136 Consitt et al. 3–4 d per week), and intensities (anywhere from walking to more intense jogging/running). These guidelines become even more complex for the person with type 2 diabetes, for whom certain types of exercise may be contraindicated owing to hypertension, heart disease, obesity, blood glucose control, medications, retinopathy, or peripheral neuropathy. This chapter summarizes research describing the effect of either aerobic- (i.e., endurance) or resistance- (i.e., weight lifting) oriented exercise training on insulin action, leading to enhanced metabolic control, in patients with type 2 diabetes. This information will provide a foundation for the development of safe and effective exercise prescriptions. Although general contraindications for exercise will be discussed, a major assumption inherent in this chapter is that the diabetic subjects performing exercise were properly cleared by a physician for initiating physical activity. AEROBIC EXERCISE Because type 2 diabetes is associated with hyperglycemia and insulin resistance, and skeletal muscle is a main source of glucose uptake (2), clinical exercise research has focused on therapeutic methods of reducing elevated glucose levels and improving insulin action. The measured improvements in insulin action may be owing to either the chronic effects of training, or simply the residual effect of the last bout of exercise. Studies of healthy endurance trained males, as well as individuals with type 2 diabetes, have shown that improved insulin sensitivity is maintained up to 16 h after a single bout of exercise (3,4), but may be diminished 60 h after the final exercise session during repeated days of exercise training (5). In spite of this finding, glucose uptake is greater in aerobically trained skeletal muscle than in untrained muscle (6). Therefore, to obtain optimal results, patients with type 2 diabetes should exercise multiple days per week, and thus obtain both the acute and chronic benefits of exercise. Several definitions are important for the implementation of an aerobic-based exercise prescription. Exercise intensity is commonly reported as a percentage of an individual’s maximal oxygen consumption (VO 2 max). This is considered the most recognized measure of an individual’s aerobic capacity, and is a strong indication of an individual’s cardiopulmonary fitness level. Because the majority of exercise sessions in a clinical setting use heart rate to gauge exercise intensity, a general point of reference is that a moderate exercise intensity of 60% VO 2 max generally equates to 70% of an individual’s maximal heart rate (7). If possible, maximal heart rate should be directly determined during a maximal exercise stress test. This test uses an incremental workload, and is commonly performed on a treadmill or stationary bicycle. For safety purposes, this assessment is performed under the supervision of a physician and a 12-lead EKG is monitored throughout. A direct measurement of maximal heart rate is considered more accurate than the value obtained using the age-adjusted maximal heart rate equation (220 -age). Effects of Aerobic Exercise on Blood Glucose Concentration The most pronounced finding during and immediately after aerobic exercise in many type 2 diabetic patients is a decrease in blood glucose levels (4,8,9). Unlike individuals with normal glucose metabolism, people with type 2 diabetes may experience an immediate decline in blood glucose levels with low to moderate exercise intensity of approx 40 min duration (8,9). The cause of this phenomenon, which appears specific to this population, has been debated. Early speculation suggested that the decline in glucose was caused by the decreased hepatic production during exercise (10). However, more recent research indicates that type 2 diabetic patients are capable of matching, if not exceeding, the glucose production of their healthy and obese counterparts during exercise (11). Martin et al (9) reported that, after 40 min of cycling at 60% VO 2 max, glucose uptake in the leg of patients with type 2 diabetes was twice that of nondiabetic controls, despite similar increases in splanchnic glucose output. The finding of greater glucose uptake in such patients has been reported by others (8,11) and likely contributes to the immediate decline in blood glucose levels exhibited in these individuals in response to aerobic exercise. It is important to note that, despite decrements in blood glucose levels in type 2 diabetic patients, blood levels still generally exceed those of healthy controls; therefore, exercise-induced hypoglycemia is not a common concern among these patients and physicians in most instances can safely recommended exercise as part of their