**The Effects of Energy Intake, Insulin Therapy and Physical Activity on Glucose Homeostasis in Children and Adolescents with Type 1 Diabetes Mellitus**

Aleksandra Żebrowska, Marcin Sikora, Przemysława Jarosz-Chobot, Barbara Głuchowska and Michał Plewa

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/57590

**1. Introduction**

Insulin therapy, dietary management, and physical activity constitute an essential element in prevention and treatment for children and adolescents with type 1 diabetes mellitus (T1DM). Regular physical activity positively affects metabolic and cardiovascular functions, and its benefits include enhanced insulin sensitivity, decreased fat mass, improved lipid profile and cardiovascular fitness [1-5]. All of these metabolic changes prevent the development of metabolic syndrome, decrease the risk of type 2 diabetes mellitus (T2DM), and are beneficial for patients with type 1 diabetes mellitus (T1DM) [6-12].

The classification of the American Diabetes Association defines four major forms of diabetes mellitus [13]. The major groups are: type 1 and type 2, gestational diabetes and diabetes due to other known causes. Type 1 diabetes mellitus is characterized by beta cell destruction caused by an autoimmune process, usually leading to absolute insulin deficiency [14-15]. Type 1 diabetes is also subdivided according to whether cell destruction is caused by the immune or other processes, and be classified as type1A or type 1B diabetes mellitus [13-14]. Type 1 diabetes, formerly known as juvenile-onset diabetes, accounts for 10-15 percent of all cases of diabetes mellitus. Approximately one-half of individuals develop the disease within the first two decades of life, making T1DM one of the most common chronic diseases of childhood. The reports of World Health Organization on the incidence of T1DM showed the greatest increase in the incidence rate among young children aged 4 to 9 years. Such high increase of incidence rate of type 1 diabetes mellitus suggests an epidemic tendency in many countries [17-18]. The

© 2014 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

fact that the incidence of type 1 diabetes mellitus is the highest among young population has increased the interest in the role of physical activity in the treatment of the disease [7, 16].

(ie. GLUT 4) and enzymes to exercising muscles [39]. At rest, muscles mainly draw their energy from fats; hormonal control is a result of balance between insulin and glucagon secretion.

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The metabolic adaptation during exercise is sequentially characteristic for each different phase of requirement of the exercising muscle. The first mechanism available for muscle contraction is to access energy from adenosine triphosphate (ATP) breakdown. Then, the high-energy phosphate from creatine phosphate (CP) is used to resynthesize ATP from adenosine diphos‐ phate (ADP). The limited supplies of CP in the muscle require increased energy production from the non-oxidative (anaerobic) glycolytic pathway [40]. The fuel for this pathway is glucose from the blood or glucose stored in the muscle in the form of glycogen. The end product of glycolysis is pyruvic acid, which may be further processed to produce energy in the oxidative pathway or can be removed to form lactic acid or alanine. In muscle cell mitochon‐ dria, the oxidative pathway can use fats or lipids as a fuel. Both glucose, through the formation of pyruvic acid, and lipids are oxidized in the tricarboxylic acid (TCA) cycle (Krebs cycle) [41]. It is well documented that the ATP resynthesis depends on glucose transport into the cell [42-43]. One of the beneficial effects of exercise on glucose homeostasis in people with diabetes is a marked stimulation of blood glucose utilization via the insulin independent mechanism. Increased synthesis of GLUT-4 through insulin-independent pathway in the muscles results in the enhancement of the glycolytic and oxidative energy produced during exercise and postexercise glycogen stores [44]. Increased glucose uptake is usually observed after a single bout

