The Diabetic Athlete
Chapter 34 The Diabetic Athlete JØRGEN JENSEN AND BRENDAN LEIGHTON Introduction Diabetes mellitus is a disease of abnormal regulation of glucose metabolism, resulting in an elevated blood glucose concentration which may arise for different reasons. Consequently, the treatments of the disease are varied. Exercise training for people with diabetes mellitus must also be viewed in the light of the aetiology of the disease, as the physiological response to exercise can differ. In one form of diabetes mellitus, training is regarded as a cornerstone in the treatment of the disease, whereas training is a challenge in the other form of diabetes. Diabetes mellitus is classiﬁed into two distinct types: 1 Insulin-dependent diabetes mellitus (IDDM, or type I or juvenile diabetes), which requires insulin replacement on a daily basis because insulin secretion is almost totally lacking. 2 Non-insulin-dependent diabetes mellitus (NIDDM, or type II), in which the early pathological lesion is a decreased sensitivity of skeletal muscle and liver to insulin (insulin resistance). The initial period of insulin resistance is associated with increased circulating concentrations of insulin, but the blood glucose concentration remains normal. NIDDM develops when the pancreatic b-cell is no longer able to secrete the appropriate amount of insulin to maintain adequate blood glucose concentrations and hyperglycaemia is the direct consequence. The incidence of diabetes mellitus has increased during recent decades. In particular, the incidence of NIDDM has increased dramatically and up to 10–20% of people over 65 years old suffer from NIDDM in many countries. NIDDM is associated with an increased risk for many diseases such as coronary heart disease, neuropathy, renal failure, and blindness (Kahn 1998). In NIDDM, the management of blood glucose concentration with prescribed pharmaceutical drugs is poor and diet and regular physical exercise are important therapeutic treatments for the disease. Only a small portion of diabetics (about 10%) are IDDM, but this group requires particularly close monitoring because IDDM develops early in life. Exercise training and physical activity are natural things for children to do and the opportunity to participate in sports is important for social development. IDDM is treated with insulin and the combination of exercise training and insulin injection may cause too high a stimulation of peripheral glucose uptake, resulting in hypoglycaemia. The requirement of insulin is inﬂuenced by exercise and the dose of insulin must therefore be varied with the intensity and duration of exercise. Thus, in people with IDDM physical exercise must be regarded as a challenge, but, with education and management, people with IDDM can participate in exercise training together with non-diabetics, and can achieve the same health beneﬁts. Regulation of carbohydrate and fat metabolism during exercise In working skeletal muscle, the demand for for- 457 458 special considerations mation of adenosine triphosphate, which fuels muscle contraction, increases enormously (Newsholme & Leech 1983). The formation of adenosine triphosphate is driven by increased ﬂux through glycolysis and the tricarboxylic cycle. Exercise mobilizes intramuscular fuels in the form of glycogen and triacylglycerol to supply glucose moieties and fatty acids, respectively. Exogenous fuels, in the form of glucose and nonesteriﬁed fatty acids (NEFA), are also taken up from the blood and oxidized together with intramuscular fuels. The glucose concentration in the blood, however, remains relatively stable because the rate of peripheral glucose uptake is matched by the rate of release of glucose into the circulation. Regulation of blood glucose concentration is complex and, in addition to exercise, several hormones participate in this regulation. Insulin is the major hormone regulating the removal of glucose from the blood. Glucose entering the circulation may be absorbed from the intestine (from food or glucose drinks) but most of the time glucose is released from the liver as a result of glycogen breakdown or glucose synthesized via gluconeogenesis. During exercise, the concentrations of glucagon, catecholamines, cortisol and growth hormone all increase and these hormones stimulate glucose release from the liver and ensure that blood glucose concentration remains relatively constant (Cryer & Gerich 1985). The hormones that stimulate glucose release into the blood (and inhibit glucose uptake) are often called counter-regulatory hormones. The rate of glucose uptake is elevated in skeletal muscle during exercise, although the insulin concentration decreases during exercise. Several studies have shown that glucose uptake is stimulated by exercise, even in the absence of insulin (Richter 1996) and the reduction of insulin concentration during exercise may be important for avoiding hypoglycaemia (Cryer & Gerich 1985). Insulin is a strong