therapeutic treatment of type 2 diabetes. Nonetheless, baseline glucose measurements should always be made before exercise, Chapter 9 / Exercise as an Effective Treatment for Type 2 Diabetes 137 and additional precaution is needed for those taking medication such as insulin and sulfonylureas, which could act synergistically with exercise to produce hypoglycemic conditions. Therefore, patients should be aware of baseline, exercise and recovery glucose levels, especially when commencing an exercise program. Blood glucose levels return to baseline within hours of exercise cessation. The health benefits of these acute reductions in blood glucose remain unknown. It is possible that repeated transient reductions trigger a more permanent decline in resting blood glucose levels. However, inconsistencies have been reported with respect to the effect of aerobic training on preexercise hyperglycemic blood levels. Researchers have reported either decreases (12,13) or no change (14–17) in fasting blood glucose levels in response to aerobic training. Examination of this research indicates that frequency of exercise (12,13), as well as early diagnosis of type 2 diabetes (18) may influence the ability of exercise training to decrease basal blood glucose levels. It appears that improvements in blood glucose levels can be achieved with low intensity exercise, as long as the frequency of exercise is high. Barnard et al (12) and Yamanouchi et al (13) reported that daily walking was a sufficient stimulus to decrease fasting blood glucose levels. The effect of aerobic training on long-term glycemic control, as assessed by HbA1c measurement, has been evaluated, with inconsistent results. Some aerobic training studies have reported statistical improvements, with decreases in HbA1c typically in the 1–2% range (19–22), although others have reported no change (16,23,24). Part of the discrepancy in the findings is likely attributed to differences in exercise protocols, including differences in exercise intensity, duration and frequency. In addition, many of these studies used subjects on different antidiabetic medications, and some studies also included diet modifications. These are all factors that may have contributed to the variability in the results. Although the prior discussion focused on the blood glucose response for low to moderate exercise intensity, it should also be mentioned that exercise at higher intensities can bring additional concerns. For the type 2 diabetic, exercise at high intensity (i.e., >80% VO 2 max) can cause a hyperglycemic response during exercise and recovery owing to the exaggerated counter regulatory hormonal response of epinephrine and glucagon (25). Exercise-induced hyperglycemia is of particular concern for those individuals with long-standing type 2 diabetes, where insulin production has been diminished. Effects of Aerobic Exercise on Insulin Action The reported increase in insulin-mediated glucose uptake that occurs during and immediately after exercise has been well documented (4,9). However, it has been more difficult to outline the effects of an endurance-oriented exercise training program on glucose dynamics through glucose tolerance tests. Some studies have suggested that as little as7dofaerobic training is sufficient to improve glucose tolerance (22,26,27), although others have reported no training effect on this glycemic variable (14,17). Based on these inconsistent findings, it is possible that the frequency of the training sessions, as well as the initial metabolic status of the individual may play a role. Studies that have demonstrated improvements in glucose tolerance typically use daily exercise at a moderate to high intensity in lean or newly diagnosed type 2 diabetic individuals (22,27). In contrast, studies reporting no effect on glucose tolerance have typically used less frequent training in older, obese individuals with type 2 diabetes (14,17). Despite variable results using both oral glucose tolerance tests (OGTTs) and intravenous glucose tolerance tests (IVGTTs) (19,22,26), exercise training studies applying the gold standard measurement of insulin sensitivity, the hyperinsulinemic euglycemic clamp, have reported dramatic increases in whole body glucose uptake over a wide range of plasma insulin concentrations (13,15,22,26). Improved insulin action has been reported immediately after low (28) and high intensity (25) aerobic exercise. Bruce et al (29) compared exercise-induced improvements in insulin sensitivity in type 2 diabetic patients with healthy controls. Exercise training consisted of 8 wk of cycling at 70% VO 2 max for 60 min, 3 times per week. Insulin sensitivity was measured at least 36 h after the last bout of exercise. These results may be a more accurate indicator of the effects of chronic exercise training, rather than showing residual effects from the last exercise bout. Type 2 diabetic patients were equally responsive to aerobic training, with similar relative increases in insulin sensitivity (∼30%) when matched for age, body composition, and fitness levels. However, as with acute exercise (4), chronic aerobic exercise does not appear to completely reverse the effects of diabetes because exercising type 2 diabetic subjects still had lower absolute insulin sensitivity (∼60%) and glucose MCR then their healthy, exercising counterparts (29). 