The management of insulin treated diabetes and sport

The management of insulin treated diabetes and sport I Gallen* Introduction Health care professionals encourage people with diabetes to do more exercise, so they might gain from the known benefits of improved glycaemic control and help with weight control, with increased quality of life. Furthermore, the timing of diagnosis of type 1 diabetes often coincides with the period in which people are most likely to become interested in sporting endeavours. For many, continued participation in sport is an essential part of life; for a talented few, sports may offer the pathway to success and fame. It is a tantalising thought that some of the children and young people attending our diabetic clinics may be able to compete in the London Olympic Games in 2012. However, the marked variation in blood glucose during and following exercise, with seemingly inexplicable hypoor hyperglycaemia, combined with poorer physical performance may be discouraging. As professionals who support people with diabetes, we should work to ensure that any sporting aspirations are not undermined by negative experience of diabetes and its treatment. There has been relatively little research to guide the health care professional when advising sportspeople with diabetes, and much of that research available has been largely conducted in subjects using older insulin preparations and regimens. Practical experience thus has an augmented role in this field of diabetic medicine. This article reviews these issues and outlines some potential strategies to assist the sportsperson with diabetes. ABSTRACT People with insulin treated diabetes should be encouraged to exercise, and many will want to perform sports, some at a competitive level. Whilst cardiovascular and muscle physiology is normal in uncomplicated diabetes, the effects of insulin treatment and the various abnormalities in the endocrine response with exercise seen in diabetes may impact on glycaemic control and increase the risk of hypoglycaemia. At higher levels of performance, diabetes may impair maximum performance. Understanding normal physiology of exercise and the changes seen with diabetes enables the athlete and their health care professional to predict the pattern of change in blood glucose with various forms of effort, and thus with appropriate changes in insulin therapy and food intake to manage these changes so that hypoglycaemia is avoided and performance is normalised. Examples of outstanding performance from athletes with insulin treated diabetes are presented and the implications of the use of insulin in competitive sport are discussed. This article reviews these issues and suggests potential strategies for the management of insulin treated diabetes with sport. Copyright 2005 John Wiley & Sons, Ltd. Practical Diabetes Int 2005; 22(8): 307 312 KEY WORDS sport and exercise; insulin treatment; type 1 diabetes Physiology of exercise in health and with diabetes Clearly to help any person with diabetes manage diabetes and exercise successfully, it helps to understand the physiology of exercise. Exercise increases oxygen and fuel demands, met by a synchronised response of the cardiopulmonary and endocrine systems. The increased oxygen demand of muscles is met by increased cardiac output and respiratory effort and, for young adults with uncomplicated type 1 diabetes, maximum oxygen consumption, carbon dioxide output, ventilatory capacity, aerobic capacity and cardiac output are similar to those of non-diabetic subjects. 1 4 The increased energy requirement is met from intramuscular glycogen and by mobilisation of other fuels from remote body stores. 5 It is this metabolic response to exercise which is altered in type 1 diabetes. 6 Muscle contraction quickly uses all available intracellular adenosine tri-phosphate (ATP) levels. This is initially replenished from phosphocreatine, 7 hence the use by some athletes of the supplement creatine to increase the storage capacity of this pathway. Glucose oxidation from intramuscular glycogen soon becomes the major fuel source. As exercise continues, translocation of GLUT-4 transporters to the cell membrane from the intracellular pool enables non-insulin dependent glucose transport into muscle. 8,9 In health, blood glucose concentration is kept within a narrow range during exercise, with muscle glucose utilisation closely balanced by liver glucose release. This stimulation of glucose production is induced by exercise and falling blood glucose, and is controlled by rapidly increasing levels of glucagon, the catecholamines, and later growth hormone. 10,11 If exercise continues, the action of the counter-regulatory hormones Ian Gallen, FRCP, Diabetes Centre, Wycombe Hospital, High Wycombe, UK *Correspondence to: Dr Ian Gallen, Diabetes Centre, Wycombe Hospital, High Wycombe HP11 2TT, UK; e-mail: Ian.GALLEN@sbucks.nhs.uk Received: 20 June 2005 Accepted: 14 July 2005 Pract Diab Int October 2005 Vol. 22 No. 8 Copyright 2005 John Wiley & Sons, Ltd. 307

