys [19,96-99] and girls [96,98-100] compared to healthy peers. This impairment in aerobic fitness is even more pronounced when diabetes control is poor [39,50,96,97,101-103]. Only 3 studies [21,50,91] have shown that physical fitness is normal in T1D adolescents, perhaps because physical activity levels were also high. Also, T1D girls presented lower values compared to T1D boys, but this gender difference was not observed in healthy adolescents [50]. This deterioration in the fitness of girls could partly be explained by the fat mass gain that occurs during puberty [37,104].

Physical activity is challenging for the child with T1D. The child and his or her family member, teacher, coach and friends need to be aware of the basic strategies to prevent hypoglycemia and maintain reasonable glucose control. Initial glycemia, time of the last rapid acting insulin injection, injection site, diet, time of the day, exercise type, etc. are all factors to be considered in order to anticipate the hypoglycemic or hyperglycemic effect of exercise (Figure 1 and 2). Moreover, the individual response to exercise can be different for each patient and sometimes even within a patient, thus making general recommendations around exercise and blood glucose management strategies difficult. Therefore, it would be interesting in future investigations to study different individualized responses to exercise, while taking into consideration the previously shown parameters that are established to influence glucose control. Thus, it could be possible to better anticipate glycemic variations during exercise and recovery. These tests could be taken into consideration in the patient’s therapeutic approach.

Figure 1: Physiological mechanisms of hypoglycemia during exercise.

Figure 2: Hypoglycemic or hyperglycemic effect during exercise?

Glycemic variations during exercise do not mean that regular exercise is not beneficial. Indeed after each exercise session, insulin receptor sensitivity improves. Moreover, regular exercise allows for the continued increase muscle mass, and muscle tissue is the single greatest “consumer” of glucose, even at rest. So physical activity, through muscle mass increase can contribute to improve glycemic control. Moreover, exercise clearly offers many health and psychological benefits. Unfortunately, T1D patients do not seem to be involved enough in exercising to reach the daily recommendations. Further studies would help to specify the barriers to physical activity, especially in young T1D girls. This information could be useful to help young patients and their families with improved self-management programs.