inhibitor of lipolysis in fat cells and of glucose release from the liver. A fall in the insulin concentration is important to optimize the supply of NEFA to the contracting muscles. The decrease in basal insulin concentration aids the release of NEFA from adipose tissue and glucose from the liver. During prolonged exercise, the concentration of glycogen in skeletal muscles decreases and glucose uptake from the blood becomes gradually more important. When skeletal muscles are depleted of glycogen, glucose uptake may account for nearly all carbohydrate oxidation (Wahren et al. 1971). When the liver is depleted of glycogen, glucose is released at much lower rates and the blood glucose concentration decreases. A decrease in blood glucose concentration is well recognized as a major factor in the fatigue that accompanies endurance exercise, and the reduced supply of carbohydrate to the central nervous system and to the muscle may both be factors in the fatigue process (Costill & Hargreaves 1992). The intensity of exercise is also an important determinant of the rate of carbohydrate utilization. During exercise of an intensity of about 50% . of Vo2max., the energy comes equally from fat and carbohydrate metabolism and, as the intensity of the exercise increases, the percentage contribution from carbohydrates rises. At intensities . of exercise above 80% Vo2max., carbohydrates become the major metabolic fuel. At this intensity of exercise, glucose uptake is also much higher, and depletion of liver glycogen will occur in 1–2 h followed by a decrease in concentration of blood glucose. During exercise of short duration and high intensity, on the other hand, the hepatic glucose output can exceed the rate of glucose uptake and lead to hyperglycaemia. Regulation of carbohydrate and fat metabolism after exercise The ability to convert chemical energy to fuel skeletal muscle contraction is essential for human movement. Skeletal muscles have, however, also an important role for regulation of the blood glucose concentration, as most of the glucose disposal stimulated by insulin occurs in skeletal muscle (Shulman et al. 1990). After a carbohydrate-rich meal, the increased the diabetic athlete concentration of glucose in the blood causes a release of insulin from the b-cells in the pancreas. Insulin binds to its receptor and stimulates glucose transport and metabolism, particularly in heart, skeletal muscle and adipose tissue. The signalling pathway for insulin has been studied extensively and during the last decade the mechanism of action of insulin has become much clearer (Kahn 1998). Glucose is transported into cells by proteins called glucose transporters. There are different isoforms of the glucose transporters and their expression is tissue speciﬁc (Holman & Kasuga 1997). GLUT-4 is expressed in tissue where insulin stimulates glucose uptake (skeletal muscle, heart and adipose tissue) and GLUT-4 is named the insulin-regulated glucose transporter. Insulin stimulates glucose uptake by recruitment of GLUT-4 from intracellular sites to the sarcolemmal membrane (Fig. 34.1). GLUT-4 is normally located in vesicles in the cells, but during insulin stimulation, GLUT-4 is translocated to the cell membrane by exocytosis (Holman & Kasuga 1997). When GLUT-4 transporter proteins are in the sarcolemmal membrane, they will transport glucose into the cells, and the amount of GLUT-4 in the sarcolemmal membrane is regarded as the regulatory step for glucose uptake. GLUT-4 will be internalized when the insulin stimulation is 459 removed and glucose transport will decrease to basal level again. Skeletal muscle makes up 30–40% of the body weight and the 70–90% of the insulin-stimulated glucose uptake occurs in this tissue (Shulman et al. 1990). Therefore, it is evident that skeletal muscles play a central role in regulation of glucose metabolism. Glucose taken up in skeletal muscle during insulin stimulation is incorporated into glycogen (Shulman et al. 1990), but skeletal muscles are unable to release glucose into the bloodstream to maintain blood glucose concentration. Skeletal muscle glycogen can, however, be broken down to lactate and released from skeletal muscle for conversion to glucose in the liver via gluconeogenesis. Skeletal muscle glycogen is therefore indirectly a carbohydrate source for maintaining blood glucose. Exercise recruits GLUT-4 to the sarcolemmal membrane in a manner similar to the effects of insulin. Although both exercise and insulin stimulate glucose uptake by translocation of GLUT-4 to the sarcolemmal membrane, this process seems to occur via different signalling pathways (Richter 1996) and exercise stimulates glucose uptake even in insulin resistant muscles (Etgen et al. 1996). Another effect of exercise is that insulin sensitivity increases in skeletal muscle after exercise (Richter 1996). This means that lower insulin br em m l el Insu li C Glucose transport ane Fusion Fission Vesicle + GLUT-4 Fig. 34.1 Schematic illustration showing regulation of glucose transport in skeletal muscle. When insulin binds to the insulin receptor, GLUT-4-containing vesicles are translocated to the sarcolemmal membrane. GLUT-4 transports glucose into the cell when they are located in the sarcolemmal membrane. In insulin-resistant muscles, translocation is reduced in response to insulin. 