Exercise has been advocated for patients with diabetes for centuries, but it was only in 1990 that the American Diabetes Association (ADA) felt there was enough evidence of benefit to recommend exercise as a routine part of the treatment of type 2 diabetes mellitus. Since that time, the use of exercise in the treatment of type 2 diabetes has become well accepted, although its place in the treatment of type 1 diabetes remains less clear. In recent years, the role of exercise in the prevention of type 2 diabetes and in the treatment of the metabolic syndrome has proven to be of particular interest.
Indeed, current research seems to confirm a role for both aerobic exercise as well as resistance training in both the treatment and the prevention of the disease. Nevertheless, our understanding of the complex interactions of exercise with diabetes is still incomplete, and the most effective ways to use exercise in the treatment of the disease are still under investigation. During exercise major cardiorespiratory and circulatory responses help to efficiently supply the increased oxygen and energy needs of the working muscles. Whole body oxygen consumption and glucose turnover may increase more than tenfold and even greater increases may occur in the skeletal muscles. In healthy individuals, a complex hierarchy of hormonal responses regulates the alterations in fuel metabolism necessary to maintain normal plasma glucose levels during prolonged activity. This metabolic response to exercise may be severely disordered in patients with diabetes mellitus. In order to understand the effects of diabetes on fuel metabolism during exercise, it is important to first review the normal physiology.
Metabolic Changes During Exercise in Normal Individuals
As exercise intensity increases there is a linear relationship between heart rate, oxygen consumption, and workload. Eventually, however, oxygen consumption plateaus in the face of increasing exercise intensity. The point at which oxygen uptake plateaus is known as the maximal aerobic exercise capacity, or VO2max. Exercise above this point can only be sustained for a short time because it represents non-aerobic metabolism and is limited by lactic acid accumulation. The VO2max is important for a number of reasons. It is a useful tool to express the degree of aerobic fitness of an individual. In general, a higher VO2max predicts better performance in endurancetype activity. It also allows comparison of individuals of widely varying fitness levels. For example, at the same percentage of any individuals VO2max, a roughly similar metabolic response will occur. In addition, the VO2max has been useful in communicating recommendations for exercise in various groups of individuals. Because the VO2max is rarely directly measured in individual patients, indirect techniques for estimating workloads as a percent of the VO2max have been developed.
Moderate Intensity Exercise (50–75% VO2max)
In the initial stages of exercise muscle glycogen is the chief source of energy. As continued exercise depletes muscle glycogen, the working muscles must take up glucose and nonesterified fatty acids (NEFA) from the circulation. Recent evidence suggests that utilization of local triglyceride stores, both intra-myocellular and extra-myocellular, in skeletal muscle may also be an important source of free fatty acid for oxidation during physical activity. In the postprandial state glucose is derived from an increased hepatic production that closely matches peripheral glucose utilization and can maintain euglycemia during moderate intensity exercise for long periods of time. However, during prolonged exercise glucose utilization may exceed splanchnic glucose output and hypoglycemia may develop.
The role of neurohormonal adaptation during exercise is twofold:
(a) to supply the exercising muscles with their increased fuel and oxygen requirements and
(b) to maintain whole body glucose homeostasis to supply the brain with adequate substrate.
It is not clear what triggers the endocrine response to exercise; it may result from the stimulation of afferent nerves from the working muscles or from subtle deviations in the blood glucose and/or from feed forward mechanisms originating within the hypothalamus. At the start of exercise, a fall in the circulating insulin levels occurs due to an increased alpha adrenergic input to the beta cells. This physiologic decrease in insulin levels promotes peripheral lipolysis and removes the inhibiting effects of insulin on hepatic glycogenolysis and gluconeogenesis. As exercise continues, an increase in the level of the counterregulatory hormone glucagon facilitates liver glycogenolysis and later gluconeogenesis, further enhancing hepatic glucose output.4 Figure 42.1 illustrates the hormonal response to exercise.