Muscle cells differ in their contractile and metabolic properties [47]. Their different recruitment depends on the exercise intensity and duration [48]. All the aforementioned processes allow describing the fuel mobilization and muscle metabolism at three levels of exercise intensity ie: low-, moderate-, and high-intensity exercise. During low-intensity exercise, energy for muscle contraction is supplied predominantly by oxidation of carbohydrates and free fatty acids (FFAs) mobilized from the adipose tissue and supplied by intramuscular triglycerides (TGs). The predominance of oxidative metabolism during low-intensity exercise is a consequence of selective recruitment of oxidative muscle fibers (type I). At moderate-intensity exercise, performed in the range of 50% to 75% of VO2max, approximately half of the expended energy is derived from intramuscular lipids whereas the rest is derived from carbohydrates. Muscle glycogen and blood glucose contribute to carbohydrate utilization in 80 and 20%, respectively. Adipose tissue FFAs provide a bit more than half of the lipid fuel, and the rest is supplied by intramuscular TGs [49]. This pattern of fuel use is a consequence of the metabolic characteristics

of the type IIa muscle fiber recruited during moderate-intensity exercise [50].

At high-intensity exercise (above 80% of VO2max), about three quarters of total energy cost of exercise is supplied by glucose mainly derived from muscle glycogenolysis [36, 51]. FFA secretion is blocked by the vasoconstrictive action of catecholamine and increased concentra‐ tion of lactic acid. High concentrations of lactate indirectly facilitate carbohydrate metabolism [52]. High concentrations of glycolytic enzymes activate ATP hydrolysis and anaerobic glycolysis [53]; type IIb glycolytic muscle fibers are preferentially recruited during high-

of exercise even when insulin level decreases [45-46].

intensity exercise [54-55].

Insulin is a hormone produced by the pancreatic β cells. It is not only central to regulating carbohydrate, protein and fat metabolism, but also acts as a critical T1DM autoantigen. Autoimmune distraction of pancreatic β cells leads to insulin deficiency and consequent metabolic decomposition of glucose homeostasis [19-22].

Multidisciplinary research on the pathogenesis of T1DM indicates an involvement of genes predisposing to autoimmune damage to the pancreatic β cells [23-24]. It has been suggested that type 1 diabetes is a complex polygenic disease. The main susceptibility genes code for polymorphic HLA molecules and, in particular, alleles of class II MHC genes [15, 25]. Risk of T1DM progression is conferred by specific HLA DR/DQ alleles (e.g., DRB1\*03-DQB1\*0201 [DR3] or DRB1\*04-DQB1\*0302 [DR4]. The HLA alleles such as DQB1\*0602 are associated with dominant protection against the disease [26]. Polymorphism of a variable nucleotide tandem repeat of the proinsulin gene and a single amino acid change of a gene termed PTPN22, a tyrosine phosphatase that influences T cell receptor signaling, are associated with increased risk for diabetes [15]. In physiological conditions there is balance between pathogenic T cells that mediate disease and regulatory cells that control autoimmunity. However, in T1DM, the balance between pathogenic and regulatory T cells is altered [27]. Thus, the ability to identify individuals at high risk for type 1 diabetes using genetic and/or autoantibody markers has been a main goal of the diabetes research and T1DM prediction strategies [20, 28].

Early diagnosis has expanded the chance for pharmacological treatments for diabetic children and adolescents. Autoimmune destruction of insulin-producing pancreatic β cells requires constant administration of various insulin preparations designed to meet basal and mealdependent insulin requirements. In recent years, several new insulin analogs have been developed including short-acting insulin analogs with different pharmacokinetic properties [29-30]; the preparations have been recommended for tight control of blood glucose concen‐ trations and significantly reduction of diabetic complications [31].

There is compelling evidence indicating that individuals who have been using intensive insulin therapy should participate in regular physical activity [1, 7, 32]. Findings from most experimental and questionnaire studies in youth suggest a positive relationship between physical activity and health benefits [33-35]. Regular physical activity in people with diabetes increases the capacity to maintain appropriate plasma glucose levels and enhan‐ ces the patient's metabolic capacity during and after exercise [36-37]. However, in chil‐ dren and adolescents with type 1 diabetes, it may also be responsible for the occurrence of some adverse reactions such as hypoglycemia, hyperglycemia, ketosis and diabetesrelated complications. These effects of exercise on glycemic control depend on several factors, such as starting levels of glycaemia, type, intensity of exercise, and the use of exogenous insulin and insulin secretagogues [38].