460 special considerations concentrations are required to remove glucose, and in line with this, highly trained people have lower circulating insulin levels and a reduced insulin response to a glucose challenge. However, the increased insulin sensitivity during and after exercise increases the risk for hypoglycaemia in insulin-treated diabetics. Insulin-dependent diabetes mellitus In people with IDDM, insulin secretion is lacking or insufﬁcient because of an almost total destruction of the insulin secreting b-cells in the pancreas. The b-cells are destroyed by the diabetic’s own immune system (autoimmune destruction). IDDM is treated with life-long insulin therapy by insulin injection several times each day. Insulin is produced as long-acting (elevates blood insulin concentration for many hours) and rapid-acting (elevates blood insulin for a much shorter period of time) forms and most patients take a mixture of both forms. In the evening (and some times morning), long-acting insulin is injected to maintain the basal insulin concentration. Before each meal, rapid-acting insulin is injected to stimulate removal of the absorbed glucose. The insulin dose required depends on the individual and it is important to measure glucose concentration often to establish the correct dose. Exercise training for IDDM IDDM normally develops at a young age and exercise is a natural activity for children. It is particularly important for their social development that they get the opportunity to participate in group exercises with other children. Although some children with IDDM develop fear of participation in sports, exercise is regarded as safe if children with IDDM are educated to adjust their dose of insulin to the intensity of exercise. Many people with IDDM participate in sport and there are several examples of athletes at the top of their sports. These athletes clearly show that it is possible for diabetic athletes to achieve a high performance level. In non-diabetics, exercise training causes adaptations in skeletal muscle and circulatory system which is the background to the increased performance (Holloszy & Booth 1976). People with IDDM seem, however, to respond to training in a similar way and there are therefore no physiological reasons for not participating in sport (Wallberg-Henriksson 1992). Exercise training for people with IDDM is, however, not without problems. The insulin concentration is important for control of the glucose concentration and too high a concentration of insulin in combination with exercise may cause hypoglycaemia. Too low a concentration of insulin, on the other hand, may cause elevation in blood glucose and ketoacidosis. The greatest problem is the development of hypoglycaemia because of the inability to regulate prevailing blood insulin concentrations. In people with IDDM the insulin concentration in blood will depend on the amount of insulin administered and the rate of release of insulin from the site of injection. The normal decrease in insulin level during exercise will therefore not occur in people with IDDM and, as exercise increases insulin sensitivity, glucose uptake in skeletal muscles may be too high. To mimic the reduction in concentration of insulin that occurs in normal subjects during exercise, insulin injections have to be avoided immediately prior to exercise in people with IDDM. Before exercise, it is important that the glucose and insulin concentrations are neither too high nor too low (Horton 1988). The concentration of glucose should be measured to give information about the insulin level. If the blood glucose concentration is below 5 mm, it may be a result of too high a concentration of insulin and there is a high risk for hypoglycaemia if exercise is performed. It is therefore not advised to participate in exercise, and glucose should be taken to raise the blood glucose concentration before exercise is performed. Furthermore, it is important that athletes with IDDM should be able to recognize the symptoms of hypoglycaemia and respond accordingly. Exercise is not recommended when the blood glucose concentration is above 16 mm (Wallberg- the diabetic athlete Henriksson 1992). Too high a glucose concentration may be a result of a low concentration of insulin. Exercise in under-insulinated diabetics may result in a further increase in blood glucose concentration as the normal inhibition of glucose release from the liver is lacking (WallbergHenriksson 1992). Low insulin concentration will also cause elevated lipolysis and the high concentration of NEFA may increase production of ketone