enables mobilisation of fatty acids and ketones. Given enough oxygen in the muscle these are the preferred fuel source. 12 If the muscles do not have enough oxygen, they cannot burn fats and other fuels and, in this situation, muscles produce lactate, which will eventually limit exercise. There are several important variations in diabetes which impact on the mobilisation of fuels and the control of blood glucose during exercise, and have the potential to reduce performance and stamina, and increase the risk of hypoglycaemia. The most significant factor altering metabolism during exercise in diabetes is that insulin therapy is injected subcutaneously, and insulin lies in depots which takes time for both its absorption and dissipation. Clearly by definition, there can be no significant endogenous portal insulin to regulate hepatic glucose output. Insulin concentrations following subcutaneous injection will result in reversal of the physiological portal to systemic insulin ratio, which may be inappropriately high or low for concurrent glucose levels. 13 The insulin levels required to regulate hepatic glucose output after subcutaneous injection at rest may cause a supra-physiological peripheral concentration, which impairs fuel mobilisation; lipolysis, glycogenolysis and gluconeogenesis are reduced. The counter-regulatory hormone response to exercise, essential for gluconeogenesis and lipolysis may be impaired in type 1 diabetes although it has been reported to be unchanged at lower work levels. 14,15 Whilst there is no difference between the genders, 16 there are different responses between upper limb and lower limb exercise, with arm exercise producing an augmented response. 17 The timing of exercise in the day also has an effect on blood glucose, with the risk of hypoglycaemia during and following exercise being less for exercise in the morning than in the afternoon. 18 The effect of these variations in counter-regulatory response may alter hepatic glucose production, which supports increased muscle glucose uptake during exercise. 19 The net effect of these changes is to produce a potential mismatch between glucose utilisation and production. 14,20 22 Blood glucose levels therefore tend to fall during prolonged exercise, rather than remain constant as is seen in the non-diabetic state. At high exercise intensity, glucose is the exclusive fuel, and blood glucose may fall more quickly. However, if the duration of this high level effort is short, or the subject unfit, the increased counter-regulatory response results in glucose production which exceeds use and, paradoxically, glucose levels may rise. At all levels of intensity, post-exercise insulin release is unavailable to balance the effects of exercise induced catecholamines, growth hormone and glucagon, resulting in post-exercise hyperglycaemia 23,24 and this may not be avoided by the use of continuous subcutaneous insulin infusion pumps. 25 In the later period postexercise, athletes with diabetes are prone to hypoglycaemia. 26 This is the result of improved muscle insulin sensitivity and restoration of hepatic and muscular glycogen. Therefore, blood glucose tends to fall during prolonged exercise, with the risk of hypoglycaemia during exercise. This is partly the result of impaired hepatic glucose output, but may be contributed to by the delayed action of insulin in the subcutaneous depots. However, blood glucose may increase with any exercise that is short, but intense, or has elements of repeated short bursts of effort, between low levels of effort, particularly if it is predominantly upper limb exercise. Alteration of insulin therapy and nutrition in sports People with diabetes and their carers concentrate largely (and appropriately) on the level of and changes in blood glucose concentration. This glucocentric model ignores the importance of other fuels and the rate of flow of glucose from the liver to muscle. The former is extremely important during prolonged aerobic exercise, and the latter during more intense exercise. Unfortunately, neither of these pathways is amenable to real time measurement outside of the exercise lab, and therefore can only be estimated during clinical practice. However, these invisible factors must be borne in mind when considering the diabetic athlete s management. The principle underlying insulin treatment is the integration of the training and event plans, food intake, and basal and bolus insulin requirement. Careful descriptions of the type, timing, intensity and duration of exercise are necessary to anticipate the likely changes in blood glucose. A 60-minute training run at 8 10km/hr (aerobic, mostly lower limb) in the morning is likely to be associated with a significant fall in glucose, and a significant risk of hypoglycaemia later. By contrast, circuit training in the gym or a game of squash (both significant upper limb exercise, with short bursts of anaerobic exercise) at the end of the afternoon are likely to raise blood glucose substantially, with a low risk of later hypoglycaemia. Clearly, extra carbohydrate will assist in the first example, but will add to hyperglycaemia in the second example. Most athletes will require multiple daily injections with short acting or analogue insulins and appropriate basal insulin support overnight. 6,27 Management is essentially similar to that for other insulin treated people with diabetes, in that the dose of insulin has to be titrated against the other variables of food ingestion and exercise. Frequent blood glucose monitoring (up to 10 times daily) is required. A review of insulin injection sites and technique is helpful as both the leg site and inadvertent intramuscular insulin injection provoke hypoglycaemia during exercise. 28,29 There is evidence that the more rapid onset and shorter duration of action characteristic of the analogue insulin lispro 30 32 or insulin aspart will assist in reducing hypoglycaemia and post-prandial hyperglycaemia. 33 One of these is recommended as the bolus component. For some, the use of insulin infusion pumps may seem to offer potentially near-physiological insulin replacement as the insulin infusion rates can be rapidly 308 Pract Diab Int October 2005 Vol. 22 No. 8 Copyright 2005 John Wiley & Sons, Ltd.