138 Consitt et al. Despite using a similar training protocol to Bruce et al (29), Poirer et al (23) reported no improvements in insulin sensitivity in type 2 diabetic patients during 12 wk of training. However, when subjects were divided into 2 groups based on percent body fat, improvements in insulin sensitivity occurred in the nonobese type 2 diabetic subgroup. These findings support an earlier report by Ronnemaa et al (18) that only a certain subgroup of type 2 diabetics may achieve significant improvements in insulin sensitivity in response to exercise training. Based on this research, it appears that obesity and poor metabolic control (i.e., fasting plasma glucose >195 mg/dL) are barriers to improvements in insulin sensitivity in type 2 diabetic patients. Factors Influencing the Effects of Exercise on Insulin Sensitivity The results of exercise studies in patients with type 2 diabetes demonstrate considerable variability. Exercise- induced insulin sensitivity is likely regulated by a number of factors, including the characteristics of the patient (i.e., age, health, and current treatment methods) and the type of exercise used. The following section discusses how some of these variables may impact attempts to improve insulin sensitivity in the type 2 diabetic. Exercise Intensity and Duration. Obesity and lack of physical fitness in the diabetic patient may make low intensity exercise a more practical and attractive option, compared to higher intensity work. In fact, moderate intensity exercise may be just as beneficial for improving insulin sensitivity as higher intensity exercise, even in young individuals (30–32). O’Donovan et al (32) reported that, in a sedentary population, 24 wk of aerobic training at 60% VO 2 max produced similar improvements in insulin sensitivity to training at a higher intensity (80% VO 2 max), when controlling for energy expenditure. Based on these findings, the authors concluded that exercise involving an expenditure of 400 kcal per session, 3 times per week, was sufficient to increase insulin sensitivity, regardless of whether the exercise intensity was moderate or high. Burnstein et al (28) reported increased insulin sensitivity 1 h after a 60 min walk in obese type 2 diabetic subjects. In addition, other studies using patients with type 2 diabetes have demonstrated increased glucose clearance with daily walking (13) and improved insulin sensitivity when low intensity training was added to sulfonylurea therapy (33). These findings support the concept that metabolic benefits can be achieved with relatively low intensity aerobic exercise. Thus, low intensity exercise, such as walking, may provide adequate metabolic improvements and be a safe, practical option for individuals with type 2 diabetes. This finding is encouraging, especially for individuals who may not tolerate higher intensity exercise. However, it is likely that diabetic patients with more severe insulin resistance or older individuals, as discussed subsequently, may need to perform exercise sessions of1hinduration using moderate intensity exercise to obtain benefits. There are few studies that examine the effects of exercise duration on insulin sensitivity in type 2 diabetic patients. However, research conducted by Houmard et al (30) with sedentary, obese individuals indicates that an exercise duration of 170 min/wk was more effective improving insulin sensitivity than 115 min/wk, regardless of exercise intensity and volume. Future research is needed to determine if this relationship also exists in patients with type 2 diabetes. Age. Insulin sensitivity has been reported to decrease with age, with an average reduction of 8% per decade after age 20 in both men and women (34). It has been suggested that increased physical activity may attenuate this trend toward insulin resistance. Unfortunately, few studies have investigated the effects of aerobic exercise on insulin sensitivity or glycemic control in the older (i.e., >60 yr) type 2 diabetic population. Those studies that have been conducted have reported no change in glucose tolerance (14,35) or insulin sensitivity (35). It is unclear if the lack of improvement is specifically related to age or to more advanced, and irreversible, metabolic dysregulation as a consequence of longstanding diabetes. In addition, it should be noted that lack of randomization, use of nonsupervised exercise sessions, and low adherence rates may have biased these results. Therefore, recent studies in older, healthy subjects are summarized below to illustrate the effect of age per se on insulin action. DiPietro et al (36) recently reported that improvements in insulin sensitivity were observed with high intensity training (80% VO 2 max), but not with moderate (65% VO 2 max) or low intensity (50% VO 2 max) training in healthy, nonobese, older (73 ± 10 yr) women. Similarly, Short et al (34) reported that middle aged and older Chapter 9 / Exercise as an Effective Treatment for Type 2 Diabetes 139 healthy individuals did not demonstrate improvements in insulin sensitivity in response to aerobic exercise at a moderate intensity (70–80% max heart rate), despite improvement in GLUT 4 content and mitochondrial enzyme activity. It is possible that, in addition to the effects of exercise intensity, energy expenditure and exercise duration may play a role in the insulin responsiveness of older type 2 diabetic patients. Although the exercise program described by Short et al (34) only included exercise sessions of 20–40 minute duration, Evans et al (37) reported that exercise of 1 h duration at a slightly higher exercise intensity (83% max heart rate) was sufficient to increase insulin action (29% increase in glucose disposal rate relative to insulin concentration during the hyperglycemic clamp), in individuals 77–87 yr old. The improved insulin sensitivity was based on an average increase in total energy expenditure of 400 kcal/d. In comparison, DiPietro et al (36) reported increases in total energy expenditure of 41 and 102 kcal/d during the low and moderate intensity programs, respectively. Therefore, it is possible that older individuals can increase insulin sensitivity, but moderate aerobic intensity, with sufficient exercise duration, may be needed to increase energy expenditure significantly. No data are yet available to determine if such exercise recommendations are applicable specifically to older, type 2 diabetic patients. Fitness Level and Weight Loss. In addition to the increased insulin sensitivity observed with aerobic training, improvements in aerobic capacity and body composition are also noted. These findings have prompted the speculation that enhancement of either of these variables may predict improvement in the metabolic control of type 2 diabetes. In general, studies observing improved insulin sensitivity have reported increases in VO 2 max of 15% (15,22). However, it is apparent that improved VO 2 max does not guarantee enhanced insulin sensitivity, as other studies showing similar relative improvements in VO 2 max have demonstrated no statistical improvement in insulin action (38,39). In addition, improved insulin sensitivity has been demonstrated despite the absence of changes in aerobic capacity (27). Therefore, it is likely that the adaptations responsible for improvements in aerobic capacity are not the sole cause of enhanced insulin sensitivity. Similarly, weight loss is not required for improvements in either glycemic control or insulin sensitivity (20,23,29). A study using multiple regression analysis demonstrated that walking, without weight loss, had a positive effect on insulin sensitivity (13). Changes in body composition resulting in decreased adipose tissue, rather than overall weight loss, may have a greater influence on insulin action. Mourier et al (20) reported that improvements in insulin sensitivity were correlated with the loss of visceral adipose tissue in patients with type 2 diabetes whose weight was not altered with 8 wk of aerobic training. Diet and Medication. Two other factors that likely contribute to the observed variability in responses to exercise training are dietary modification and the use of antidiabetic drugs. In many instances, diet recommen- dations are made in addition to exercise as part of an overall lifestyle modification. The addition of regular exercise to dietary therapy improves glycemic control and insulin sensitivity compared to diet alone (13,15).In addition, it has been suggested that exercise, apart from negative energy balance, is effective in improving insulin sensitivity (40). Trovati et al (22) reported that daily walking improved insulin sensitivity in nonobese type 2 diabetic patients, despite the addition of 400 kcal per day to their diet to compensate for calories burned during the daily exercise regimen. Unfortunately, no known studies