bodies, resulting in ketoacidosis (Wallberg-Henriksson 1992). In case of high glucose concentration, it is recommended that ketone body levels should be checked in urine (Horton 1988). However, if a large meal has been eaten shortly before exercise and minimal rapid-acting insulin is taken, exercise will decrease glucose concentration to a normal level (Sane et al. 1988). Although exercise decreases blood glucose concentration and increases insulin sensitivity in skeletal muscle, exercise may not be regarded as a treatment for IDDM (Kemmer & Berger 1986; Horton 1988; Wallberg-Henriksson 1992). In contrast to NIDDM, training does not seem to improve glycaemic control in IDDM (WallbergHenriksson et al. 1984; Wallberg-Henriksson 1992; Ebeling et al. 1995). Elite athletes require a higher amount of carbohydrates in the diet, which makes the regulation of blood glucose more difﬁcult. Furthermore, participation in elite sport is often accompanied with travelling and other changes in their daily routine which also make administration of insulin more difﬁcult. For elite athletes it is therefore important that the blood glucose is monitored carefully and athletes must learn to correct the insulin requirements to the exercise performed. In learning this, it is recommended that the athletes write down the blood glucose concentration before and after exercise of different type, intensity, and duration and relate it to ingestion of carbohydrates and injection of insulin. Dietary considerations An important part of treatment of IDDM is education. Today it is normal to have a small blood glucose analyser at home to monitor glucose 461 concentration on a regular basis. The dose of insulin needed differs between individuals and the requirement for insulin to handle a meal varies even within the same individual since, for example, exercise increases insulin sensitivity and decreases the requirement for insulin. Ideally, IDDM subjects will want to achieve a normal pattern of food consumption. However, some foods with a high glycaemic index will be absorbed rapidly (e.g. glucose in a soft drink) and this may cause some metabolic problems. Importantly, the amount of insulin taken before a meal should be matched with the anticipated dietary glucose uptake. This means that if the blood glucose concentration is high after a meal, the insulin dose is increased and vice versa. If postprandial exercise is planned, precautions can be taken to improve glucose regulation. To avoid hypoglycaemia, Horton (1988) suggests eating a large meal 1–3 h before planned exercise and to reduce insulin injection before this meal. Although it is difﬁcult to give a standard recommendation, a reduction of 30–50% in rapidacting insulin may be a starting point for adjustment of the dose to endurance exercise. Reduction of the insulin dose before strength training and ball games may be smaller. However, it is important to measure blood glucose concentration frequently, particularly when a new type of exercise is performed or when intensity or duration is changed. The dose of insulin before meals must be optimized to the new and unfamiliar exercises. If the duration of the exercise is more than 30 min, extra glucose should be supplied. This glucose ingestion has two effects in IDDM; avoiding dangerous hypoglycaemia and improvement of performance. As in non-diabetics, glucose ingestion increases performance in prolonged endurance sport. In IDDM, glucose ingestion should also prevent hypoglycaemia. Severe hypoglycaemia causes coma and hypoglycaemic coma is potentially fatal for the diabetic (Cryer & Gerich 1985). The only energy substrate for the brain is glucose and severe brain damage will occur within minutes at very low glucose concentrations (Cryer & Gerich 1985). It 462 special considerations is therefore required that glucose, which can be rapidly absorbed, is available when IDDM athletes perform exercise training, to prevent hypoglycaemia and to reduce the risk of coma if hypoglycaemia occurs. This is particularly important when running or cycling is performed in conditions where it will be difﬁcult to obtain carbohydrates. It seems that ingestion of 40 g carbohydrate · h–1 is sufﬁcient to avoid hypoglycaemia (Sane et al. 1988). Athletes with IDDM performed a 75-km ski race and ingested glucose at an average rate of 40 g · h–1 (more in the later part of the exercise); ingestion of glucose at this rate prevented hypoglycaemia when insulin injection also was reduced (Fig. 34.2). The glucose concentration was, however, in the lower range for many of the IDDM athletes at the end and more glucose may have improved performance. Horton (1988) suggested that glucose should be ingested at a rate of 24 Blood glucose (mmol.I–1) 20 16 70–80 g · h–1 during prolonged exercise. In normal subjects, glucose ingestion at a rate of 60 g · h–1 is recommended (Costill & Hargreaves 1992) and glucose should be ingested at the same rate in athletes with IDDM. Furthermore, in