adjusted to meet requirements. 34,35 Some athletes may find the pump cumbersome, and current use may be limited by cost. There is considerable controversy regarding which basal insulin is most appropriate. Many diabetologists now use one of the new analogues (insulin glargine or detemir) as their preferred basal insulin. However, the very pharmacological characteristics which optimise glycaemic control (prolonged action and control of gluconeogenesis) may be detrimental for the sportsperson with diabetes. Exercise does not appear to alter the rate of insulin absorption of glargine, but there is a rapid fall in blood glucose with effort. 36 It is not known whether exercise induced fall in blood glucose is greater with glargine, detemir or NPH insulin; however, it is likely that both newer analogues impair fuel mobilisation to a greater degree than NPH insulin. Therefore, care must be exercised in the choice of basal insulin, particularly if the exercise is predominantly prolonged aerobic (running or cycling) in the early part of the day following evening or bed-time injection. It may be necessary, often to the surprise of the person with diabetes, to switch from analogue insulin to NPH to improve performance and reduce the likelihood of hypoglycaemia. However, whichever system of insulin replacement is chosen, a process of trial and error must individualise adjustments to the basic insulin regimen, although some guidelines can be set out. In a study of type 1 diabetic subjects treated on multiple daily insulin regimens, reduction in the pre-exercise, pre-meal insulin dose resulted in near euglycaemia. 37 When the usual insulin dose was given with the breakfast (60g carbohydrates) prior to a 60-minute exercise session on an ergocycle at moderate intensity, hypoglycaemia requiring treatment was seen in twothirds of subjects. However, when the breakfast insulin dose was reduced by 90%, blood glucose did not significantly change. 38 When the pre-event soluble insulin meal dose was reduced by approximately 30%, blood glucose fell by 10 18mmol/L during very prolonged aerobic exercise (skiing, semi-triathlon) taking 7 11 hours following a pre-event meal of 60 90g carbohydrate, with an average carbohydrate intake during the event of 36g per hour. When athletes with diabetes were instructed to reduce pre-race carbohydrate intakes and to reduce insulin by 40%, the athletes were less hyperglycaemic at the start, and the fall in blood glucose was reduced. 15 These investigations give us a template on which to estimate the scale of change in insulin therapy related to forthcoming exercise. A combined approach in which significant increases in carbohydrate intake during and following exercise, with a smaller reduction in preexercise insulin dose is also effective in reducing the risk of hypoglycaemia; 39 however, it is not known which strategy is best for optimum performance or long-term weight management. Thus, a vigorous pro-active reduction in pre-exercise insulin dose combined with an increase in carbohydrate intake during exercise will substantially reduce the risk of hypoglycaemia during and following exercise. On completing the training period, insulin should be given with the post-training snack or meal. The dietary requirements of athletes, with or without diabetes, are similar, and nutrition is the key to promotion of performance and endurance. Therefore, advice from a specialist dietitian is helpful. With adequate replacement on training days, there is no need to take extra carbohydrate on rest days, as this can impair overall glycaemic control without improving muscle glycogen stores. 40 Extra carbohydrate during, and following, exercise improves exercise capacity and protects against hypoglycaemia. 