have directly compared the effectiveness of antidiabetic medication versus regular exercise in type 2 diabetic patients. Many studies have not been able to control for medication use or dietary intake when examining the value of regular exercise, which has likely contributed to the confusion over the effectiveness of exercise alone as a therapeutic model for type 2 diabetic patients. However, comparing the results from separate studies has highlighted the usefulness of regular exercise. Individuals following a regular exercise program can have similar improvements in insulin sensitivity and glycemic control to those produced by the use of some oral antidiabetic medications. For example, Bailey et al (41) reported that in type 2 diabetic patients, 24 wk of high dose (3 g/d) Metformin (MET) or a combination treatment of Rosiglitizone (RSG) and MET improved insulin sensitivity by 7% and 34%, respectively. In comparison, regular exercise has been reported to increase insulin sensitivity by approx 30% in patients with type 2 diabetes. Furthermore, the Diabetes Prevention Program Research Group (42) reported that a lifestyle intervention program including diet and exercise was more effective than metformin in preventing type 2 diabetes in individuals considered at risk. Results from this randomized, 140 Consitt et al. multi-center clinical trial demonstrated a risk reduction of 58% and 31% in the lifestyle intervention group and metformin group, respectively, in comparison with the placebo group. Thus, based on the improvements in insulin sensitivity, glycemic control, and the many other health benefits associated with exercise, regular exercise may be effective in the prevention and early treatment of diabetes. In addition, regular exercise may serve as a useful adjunctive therapy in combination with medication for those with advanced diabetes. Mechanisms of Improved Insulin Action with Aerobic Exercise Glucose uptake occurs through insulin-dependent and insulin-independent mechanisms (2). A number of possible explanations have been suggested to account for the immediate increase in glucose uptake during exercise, including exercise-induced increases in blood flow and capillary surface area (43). In addition, significant hyperglycemia itself may promote uptake through a mass action effect (8,11). The effect of exercise to increase glucose uptake during and immediately after exercise appears to be mediated via changes in the main glucose transporter in skeletal muscle, GLUT4. When skeletal muscle is in an unstimulated state, the majority of GLUT4 protein resides in storage sites within the muscle fiber. It has been suggested that at least 2 separate intracellular “pools” of GLUT4 exist within the muscle fiber, one stimulated by insulin and one by muscle contraction (44). Although people with type 2 diabetes have lower absolute levels of GLUT4 protein compared to their healthy counterparts, they appear to have a similar capacity to translocate GLUT4 to the plasma membrane in response to acute aerobic exercise (45). Therefore, it appears that the capacity for acute exercise- induced recruitment of GLUT4 from intracellular compartments remains intact in the type 2 diabetic patient. Although acute mechanisms such as increased blood flow and translocation of GLUT4 could be involved in the immediate increase in glucose uptake in the type 2 diabetic patient, the explanation of the long term improvement in insulin-mediated glucose uptake post exercise is less clear. Sustained increases in GLUT4 protein content occur after repeated bouts of exercise, and therefore this training effect could account for the improved glucose clearance in trained versus untrained muscle (46). In addition, individuals with type 2 diabetes often have depressed insulin receptor tyrosine kinase and phosphoinositide kinase-3 (PI3K) activity (47). Houmard et al (48) reported that as little as7dofaerobic training elicited increased insulin sensitivity associated with increased insulin stimulated PI3K activity in healthy men. However, preliminary studies suggest that the effect of exercise on the insulin signaling pathway may be impeded in insulin resistant patients with type 2 diabetes (49,50). Therefore, it is possible that other intracellular pathways are activated in type 2 diabetes, resulting in exercise-induced improvement in glucose uptake (51). Risks and Complications Associated with Aerobic Exercise Before initiating an exercise program, patients with type 2 diabetes should undergo a thorough medical evaluation. This evaluation should include an assessment of glucose control, questioning for any history of recurrent hypoglycemia or hypoglycemia unawareness, review of prescribed medications, and an