addition to supply of carbohydrates, athletes with IDDM must always be aware of the risk of hypoglycaemia and ingest glucose when symptoms of hypoglycaemia come. Exercise per se stimulates glycogen synthesis after the training session when glucose is available. In diabetics, regulation of blood glucose concentration is normally the focused subject and glycogen synthesis in skeletal muscles is regarded prerequisite for regulation of blood glucose. In sport, on the other hand, the replenishment of muscle glycogen stores is normally viewed from a performance perspective. Muscle glycogen is the most important energy substrate in most types of sport and for optimal performance, it is important that the glycogen stores are replenished after each bout of exercise (Ivy 1991). Glycogen can be synthesized in people with IDDM even in the absence of insulin injection after exercise (Mæhlum et al. 1978). In the absence of insulin, however, only half of the glycogen store seems to be replenished (Fig. 34.3). Injection of insulin is therefore necessary for optimal glycogen synthesis, even though the administration of insulin after exercise increases the risk for hypoglycaemia. 12 Conclusion 8 4 0 10 33 Distance (km) 75 Fig. 34.2 Blood glucose concentration (individual and mean) in athletes with IDDM during a 75-km ski race. The shaded area shows healthy controls. The athletes with IDDM reduced their daily insulin dose by about 35% and ingested about 270 g of carbohydrate during the exercise (36 g · h–1). Adapted from Sane et al. (1988). The nature and intensity of any exercise training programme combined with the personal requirements of a person with IDDM make it difﬁcult to generalize about factors, such as dose of insulin administered before exercise and amount of dietary intake. Monitoring the concentration of glucose prior to any exercise ensures that the performance is not undertaken in conditions which may be adverse for the IDDM subject. If the blood glucose level is low then the intensity of exercise should be decreased or delayed until ingested carbohydrate has time to boost the blood glucose concentration. High blood glucose the diabetic athlete 463 Recovery Exercise Fig. 34.3 Glycogen synthesis in IDDM subjects after exercise in the presence (䊉) or absence (䊊) of insulin. Subjects exercised at 75% of . Vo2max. until exhaustion and received a carbohydrate-rich diet and their normal insulin injection in the control experiment. On the other experimental day, insulin was not injected. Adapted from Mæhlum et al. (1978). Muscle glycogen content (mmol.kg–1 wet wt) 80 60 40 20 0 concentration should lead to the postponement of exercise for the reasons given above. The dose of insulin administered before any exercise should be scaled down to reﬂect the degree of intensity and duration of exercise. However, individual IDDM subjects may have to reach the optimum pre-exercise insulin dose by monitoring post-exercise glucose levels. Non-insulin-dependent diabetes mellitus NIDDM is a world health problem and the disease is often regarded as a disease of abnormal lifestyle. About 90% of all diabetics are NIDDM and the disease develops gradually and is normally associated with obesity and hypertension. Initially, the skeletal muscles and liver becomes insulin resistant, but the body responds by producing more insulin and glucose concentration remains normal. However, as the insulin resistance increases, the pancreas becomes unable to produce enough insulin to regulate the metabolism of blood glucose concentration and hyperglycaemia occurs. The pharmacological treatment of NIDDM is poor. As the muscles are insulin resistant, insulin therapy is not a satisfactory treatment of the disease. There are some other drugs prescribed, such as sulphonylureas and metformin. NIDDM is in most case initially treated with dietary manipulation and exercise. This treatment is sufﬁcient for many people with NIDDM if the 0 2 4 6 8 10 12 Time (h) disease has not progressed too far. Exercise of moderate intensity in people with NIDDM is usually associated with a decrease in blood glucose towards the normal range. A further beneﬁt of regular exercise is that it increases the sensitivity of skeletal muscle to insulin, which will have the beneﬁcial effect of lowering the requirement for circulating insulin concentration. It is important to recognize that exercise also lowers the risk factors for cardiovascular disease in people with NIDDM. Exercise training for NIDDM NIDDM is normally associated with obesity and a low exercise capacity. NIDDM develops later in life than IDDM and the majority of patients are over 50 years old. The aims of exercise training for people with NIDDM are therefore often different from those of young people with IDDM. People with NIDDM are often untrained and an improved level of physical ﬁtness is normally the main goal. As for untrained people in general, there are large opportunities for improvement