Fig. 42.1 The hormonal response to exercise
With more prolonged exercise insulin secretion continues to fall and there is a further release of counterregulatory hormones. A rise in circulating epinephrine levels and falling insulin levels lead to an increase in blood NEFA levels due to both increased lipolysis and decreased NEFA re-esterification in the liver. The liver utilizes the glycerol released during triglyceride breakdown as a substrate for gluconeogenesis and the NEFA are delivered to the working muscles as an energy source. The increased availability of NEFA for muscle metabolism helps restrain the rate of muscle glucose utilization and therefore helps to limit the fall in glucose during prolonged exercise. In fact, the major role of catecholamines during prolonged exercise is to stimulate lipolysis. Their main impact on hepatic gluconeogenesis is probably via the mobilization of gluconeogenic precursors from peripheral sites and the provision of free fatty acids as an energy source for gluconeogenesis. Catecholamines also stimulate glycogenolysis in inactive muscles during the later stages of prolonged exercise. In this situation the glycogen is metabolized to lactate in non-exercising muscle. Lactate can then be delivered to exercising muscle where it can be oxidized as fuel, as well as to the liver for gluconeogenesis. This complex and redundant series of hormonal responses regulate blood glucose during exercise with remarkable efficiency and the redundancy of the system insures that glucose homeostasis is robust.
High Intensity Exercise (>75% VO2max)
During very high intensity exercise the relationship between peripheral glucose utilization and hepatic glucose production may be reversed. Because virtually all of the fuel for high intensity activity is provided by local energy stores of muscle glycogen, hepatic glucose production often significantly exceeds peripheral glucose utilization leading to hyperglycemia that persists into the postexercise state. The added glucose production most likely originates from hepatic glycogenolysis and epinephrine may be involved in its regulation. There may also be a brief period of relative insulin resistance following very intense exercise causing elevated blood glucose. When postexercise hyperglycemia occurs in normal individuals, it is transient and self-correcting.
Muscle Glucose Uptake During Exercise
The increased muscle glucose uptake during exercise is related to the intensity of the exercise once a steady state has been achieved. In general, the greater the exercise intensity, the greater the relative utilization of carbohydrate as an energy source. For example, at exercise of roughly 50% of an individual’s VO2max, half of the energy requirement is supplied by carbohydrate while 80% of energy requirements may be supplied by carbohydrate at exercise approaching 80% of the VO2max. Since plasma insulin levels fall during exercise, the increased muscle glucose uptake must be mediated by insulin-independent mechanisms or via an increased insulin action on muscle. Exercise probably acts in both ways but the insulin-independent mechansm predominates. During exercise there is an insulin-independent increase in the concentration of the main glucose transporter protein GLUT 4 on the muscle membrane. This is thought to be due to the translocation of the GLUT 4 from the cytoplasm to the sarcolemma. This increase in the number of GLUT 4 on the surface of the cell leads to an increase in the glucose uptake from the circulation into the muscle cell. In addition to changes within the muscle itself, enhanced muscle perfusion during exercise improves glucose uptake through increased delivery of insulin and glucose to working muscle.
In the postexercise period the hormones return to basal levels and glycogen and triglyceride stores are repleted. If exercise is of sufficient intensity and duration to deplete muscle glycogen and adequate carbohydrate is made available, the amount of glycogen will rebound to well above pre-exercise levels, a phenomenon called supercompensation. Of great therapeutic importance is the observation that muscle insulin sensitivity is enhanced for prolonged periods of time following a single bout of moderately intense activity. Insulin sensitivity is typically enhanced for 12–24 h, but after sufficient exercise, alterations lasting up to 72 h have been noted. This results in a sustained improvement of insulin sensitivity in individuals who exercise every other day or more. The mechanisms by which exercise results in these sustained benefits are unclear.
A relationship to muscle glycogen levels is suggested by the observation that exercise of intensity and duration sufficient for glycogen depletion is generally required for this effect to occur. In addition, athletes who take in large amounts of glucose following exercise and achieve glycogen levels above basal have been reported to have impaired insulin sensitivity. On the other hand, the increase in insulin sensitivity that follows exercise clearly persists at a time when glycogen stores have returned to normal. Another mechanism for improved carbohydrate utilization following exercise may relate to the activation of the enzyme AMPK (AMP-activated protein kinase) (see Fig. 42.2). During exercise, ATP is broken down to AMP to release energy. As AMP builds up, it increases the activity of the enzyme AMPK. This enzyme is activated during exercise of the intensity required to lead to improved postexercise glucose uptake. In addition to shifting fuel utilization acutely toward the oxidation of FFA it may also stimulate subsequent glucose utilization by mechanisms independent of insulin action, possibly involving the nitrous oxide system.