Contraction of skeletal muscle increases glucose metabolism through an insulin-independent pathway. In this mechanism, glucose delivery is facilitated by an increase in blood flow to the working muscle groups. Regular aerobic exercise increases the synthesis of glucose transporter (ie. GLUT 4) and enzymes to exercising muscles [39]. At rest, muscles mainly draw their energy from fats; hormonal control is a result of balance between insulin and glucagon secretion.

fact that the incidence of type 1 diabetes mellitus is the highest among young population has increased the interest in the role of physical activity in the treatment of the disease [7, 16].

Insulin is a hormone produced by the pancreatic β cells. It is not only central to regulating carbohydrate, protein and fat metabolism, but also acts as a critical T1DM autoantigen. Autoimmune distraction of pancreatic β cells leads to insulin deficiency and consequent

Multidisciplinary research on the pathogenesis of T1DM indicates an involvement of genes predisposing to autoimmune damage to the pancreatic β cells [23-24]. It has been suggested that type 1 diabetes is a complex polygenic disease. The main susceptibility genes code for polymorphic HLA molecules and, in particular, alleles of class II MHC genes [15, 25]. Risk of T1DM progression is conferred by specific HLA DR/DQ alleles (e.g., DRB1\*03-DQB1\*0201 [DR3] or DRB1\*04-DQB1\*0302 [DR4]. The HLA alleles such as DQB1\*0602 are associated with dominant protection against the disease [26]. Polymorphism of a variable nucleotide tandem repeat of the proinsulin gene and a single amino acid change of a gene termed PTPN22, a tyrosine phosphatase that influences T cell receptor signaling, are associated with increased risk for diabetes [15]. In physiological conditions there is balance between pathogenic T cells that mediate disease and regulatory cells that control autoimmunity. However, in T1DM, the balance between pathogenic and regulatory T cells is altered [27]. Thus, the ability to identify individuals at high risk for type 1 diabetes using genetic and/or autoantibody markers has

been a main goal of the diabetes research and T1DM prediction strategies [20, 28].

trations and significantly reduction of diabetic complications [31].

exogenous insulin and insulin secretagogues [38].

Early diagnosis has expanded the chance for pharmacological treatments for diabetic children and adolescents. Autoimmune destruction of insulin-producing pancreatic β cells requires constant administration of various insulin preparations designed to meet basal and mealdependent insulin requirements. In recent years, several new insulin analogs have been developed including short-acting insulin analogs with different pharmacokinetic properties [29-30]; the preparations have been recommended for tight control of blood glucose concen‐

There is compelling evidence indicating that individuals who have been using intensive insulin therapy should participate in regular physical activity [1, 7, 32]. Findings from most experimental and questionnaire studies in youth suggest a positive relationship between physical activity and health benefits [33-35]. Regular physical activity in people with diabetes increases the capacity to maintain appropriate plasma glucose levels and enhan‐ ces the patient's metabolic capacity during and after exercise [36-37]. However, in chil‐ dren and adolescents with type 1 diabetes, it may also be responsible for the occurrence of some adverse reactions such as hypoglycemia, hyperglycemia, ketosis and diabetesrelated complications. These effects of exercise on glycemic control depend on several factors, such as starting levels of glycaemia, type, intensity of exercise, and the use of

Contraction of skeletal muscle increases glucose metabolism through an insulin-independent pathway. In this mechanism, glucose delivery is facilitated by an increase in blood flow to the working muscle groups. Regular aerobic exercise increases the synthesis of glucose transporter

metabolic decomposition of glucose homeostasis [19-22].