and training studies have shown that endurance training increases maximum oxygen uptake and oxidative capacity in skeletal muscle (WallbergHenriksson 1992). Obesity may hinder training and a high body mass increases the risk of injury to joints and tendons. In people with NIDDM, it is also important to be aware of the risk for foot problems, particularly in diabetics with peripheral neuropathy, 464 special considerations and good shoes and attention to hygiene must be stressed. In previously untrained NIDDM, the training must start slowly, as with all sedentary individuals who embark on an exercise programme. However, although a larger percentage of energy comes from fat at lower intensity endurance training, it is important to achieve a progressive increase in intensity to obtain the largest improvement in glucose tolerance. Endurance training at higher intensities is probably the most effective way to reduce body weight and increase insulin sensitivity (Koivisto et al. 1986; Kang et al. 1996). In people with NIDDM, insulin-stimulated glucose uptake is reduced in skeletal muscles (Shulman et al. 1990). Much research is directed at ﬁnding the reason for this reduced insulin sensitivity. The amount of GLUT-4 is normal in insulin-resistant muscle but insulin is unable to translocate GLUT-4 to the cell membrane (Etgen et al. 1996). Exercise training, however, stimulates glucose uptake in skeletal muscle and increases insulin sensitivity in insulin-resistant muscles (Koivisto et al. 1986; Etgen et al. 1997). Insulin resistance in skeletal muscle develops prior to NIDDM and endurance training seems to prevent the development of insulin resistance. Furthermore, endurance training increases insulin sensitivity in people with NIDDM and improves the regulation of blood glucose concentration. Strength training is normally not regarded to be as effective as endurance training in increasing insulin sensitivity (Koivisto et al. 1986). However, most people with NIDDM are older, untrained people and with increasing age the skeletal muscle atrophies. Reduction in the mass of muscle available to remove glucose from the blood during insulin stimulation decreases glucose tolerance. Strength training which increases muscle mass in older, untrained people with NIDDM may be more effective than endurance training to increase glucose tolerance. Strength training may, however, cause vascular side-effects and precautions should be taken (Wallberg-Henriksson 1992). Dietary considerations for NIDDM NIDDM is often associated with obesity, hypertension and hyperlipidaemia (Koivisto et al. 1986). Obesity is a risk factor for NIDDM and weight reduction improves insulin sensitivity in skeletal muscles. Weight reduction is therefore, together with training, central in the treatment of most people with NIDDM. For the reduction of body mass, energy intake must be lower than energy utilization and food intake must normally be reduced. Furthermore, a high-fat diet causes insulin resistance in skeletal muscles. People with NIDDM are therefore recommended to reduce their fat intake. Furthermore, in contrast to IDDM, insulin treatment is unable to stimulate glucose disposal after a large meal in NIDDM. Large meals will therefore cause an elevation in blood glucose. It is therefore advised that people with NIDDM eat smaller meals and that the content of complex carbohydrates is high. Hypoglycaemia during and after exercise is not a major problem in NIDDM when the therapy is changed diet and increased exercise training. Pharmacological treatments of NIDDM with insulin, sulphonylureas or metformin may increase the risk of hypoglycaemia. However, the risk for development of hypoglycaemia in pharmacologically treated diabetics with NIDDM is still much lower than in people with IDDM. During exercise, carbohydrate supply is normally not necessary in people with NIDDM and water should be drunk to replace ﬂuid. Replenishment of glycogen stores is important for performance (Ivy 1991). However, in most people with NIDDM, improved regulation of the blood glucose concentration is more important than improved performance. Most of the glucose taken up during insulin stimulation is incorporated into glycogen and a high glycogen concentration in skeletal muscle reduces insulinstimulated glucose uptake ( Jensen et al. 1997). Normal regulation of blood glucose metabolism requires that glucose can be incorporated into glycogen in skeletal muscles and a high glycogen the diabetic athlete content impedes this. The reduced glycogen concentration after exercise in people with NIDDM is important for improved glucose metabolism and reduced glycogen stores will aid the disposal of blood glucose. Conclusion NIDDM is often associated with obesity and reduction of body mass is important to improve glucose metabolism. Exercise increases energy consumption and has an important role is any weight-loss programme. 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