39,41,42 Whilst there is evidence to suggest that a low glycaemic index meal before exercise may improve performance in athletes, 43 there is little evidence to advise us on the type of carbohydrate, protein or fat content for athletes with diabetes. Until such data are available, it seems sensible to recommend that the ideal components of the diabetic diet remain as low glycaemic index carbohydrates and protein and a low fat content. Predicting, avoiding and detecting hypoglycaemia The avoidance of hypoglycaemia is central to the management of diabetes and sport. Hypoglycaemia occurring during training impairs performance, and may be dangerous if it occurs in a remote environment. Furthermore, there are concerns about the possibility of life threatening arrhythmia with hypoglycaemia. However, detection of hypoglycaemia is difficult as exercise produces similar symptoms, and concentration is diverted to sport. Therefore, blood glucose must be checked frequently at the start, during and at the end of exercise. The athlete soon sees the pattern of response, and learns to predict when and how much extra glucose is needed, and how great a reduction in the pre-exercise meal insulin doses is required. Previous advice to avoid hypoglycaemia has been to start exercise with blood glucose in the mid-teens, pre-loading with glucose or sugary containing foods. Whilst this will reduce the likelihood of hypoglycaemia, the resultant preexercise hyperglycaemia impairs physical performance. A more appropriate strategy is to start exercise with blood glucose in the range 7 10mM, and then take glucose in small amounts regularly when blood glucose starts to fall. Ingestion of glucose during exercise (up to 1g/kg/hr) improves performance and endurance, and reduces the frequency of hypoglycaemic events during and following exercise. 40,41,44 It can be taken as a drink. Sports drinks typically contain about 6g of glucose per 100ml, and have some sodium and potassium. These are useful for replacing fluids when blood glucose is not falling rapidly. Higher concentration glucose drinks which contain about 15g of glucose per 100ml, and no salts, are appropriate for raising glucose quickly and replacing glucose when the athlete wants to limit fluid intake. Powdered sports drinks can be made up to vary glucose and water content, and thereby satisfy individual requirement for exam- Pract Diab Int October 2005 Vol. 22 No. 8 Copyright 2005 John Wiley & Sons, Ltd. 309

ple, a cyclist may need less fluid and more glucose than a climber, who is becoming dehydrated. These products are made from complex glucose polymers (maltodextrin), and have low osmotic pressure even at high concentrations. After exercise, carbohydrate needs to be taken to replenish muscle and liver stores of glycogen typically 60 120g as a drink or in snack form. 41 This will need to be taken with further bolus insulin. Hypoglycaemia during the previous day reduces the counter-regulatory hormone response provoked by exercise and increases the likelihood of hypoglycaemia during exercise. 45 It seems sensible to advise athletes that, if they have had a significant hypo on the day before or during the night before exercise, they should consider whether exercise is possible or sensible, i.e. to be aware of the heightened risk. Diabetologists and specialist nurses routinely advise the reduction of the basal insulin after exercise because of post-exercise augmentation of insulin sensitivity. However, this may not be necessary if the exercise is very frequent, as insulin sensitivity is maintained. Famous athletes with diabetes The experience of outstanding athletes with diabetes is instructive. Sir Steven Redgrave s (five times Olympic Gold medallist) chosen sport, rowing, required extensive endurance training, with the event being approximately 6 8 minutes of the highest intensity exercise. Sir Steven s energy requirement was vast, at around 7000 calories per day, taken as high glycaemic index food. This necessitated very frequent bolus analogue insulin with each meal and his frequent snacks. In spite of this, Sir Steven had noted a loss of power during the second part of training races, and during a typical race his blood glucose could fall as much as 5mM. This observation was confirmed by comparison with prediagnosis data. Physiological investigations identified a specific defect in gluconeogenesis during exercise, leading to a deficit in glucose flux to the exercising muscle. This was managed by an innovative technique in Sir Steven Redgrave is five times Olympic Gold medallist. Sir Steven s chosen sport, rowing, requires extensive endurance training with the event being approximately 6 8 minutes of the highest intensity exercise the post-exercise period of relative muscle insulin resistance which was used to take a large glucose load with bolus analogue insulin to promote and replenish hepatic glucose storage. 