examination for the presence of possible complications (i.e., cardiovascular disease, peripheral neuropathy, retinopathy, and/or nephropathy). In addition, based on the age of the individual and the duration of diabetes, an exercise stress test is advised. The American College of Sports Medicine (ACSM) and the American Diabetes Association (ADA) recommends that all type 2 diabetic patients over the age of 35 have a stress test performed before participating in an exercise program (52,53). The following possible areas of concern should be considered when prescribing exercise for patients with type 2 diabetes. Exercise-Induced Hyperglycemia The potential for exercise-induced hyperglycemia is a concern for type 2 diabetic patients, especially those with long-standing diabetes or those participating in high intensity exercise (>80% VO 2 max). Moderate to high intensity exercise requires increased glucose use to meet energy demands. As a result, counteregulatory hormones such as epinephrine and glucagon are released and increase the production and availability of glucose. In the healthy individual, there is typically a small hyperglycemic response that occurs during exercise and recovery, which results in a hyperinsulinemia to allow glucose concentrations to return to basal levels. However, in type 2 diabetes there is often an exaggerated response by epinephrine and glucagon during high intensity exercise, which Chapter 9 / Exercise as an Effective Treatment for Type 2 Diabetes 141 can produce hyperglycemia (25). In addition, patients with long-standing type 2 diabetes often lack the ability to release insulin to offset the exercise-induced hyperglycemia, which may result in dangerously high blood glucose levels. Therefore, blood glucose should be measured at baseline, during exercise, and throughout1hofrecovery in the type 2 diabetic patient, especially when initiating an exercise program. Cardiovascular Disease Patients with diabetes are at increased risk of myocardial infarction. Therefore, an exercise prescription should be under physician supervision if abnormalities are observed during the initial exercise stress test. Diabetic patients with known coronary artery disease, but without cardiac ischemia or signs of heart arrhythmias, may participate in supervised, approved exercise.(54,55). Autonomic Neuropathy Autonomic neuropathy can decrease maximal heart rate and blood pressure, as well as elevate resting heart rate. A physician should evaluate all patients with this complication before an exercise program is started owing to increased risk of postural hypotension and the potential to miss early warning signs of ischemia (55). Owing to the lower fitness level of individuals with autonomic neuropathy (56), the exercise prescription should generally include low-intensity daily activities (55). In addition, owing to the effects of autonomic neuropathy on heart rate and blood pressure, it is advised that a rating of perceived exertion (RPE) be used to monitor exercise intensity. The Borg RPE scale is the most frequently used method of determining exercise intensity (57). With its use, the exerciser is told to subjectively rate his or her perceived exertion on a scale that ranges between 6 (no exertion) and 20 (maximal exertion). Typically, moderate intensity exercise elicits ratings between 12 and 14. It is also suggested that exercise sessions avoid hot or cold environments because individuals with autonomic neuropathy tend to have impaired thermoregulation (58). Peripheral Neuropathy Peripheral neuropathy is of concern to the exercising type 2 diabetic patient because the loss of distal sensation to the lower legs and feet can lead to musculoskeletal injury, or cutaneous injury or infection. Individuals with peripheral neuropathy should participate in nonweight- bearing activities such as cycling or swimming (55). Proper footwear (i.e., gel or air running shoes) and daily examination of the feet is necessary when weight-bearing activities are included, to detect any foot lesions that could lead to serious infection. Nephropathy It is unclear how the acute exercise-induced increase in blood pressure might affect nephropathy, but it is suggested that exercise training may control factors (i.e., blood pressure and blood glucose) thought to contribute to the progression of this problem. Individuals with diagnosed nephropathy should avoid exercise causing systolic blood pressure to rise to values above 180 mmHg (55). Therefore, high intensity aerobic and resistance exercise should be avoided. Maintenance of proper hydration levels is imperative in individuals with nephropathy. Retinopathy Because increasing blood pressure in the exercising diabetic patient is a concern, and might