72 Glucose Homeostasis

The metabolic adaptation during exercise is sequentially characteristic for each different phase of requirement of the exercising muscle. The first mechanism available for muscle contraction is to access energy from adenosine triphosphate (ATP) breakdown. Then, the high-energy phosphate from creatine phosphate (CP) is used to resynthesize ATP from adenosine diphos‐ phate (ADP). The limited supplies of CP in the muscle require increased energy production from the non-oxidative (anaerobic) glycolytic pathway [40]. The fuel for this pathway is glucose from the blood or glucose stored in the muscle in the form of glycogen. The end product of glycolysis is pyruvic acid, which may be further processed to produce energy in the oxidative pathway or can be removed to form lactic acid or alanine. In muscle cell mitochon‐ dria, the oxidative pathway can use fats or lipids as a fuel. Both glucose, through the formation of pyruvic acid, and lipids are oxidized in the tricarboxylic acid (TCA) cycle (Krebs cycle) [41]. It is well documented that the ATP resynthesis depends on glucose transport into the cell [42-43]. One of the beneficial effects of exercise on glucose homeostasis in people with diabetes is a marked stimulation of blood glucose utilization via the insulin independent mechanism. Increased synthesis of GLUT-4 through insulin-independent pathway in the muscles results in the enhancement of the glycolytic and oxidative energy produced during exercise and postexercise glycogen stores [44]. Increased glucose uptake is usually observed after a single bout of exercise even when insulin level decreases [45-46].

Muscle cells differ in their contractile and metabolic properties [47]. Their different recruitment depends on the exercise intensity and duration [48]. All the aforementioned processes allow describing the fuel mobilization and muscle metabolism at three levels of exercise intensity ie: low-, moderate-, and high-intensity exercise. During low-intensity exercise, energy for muscle contraction is supplied predominantly by oxidation of carbohydrates and free fatty acids (FFAs) mobilized from the adipose tissue and supplied by intramuscular triglycerides (TGs). The predominance of oxidative metabolism during low-intensity exercise is a consequence of selective recruitment of oxidative muscle fibers (type I). At moderate-intensity exercise, performed in the range of 50% to 75% of VO2max, approximately half of the expended energy is derived from intramuscular lipids whereas the rest is derived from carbohydrates. Muscle glycogen and blood glucose contribute to carbohydrate utilization in 80 and 20%, respectively. Adipose tissue FFAs provide a bit more than half of the lipid fuel, and the rest is supplied by intramuscular TGs [49]. This pattern of fuel use is a consequence of the metabolic characteristics of the type IIa muscle fiber recruited during moderate-intensity exercise [50].

At high-intensity exercise (above 80% of VO2max), about three quarters of total energy cost of exercise is supplied by glucose mainly derived from muscle glycogenolysis [36, 51]. FFA secretion is blocked by the vasoconstrictive action of catecholamine and increased concentra‐ tion of lactic acid. High concentrations of lactate indirectly facilitate carbohydrate metabolism [52]. High concentrations of glycolytic enzymes activate ATP hydrolysis and anaerobic glycolysis [53]; type IIb glycolytic muscle fibers are preferentially recruited during highintensity exercise [54-55].

It has been well documented that participation in low and moderate-intensity exercise by individuals with T1DM results in decreased blood glucose concentrations [6, 56-57]. In patients with diabetes, the effect of low-to-moderate intensity exercise varies according to the starting levels of glycaemia. In T1DM patients with pretraining hyperglycemia and ketosis resulting from insulin underdosing, a session of moderate-intensity exercise may increase hyperglyce‐ mia [36, 58]. In contrast, when patients with type 1 diabetes are treated with insulin and display mild to moderate hyperglycemia, exercise can lower plasma glucose concentrations thus preventing an episode of hypoglycemia [59-60].

**2. Methods**

**3. Measures**

**2.1. Study participants**

The study group comprised a total of 53 (27 girls and 26 boys) children and adolescents with type 1 diabetes mellitus (T1DM). Mean age was 11.8 ± 2.4 years (range 5 to 17 years); duration of diabetes was 2.8 ± 1.6 years (Table 1). All subjects lived and attended schools in Silesian Industrial Region in Poland and were recruited at the Diabetes Clinic of the Silesian Center for Child Health. They were treated with recombinant human insulin divided into daily doses, and performed self-monitoring of blood glucose on glycaemic control. The types of insulin used were: NovoRapid, Lantus, Humalog, Apidra. Only patients free of diabetic complications were enrolled. The other criteria for inclusion were no personal history of other cardiovascular or metabolic diseases, no simultaneous participation in another clinical trial, being free of any