46 This technique improved his performance significantly, and is now used by many endurance athletes with diabetes. As with Sir Steven, Gary Hall Jnr, Olympic Gold medallist in Athens 2004, was a proven athlete, winning Silver medal in the 50-metre freestyle in 1996, before he developed type 1 diabetes in 1998, and tying for Gold in the 2000 Olympics. However, by contrast with Sir Steven s endurance event, Gary competes in the ultimate sprint event. When Gary trains, his intake is 4000 5000 calories per day, with 60% or so of his calories coming from carbohydrate. Gary took between four and eight injections of Humalog insulin daily with very frequent blood sugar monitoring. He took high carbohydrate drinks before and following training and events, and kept his blood glucose above 10 prior to racing. Again in contrast to Sir Steven, his races (only 22 seconds) have little effect on blood glucose. Whilst an insulin infusion pump may seem an ideal solution for his physiologic needs, Gary did not want one because of the drag of the tape and infusion site on his skin against the water. Gary Hall Jnr, Olympic Gold medallist in 2004, was a proven athlete, winning Silver medal in the 50-metre freestyle in 1996, before he developed type 1 diabetes in 1998, and tying for Gold in the 2000 Olympics. By contrast with Sir Steven Redgrave s endurance event, he competes in the ultimate sprint event Rod Kafer was diagnosed at the age of 15, and played rugby culminating in being part of Australia s World Cup Winning team in 1999. He used a combination of Actrapid Insulin three times a day 2 8 units before meals, with Insultard at night (30 34 units). In contrast to the previous athletes, Rod limited carbohydrate intake to reduce his body fat. He did not notice a reduction in energy for training or performance. He checked his blood glucose very frequently. On game days, he took his normal breakfast of bacon and eggs and normal dose of insulin, 2 4 units of Actrapid. He would generally not require any more food until he played, at around 3pm, monitoring blood sugar levels throughout the day. It is likely that his blood glucose remained stable because of the declining action of his NPH insulin, and the balance between glucose production and use during the match. 47 Insulin and anti-doping regulations The use of pharmacological agents to promote performance has unfortunately been widespread in the past. To protect the health of athletes, and the integrity of sport, elaborate regulation and testing have developed. The World Anti-doping Agency set out the regulations for the use and prohibition of pharma- 310 Pract Diab Int October 2005 Vol. 22 No. 8 Copyright 2005 John Wiley & Sons, Ltd.

Rod Kafer was diagnosed at the age of 15, and played rugby culminating in being part of Australia s World Cup Winning team in 1999. ( Leicester Mercury) Key points Cardiovascular and muscle physiology is normal in uncomplicated diabetes Insulin treatment and the abnormalities of the endocrine response with exercise in diabetes alter the normal supply of fuel to the exercising muscle Various physical activities have different fuel requirements There is a potential for mismatch between glucose production and use with exercise, and therefore the risk of both hypoglycaemia or hyperglycaemia during and post-exercise At higher levels of effort, the relatively excessive ambient insulin levels can impair performance It is possible to predict the changes in blood glucose with effort and thus to alter insulin therapy and food intake to help normalise blood glucose and reduce the likelihood of hypoglycaemia Careful management can normalise maximum physical performance in diabetes cological agents in world sport in 2003. This document, The Code, states that athletes are able to request medical exemption with appropriate documentation to use banned substances (Article 4.4). Because of the illicit use of insulin by some athletes (particularly weight lifters and wrestlers), insulin is on the list of