ADA/JDRF Type 1 Diabetes Sourcebook, Excerpt #20: Physical Activity, Part 2

Regulation of Glucose Metabolism: Effect of Physical Activity on Metabolic Control

Importantly, the glycemic response to aerobic exercise has some degree of reproducibility within an individual with T1D, as long as many of the variables known to impact glucose homeostasis are held constant (such as pre-exercise meal, insulin dose, and the exercise task itself).⁴⁹ Unfortunately, the glycemic response differs markedly from patient to patient even if the relative exercise intensity and timing are identical, thereby making universal guidelines for the prevention of exercise-associated dysglycemia difficult.^49–52

Lipid levels and blood pressure. Regular physical activity may be considered the best non-pharmacological and most cost-effective approach for maintaining optimal lipid and blood pressure levels. Reductions in lipid levels, increased C-reactive protein (CRP) level, and increased plasminogen activator inhibitor-1 (PAI-1) levels are thought to play a role in the maintenance of an inflammatory state and in the development of cardiovascular disease. Elevations in PAI-1 are also linked with muscle dysfunction in rodent models of T1D.⁵³ Importantly, individuals who are physically trained have improvements in lipid profile and lower PAI-1 levels compared to sedentary individuals.⁵⁴ Lifestyle intervention improves lipid profiles and lowers PAI-1 levels in patients with T2D, according to the Look AHEAD study.⁵⁵ A majority of other studies of physical activity and T1D show a beneficial effect on lipid levels. ^{33,35,56–63} Studies lasting up to 4 months demonstrate increases in HDL-cholesterol by 8–14%, reductions in LDL-cholesterol by 8–14% and triacylglycerols by 13–15%.² In general, the improvements in lipid profile appear independent of changes in glycemic control and weight and are more evident in those with a poor initial lipid profile.²

Evidence that regular exercise improves blood pressure levels in T1D is equivocal, with some studies showing a small improvement (2–3% reduction)^35,58 and others no effect.^56,60 However, these studies typically had small numbers of young subjects who did not have elevated blood pressure levels. A large cross-sectional study found a small effect of physical activity levels on the risk of having elevated diastolic blood pressure.³³

Exercise Intensity or Type and Hormonal Responses to Physical Activity

The metabolic regulation of glucose homeostasis during exercise is complex and regulated by several hormonal and non-hormonal factors (e.g., contraction-mediated changes in insulin sensitivity). In general, more strenuous aerobic activities utilize more blood glucose as fuel.⁶⁴ In the postabsorptive state, the liver is the key organ responsible for glucose production during exercise to help maintain glucose supply to the working muscles and the central nervous system. Glucose production by the liver in individuals without diabetes increases ~2–3-fold during low- to moderate-intensity exercise.^65,66 At higher exercise intensities, glucose production via the liver exceeds its uptake into the periphery because of elevations in catecholamines, and hyperglycemia ensues^.67 Blood glucose utilization also increases with the duration of exercise as muscle glycogen levels decline.⁶⁶ When liver glycogen levels become depleted, or if glucose production is impaired because of elevations in circulating insulin levels, then hypoglycemia and fatigue develops, even in people without diabetes.^68,69 In general, the glucose disappearance from the circulation is similar in individuals with T1D and those without diabetes, as long as the T1D patients are well-insulinized.⁷⁰ However, it may be that T1D patients rely more heavily on muscle glycogen as a fuel during exercise and have a somewhat limited capacity to oxidize orally ingested glucose as an energy source, particularly if they are underinsulinized.^71–73 As described below, despite near normal substrate utilization during exercise, the maintenance of euglycemia is challenging for the patient with T1D.

Figure 11.1 illustrates a simplified schematic of the regulation of glucose homeostasis during exercise in healthy people or in people with diabetes who have taken the correct amount of insulin for exercise and who have normal glucose counterregulatory responses to exercise. Figure 11.1 also illustrates the mechanisms for exercise-associated hypoglycemia or hyperglycemia. A number of neuroendocrine mechanisms normally exist to defend against hypoglycemia, both at rest and during exercise. Interestingly, the hormonal responses to hypoglycemia and prolonged exercise are nearly identical. During exercise or hypoglycemia, insulin secretion diminishes while increases in glucagon, catecholamines, growth hormone, and cortisol occur.⁷⁴ However, the normal counterregulatory hormone response to exercise is amplified by simultaneous hypoglycemia in individuals without diabetes, thereby helping to augment glucose production by the liver and limit glucose uptake into working muscle. These hormonal changes during exercise help to maintain fuel supply to the central nervous system and protect against hypoglycemia.^75,76 Unfortunately, the counterregulatory response to hypoglycemia (both at rest and during exercise) and to exercise performed after a bout of hypoglycemia is impaired in patients with T1D.⁷⁷ The reciprocal effects of antecedent hypoglycemia and antecedent exercise on glucose counterregulation are described in the following sections.