Fig. 42.2 The role of AMP kinase in enhancing free fatty acid utilization during exercise. During exercise, ATP is broken down to AMP which activates the enzyme AMP kinase. AMP kinase causes a downstream decrease in the inhibition of CPT1 allowing increased free fatty acid oxidation in the mitochondria. AMP = adenosine monophosphate, PO4 = phosphate group, ACC = acetyl-CoA carboxylase, M-CoA = malonyl-CoA, CPT1 = carnitine palmitoyltransferase, FFA = free fatty acids
Recently, attention has turned to the role of intra-myocellular triglyceride metabolism as a regulator of insulin sensitivity. In general, states of increased triglyceride accumulation in skeletal muscle and liver are associated with insulin resistance. Breakdown products of the metabolism of free fatty acids (FFA), the building blocks of triglycerides, can activate serine kinases and suppress the activity of the insulin receptor and insulin receptor substrates. Reduction of fat stores in skeletal muscle during exercise could be a mechanism enhancing subsequent insulin sensitivity. Nevertheless, when highly trained endurance athletes are studied, levels of triglyceride in skeletal muscle are actually increased in between exercise bouts. Despite this increase in myocellular fat stores, such athletes are characterized by a high degree of insulin sensitivity. This has been called the “athlete’s paradox.” New information suggesting that the breakdown products of FFA metabolism and not the storage triglyceride themselves may induce insulin insensitivity helps to clarify this apparent problem. In the postexercise period rapid restoration of triglyceride stores may actually result in a decrease in these metabolically active intermediates, thus improving insulin sensitivity.
Adaptations to Physical Training
Exercise performed on a regular basis with an intensity, duration, and frequency sufficient to improve cardiorespiratory fitness, strength, and flexibility is called physical training. Alterations in cardiac and respiratory efficiency and in the neurologic coordination of motor activity are an important factor in improved performance. In addition, there are important cellular adaptations of skeletal muscles with physical training (see Table 42.1). This response differs during aerobic training (i.e., low to moderate intensity) as compared to resistance training. The changes associated with aerobic training include the following: (a) An increase of the oxidative capacity of the type I slow twitch fibers as well as a change in the type II fast twitch fibers toward the so-called type IIa fiber type with a greater oxidative capacity. (b) An increase in the number of capillaries around muscle fibers which allows for more efficient exchange of nutrients and waste products. (c) An increase in the size, number, and metabolic activity of mitochondria16 with a greater capacity for ATP production and oxidative phosphorylation. (This may be mediated in part through the activation of AMPK.) (d) An increase in the number of GLUT 4 transporters available for translocation to the cell surface. (e) An increase in the activity of the enzymes hexokinase and glycogen synthase with an improved capacity for increased glucose uptake, glucose phosphorylation, and storage, respectively. (f) An increase in the expression of adiponectin receptors, as well as a decrease in inflammatory cytokines known to be associated with insulin resistance.
Table 42.1 Adaptations to aerobic training
– Transformation of the glycolytic type IIb muscle fibers to type IIa muscle fibers with a greater oxidative capacity
– Increased number of muscle capillaries and muscle perfusion
– Increased size, number, and metabolic capacity of mitochondria
– Increased availability of muscle glucose transporter GLUT 4
– Increased activity of the enzymes hexokinase and glycogen synthase
– Increased adiponectin receptors (adiponectin is a hormone produced by adipose tissue that is a major mediator of insulin sensitivity)
– Decreased inflammatory cytokines
These changes occur in the face of little or no muscle hypertrophy and are most obvious in the type 1 and type 2a oxidative fibers. The adaptive response to resistance training results predominantly in the hypertrophy of type 2b fast twitch fibers with minimal changes in oxidative capacity or vascularization. In addition to hypertrophy, much of the early improvement in strength during resistance training is related to more efficient neurologic regulation of fiber recruitment within the muscle. These changes in muscle function along with the cardiorespiratory and circulatory adaptations to physical training lead to a more efficient use of energy and improvements in aerobic endurance. There is no evidence that the adaptations to exercise in patients with diabetes differ substantially from those of normal individuals.
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