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The medical history and information about diabetes etiology of the study participants were prepared by medical personnel. The adolescents and their parents were presented with a comprehensive description of the aim and methods of the study. Written consents were requested and obtained from all parents. The study protocol was approved by the Ethics Committee of the Academy of Physical Education in Katowice, Poland, and conformed to the

Height and body mass (mean ± SD) of the participants were measured according to standard procedures [78]. Body mass index (BMI) was calculated as weight (kg) divided by height (m) squared. All subjects were characterized by normal-weight according to international BMI

The first group were monitored during their school classes (GrS; n=25). We assessed glycemia, diet and physical activity during the school day and leisure time. The other group comprised participants of a rehabilitation programme at a summer camp for diabetic children, organized

Physical activity (PA) assessment was performed using accelerometers (accelerometer ActiGraph GT3X+, USA). The first PA indicator was the number of steps per day (steps/day) while the other indicator was daily energy expenditure of physical activity (kcal/kg/day). According to recommendations, the children wore a device placed firmly on an elastic belt on the right hip. During the seven-day monitoring period, the accelerometers were taken off only at bedtime and before potential contact with water [33, 80-81]. The criteria of the 2001–2002 President's Challenge Physical Activity and Fitness Awards Program were used to assess physical activity [82]. The authors recommended that the daily number of steps, hops or position changes should be about 13,000 in boys and 11,000 in girls at least 5 days a week for

by the Polish Society for Children and Youth with Diabetes. (GrR; n=28).

acute infections up to one week prior to the study, and HbA1c < 7.5%.

standards set by the Declaration of Helsinki.

cutoff values and BMI centiles [79] (Table 1).

The currently available data suggest that patients with T1DM are less likely to develop hypoglycemia during high-intensity exercise than when they engage in low-intensity exercise [57, 61]. There is evidence that high-intensity exercise added to low-or moderate-intensity exercise may maintain blood glucose levels within the normal physiological range and thus minimize the risk of hypoglycemia [62-63]. Guelfi et al. 2005 first demonstrated beneficial effects of the above mentioned exercise combinations on blood glucose levels. The effect is partly due to the fact that intermittent high-intensity exercise (defined as exercise involving repeated bouts of short duration), intense activity and alternating intervals of low-to moderateintensity exercise are typical of many field sports and spontaneous physical activity in children and adolescents [36, 64-65].

The knowledge of the interactions between specific insulin preparations and various forms of exercise is essential to optimizing glycaemic control with minimizing the potential for derangements in glucose homeostasis [66]. The challenge in diabetic patients is to maintain glucose control during physical activity of varying intensity and to effectively decrease hyperglycemia as a result of lower catecholamine levels [67-68].

One of the most important therapeutic recommendations in type 1 diabetes is to lower the percentage of serum glycated hemoglobin, a long-term indicator of glycaemic status [69-70]. Glycated hemoglobin A1c (HbA1c) indicates the percentage of total hemoglobin that is bound by glucose and is formed in a non-enzymatic glycation pathway by hemoglobin's exposure to plasma glucose. International Expert Committee has recently recommended that HbA1c might be a better means of diagnosing diabetes than measuring fasting and/or post-challenge glucose, and established HbA1c ≥ 6.5% as the cut point for diagnosing the disease [69-73].

Type 1 diabetes is among the most common chronic conditions in childhood, occurring with increasing frequency, particularly in children aged five years or less [74]. Considering its complexity as well as invasive and continuous treatment, the disease can have a significant effect on children, parents and other family members by affecting many aspects of their lives. One of the beneficial effects of exercise on glucose homeostasis in people with diabetes is a marked stimulation of blood glucose utilization via the insulin independent mechanism. However, the effect of exercise on glycemic control in diabetes depends on several factors including exercise intensity, starting levels of glycaemia and use of exogenous insulin [75-77]. Therefore, the aim of the study was to investigate the effect of physical activity on glycaemic control in children and adolescents suffering from type 1 diabetes mellitus. Another study objective was to evaluate changes in glucose concentrations, glyceaemia, and glycated hemoglobin level in diabetic patients in response to regular exercise during diabetes camps.