prohibited substances (2005). Any athlete with diabetes who wishes to enter competitive sport events subject to The Code, or organisations who follow its regulation, will need appropriate documentation which outlines the diagnosis of diabetes and its treatment. Regulators are likely to be suspicious of any significant alteration in therapy prior to major events, and are likely to require assurance from the attending physician that any change is for therapeutic reasons. Conclusion People with uncomplicated type 1 and insulin treated type 2 diabetes, who want to start, or continue in their chosen sport, can be encouraged to do so. Appropriate education of the person with diabetes and support by their health care professional are necessary, and careful consideration of the nature of the sport is required. Further research into the most appropriate strategies for insulin therapy and carbohydrate intake in the era of modern insulin, and on the role of different fuel metabolism in diabetes is required. The gain for people with diabetes is substantial, and the skills acquired by the health care professional are likely to assist in the management of all people with diabetes. Further information on the management of diabetes and specific sports can be found at http://www. runsweet.com. References 1. Fisher MBM, Cleland JGF, Dargie HJ, et al. Non-invasive evaluation of cardiac function in young patients with type 1 diabetes. Diabetic Med 1989; 6: 677 681. 2. Wanke T, Formanek D, Auinger M, et al. Pulmonary gas exchange and oxygen uptake during exercise in patients with type 1 diabetes. Diabetic Med 1992; 9: 252 257. 3. Nugent AM, Steele IC, al-modaris F, et al. Exercise responses in patients with IDDM. Diabetes Care 1997; 20: 1814 1821. 4. Veves A, Saouaf R, Donaghue VM, et al. Aerobic exercise capacity remains normal despite impaired endothelial function in the micro- and macrocirculation of physically active IDDM patients. Diabetes 1997; 46: 1846 1852. 5. Romijn JA, Coyle EF, Sidossis LS, et al. Regulation of endogenous fat and carbohydrate metabolism in relation to exercise intensity and duration. Am J Physiol 1993 Sep; 265(3 Pt 1): E380 E391. 6. Gallen IW. Helping the athlete with type 1 diabetes. Br J Diabetes Vasc Dis 2004; 4: 87 92. 7. Medbo JL, Tabata I. Relative importance of aerobic and anaerobic energy release during short-lasting exhaustion bicycle exercise. J Appl Physiol 1989; 67: 1881 1886. 8. Daugaard JR, Nielsen JN, Kristiansen S, et al. Fiber type-specific expression of GLUT4 in human skeletal muscle: influence of exercise training. Diabetes 2000; 49(7): 1092 1095. 9. DeFronzo RA, Ferrannini E, Sato Y, et al. Synergistic interaction between exercise and insulin on peripheral glucose uptake. J Clin Invest 1981; 68(6): 1468 1474. 10. Hirsch IR, Marker JC, Smith LJ, et al. Insulin and Glucagon in prevention of hypoglycemia during exercise in humans. Am J Physiol 1991; 260: E695 E704. 11.Cryer PE. Glucose counterregulation: Prevention and correction of hypoglycemia in humans. Am J Physiol 1993 Feb; 264(2 Pt 1): E149 E155. 12. Randle PJ, Newsholme EA, Garland PB. Regulation of glucose uptake by muscle. Biochem J 1964; 93: 652 655. 13.Wasserman DH, Abrumrad NN. Physiological basis for the treatment of the physically active individual with diabetes. Sports Med 1989; 7: 376 392. 14. Koivisto VA, Sane T, Fyhrquist F, et al. Fuel and fluid homeostasis during long-term exercise in healthy subjects and type I diabetic patients. Diabetes Care 1992; 15: 1736 1741. 15. Ahlborg G, Lundberg JM. Exerciseinduced changes in neuropeptide Y, Pract Diab Int October 2005 Vol. 22 No. 8 Copyright 2005 John Wiley & Sons, Ltd. 311

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CONFERENCE NOTICE International Diabetes Federation 19 th World Diabetes Congress 3 7 December 2006 Cape Town International Convention Centre, Cape Town, South Africa For further information and to register please contact: 19 th World Diabetes Congress, IDF, Congress Unit, Avenue Emile De Mot 19, B-1000 Brussels, Belgium. Tel: +32 2 5431631, fax: +32 2 5385114, e-mail: worlddiabetescongress@idf.org, website: www.idf2006.org 312 Pract Diab Int October 2005 Vol. 22 No. 8 Copyright 2005 John Wiley & Sons, Ltd.