Metabolic Dysregulation During Physical Activity Hypoglycemia.

Hypoglycemia during physical activity occurs typically when circulating insulin levels are too high during the activity (i.e., too much insulin on board), although the exact mechanisms for the high risk for hypoglycemia during exercise in T1D are likely complex and multifactorial. In rare circumstances, hypoglycemia can also occur when hepatic glycogen stores are exhausted because of prolonged fasting or exercise, even in those who do not have diabetes and with low circulating insulin levels.⁷⁸ Even if it does not suppress hepatic glycogen mobilization, relative hyperinsulinemia during exercise may also increase peripheral glucose uptake (into exercising muscle and other tissues) and may reduce hepatic gluconeogenesis, thereby contributing to hypoglycemia risk.⁷⁹ An additional factor that contributes to increased risk for exercise-associated hypoglycemia is the deficiency in glucose counterregulation to exercise or to hypoglycemia, which can occur during the activity^.80 Thus, for individuals with T1D, the inability to reduce circulating insulin concentrations at the onset of exercise because the insulin has already been injected or infused prior to the activity, as well as other factors, contributes to the high risk for exercise-associated hypoglycemia.

Due to increased blood flow and circulatory responses, exercise itself may increase insulin absorption kinetics.⁸¹ Even if mealtime bolus insulin has not been injected or infused in the hours prior to exercise, it is still possible to have exercise-associated hypoglycemia, likely because basal insulin levels tend to be higher than what would normally occur during physical activity in people without diabetes.⁸² Indeed, one of the challenges clinically is that basal–bolus therapy is normally titrated initially to sedentary days, rather than to days in which habitual activity occurs.

During exercise, relative hyperinsulinemia may limit the effect of glucagon on hepatic glucose production and promote increases in peripheral glucose disposal, thereby reducing circulating levels rapidly.⁸³ Since the total amount of glucose in the circulation is only ~4 g and because exercise increases glucose utilization rates five- to sixfold above rest, hypoglycemia can ensue within minutes if circulating insulin levels are not adjusted for the activity or if exogenous carbohydrates are not consumed.^84,85 In addition to relative hyperinsulinemia, a failure in glucagon response during exercise or during hypoglycemia may also exist if a recent episode of exercise or hypoglycemia occurred.⁸⁰ Finally, other factors such as an impaired adrenergic response to hypoglycemia during exercise or a reduced level of liver glycogen because of recent hypoinsulinemia may contribute to exercise-associated hypoglycemia.^86,87 Based on euglycemic clamp studies of adolescents with T1D, it would appear that insulin sensitivity is elevated during exercise and immediately in recovery and again hours later.⁸⁸ This biphasic increase in the glucose requirements to maintain euglycemia may predict the risk for postexercise hypoglycemia. Indeed, the glycemic nadir after exercise appears to be about 7–11h after the end of exercise.^89–94

Hyperglycemia. The development of hyperglycemia during and after exercise may occur for a number of reasons. First, the high likelihood of hypoglycemia caused by exercise may force individuals to consume excessive carbohydrates before and following exercise. Second, the fear of hypoglycemia may promote an overly aggressive reduction in insulin dose before the activity, with some individuals omitting insulin administration altogether. Third, the stress of competition may increase catecholamine and cortisol levels, which leads to greater glucose production by the liver and limited peripheral glucose disposal. Finally, brief periods of intense aerobic or anaerobic activities promote dramatic increases in catecholamine release, which would normally be compensated for by increased insulin secretion in the individual without diabetes.⁹⁵ This latter phenomenon caused by intense exercise has been shown to particularly aggravate postexercise hyperglycemia in people with T1D, even if insulin is administered during recovery.⁹⁶

With respect to the second reason given, individuals using pump therapy may find that discontinuing insulin infusion (i.e., pump disconnect) during exercise may cause hyperglycemia, particularly if the activity is prolonged.⁹⁷ Strategies to limit exercise-associated hyperglycemia, based on limited experimental data, are described in the following section.

Effects of glycemia on maximal oxidative capacity and performance. Maintenance of normal glucose homeostasis during exercise in people with T1D is challenging for a number of physiological and psychosocial or behavioral reasons. Behaviorally, a fear of hypoglycemia caused by exercise may promote hyperglycemia, while at the same time, the sophisticated hormonal regulatory system that maintains euglycemia during the activity is often defective when disease is long-standing.^32,83 Thus, many patients are exercising when blood glucose levels are suboptimal; this may affect exercise and sports performance. Moreover, a number of physiological processes may be compromised by prolonged suboptimal glycemic control.

If impairment in physical work capacity exists in patients with T1D, it would appear to be related to the level of glycemic control. For example, two studies report that physical capacities are inversely related to the level of metabolic control, as measured by A1C.^22,98 It is unclear, however, if a reduced work capacity in youth with T1D is a result of poorer oxygenation of muscle or a lower amount of muscle capillarization, or if poorer metabolic control is a function of lower amounts of habitual physical activity.^99–101

Studies investigating muscular strength and endurance capacity in individuals with T1D have shown mixed results, although a generalized myopathy does exist if glycemic control is poor.¹⁰² Fatigue is a common complaint in diabetes, particularly at the time of diagnosis or with elevated glycemia.^103,104 Surprisingly, the effect of T1D on exercise endurance capacity is not clear. Compared to controls, patients with T1D have been reported to have both impaired¹⁰⁵ and enhanced¹⁰⁶ endurance capacity during relatively brief bouts of intense exercise. Ratings of perceived exertion during prolonged aerobic exercise have been reported to be higher in boys with T1D compared to controls without diabetes.¹⁰⁷ During prolonged aerobic exercise, those with T1D who are under reasonable glycemic control have a higher glycolytic flux and rely more on muscle glycogen utilization, thereby resulting in premature fatigue.^71,108 Exercising while hyperglycemic has been shown to increase reliance on muscle glycogen compared to exercising while euglycemic, and the individual who is exercising while hypoinsulinemic and hyperglycemic would be prone to early dehydration and acidosis, all factors that might promote early fatigue.^109,110 A diet rich in carbohydrate (~60% of total energy) for 3 weeks has been shown to increase glycemia and insulin requirements, reduce muscle glycogen levels, and lower exercise capacity compared to a lower carbohydrate diet (50% of total energy) in athletes with diabetes.¹¹¹ More-over, increasing blood glucose levels to 288 mg/dl (16 mmol/l) has been shown to reduce isometric muscle strength, but not maximal isokinetic muscle strength, compared with strength measured at normal glycemia.¹¹² This reduction in isometric strength might play a role in the development of early fatigue during certain types of resistance and anaerobic activities.

If individuals with T1D are actively engaged in regular exercise and are under reasonable glycemic control, then they can achieve elite level performance. One German study of 10 middle-aged long-distance triathletes with T1D followed over 3 years showed that overall endurance performance was normal, despite documented hyperglycemia during the early part of a race, then hypoglycemia during the marathon leg.¹¹³ Another study found that good glycemic control, as measured by A1C, was associated with a normal peak cardiopulmonary exercise response and performance, while suboptimal control was associated with deterioration in athletic performance.²³

The degree to which acute blood glucose levels influence sports skill performance or exercise performance has also been examined.^{107,114–116} In one study of prepubertal boys with T1D (n = 16), lowering the insulin dose prior to exercise to reduce the likelihood of hypoglycemia did not influence aerobic capacity during cycling compared to the usual insulin dose.¹¹⁴ In eight endurance-trained adults with T1D, elevating blood glucose levels from 95 to 225 mg/dl (5.3 mmol/l to 12.4 mmol/l) failed to change peak power output or other physiological end points, such as lactate, heart rate, or respiratory exchange ratio.¹¹⁶ In another study, compared with hyperglycemia or euglycemia, exercise capacity was reduced and ratings of perceived exertion increased with hypoglycemia in a group of youth with T1D, although the research investigators (not the subjects) always stopped the exercise for possible safety reasons.⁵² Another study demonstrated that the oral administration of dextrose at 1g/kg body mass 30 min before cycling exercise (55–60% Vo2max) results in a 12% improvement in cycling performance time compared with placebo, perhaps as euglycemia is facilitated and because working muscles are provided more fuel for oxidation.^117,118 A sports camp field study of 28 youth with T1D found that the ability to carry out fundamental sports skills was shown to be markedly reduced by mild hypoglycemia of 55 mg/dl (3 mmol/l) compared with either euglycemia or hyperglycemia of 300 mg/dl (~17 mmol/l).¹¹⁵ Importantly, this finding of significantly impaired sports performance with hypoglycemia appeared universally across nearly all subjects and is similar to the well-documented detrimental effects of hypoglycemia on cognitive processing.¹¹⁹

Profound or sustained hyperglycemia also likely impairs endurance performance in those with T1D, although the evidence for this statement is somewhat limited. Prolonged hyperglycemia with low insulin levels would be expected to lower muscle glycogen levels, reduce muscle strength, and predispose the individual to dehydration and electrolyte imbalance.¹²⁰ Exercising while hyperglycemic has been shown to increase the reliance on muscle glycogen as a fuel source and limit the capacity to switch from carbohydrate to lipid as an energy source.¹⁰⁹ Thus, overall, evidence suggests that optimal glycemic control and regular exercise may be needed to maximize muscle strength and endurance performance.

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