adversely affect retinopathy, all type 2 diabetic patients with retinopathy should be evaluated by an opthalmologist before starting an exercise program. If proliferative or severe retinopathy is present, the individual is generally instructed to avoid high intensity exercise or exercise involving jarring movement, such as high-impact aerobics or activities that involve lowering the head such as yoga or gymnastics (53). Instead, low intensity exercise, such as walking or stationary cycling, is recommended. RESISTANCE EXERCISE Resistance-oriented exercise training can have positive effects on glucose disposal, insulin action, and lipid metabolism. Improvements in insulin sensitivity and glucose disposal in normal (59), insulin resistant (60), and type 2 diabetic populations (61,62) have been shown following resistance training programs. As little as one 142 Consitt et al. resistance exercise session may improve insulin action, as evidenced by a decreased insulin response during an oral glucose tolerance test with no change in glucose response (63), although greater benefits appear to accompany exercise training (64,65). Most studies of resistance exercise in type 2 diabetic patients utilize a progressive intensity program, increasing load as muscular strength increases, to maintain exercise intensity. Several groups have begun to examine the additional benefits of high intensity resistance training, particularly in elderly type 2 diabetic patients (61,66,67). At present, it is difficult to determine an ideal training intensity owing to the lack of continuity among study assessments. Nevertheless, no adverse effects have been reported in the general diabetic population who reach training intensities of 80–85% of the maximum amount of weight an individual can lift at one time (generally referred to as the 1 repetition maximum or 1 RM), even among the elderly (67). With a 90–100% compliance rate reported (61,67,68), resistance exercise represents an often underused preventative and treatment modality for type 2 diabetes. Effects of Resistance Exercise on Blood Glucose Concentration It is well accepted that resistance exercise improves glycemic control (69). Type 2 diabetic patients show improvements in fasting blood glucose concentrations after as little as 10 wk of moderate to high intensity resistance exercise (50–85% of 1RM), performed 3 d/wk (16,61,67,68). Some report improvements in HbA1c concentrations after 10 wk of a similar intervention, although most observe significant improvements following a protocol of longer duration (16,66–68). In these studies, patients with type 2 diabetes performed progressive resistance training at a moderate to high intensity 3 d/wk for 4–6 mo. On each day of exercise, patients performed 1–2 sets of 10–15 repetitions to fatigue. A similar protocol (64) used a continuous glucose monitoring system (CGMS) to examine changes in glucose regulation during a 48-h period, and noted a 16% improvement in mean blood glucose levels. Nevertheless, others have reported nonsignificant changes in fasting glucose (70) and HbA1c (70,71) despite similar subject populations and exercise protocols. The reason for this discrepancy remains unknown, although the large range in exercise intensity and/or differences in training duration used in these studies may have played a role. Initial concern that high intensity resistance exercise could impair muscle mediated glucose uptake, as a result of acute muscle damage, has not been supported by research. Improved glycemic control (12–15%) during oral glucose tolerance tests within 24 h of the last exercise bout have been reported in type 2 diabetic patients as well as subjects with impaired glucose tolerance (65,72). Results from an oral glucose tolerance test performed 18 h after exercise demonstrated that a single resistance exercise bout, consisting of 3 sets of 10 repetitions using 7 exercises, improved insulin profiles but did not affect glucose in either young healthy individuals or older patients with type 2 diabetes (63), indicating an improvement in insulin action. Effects of Resistance Exercise on Insulin Action Several reports have used the hyperinsulinemic-euglycemic clamp to determine insulin sensitivity in type 2 diabetic patients following resistance exercise training. Insulin sensitivity improved by 48% after only 4–6 wk of progressive resistance exercise (5 d/wk) in nonobese patients with type 2 diabetes (BMI = 22 kg/m 2 ), using 2 sets of 10 and 20 repetitions for upper and lower body exercises, respectively (62). Similarly, 6 mo of resistance training in insulin resistant patients training 3 d/wk, using 1–3 sets of 8–15 repetitions, showed a 10% improvement in insulin sensitivity (73). Factors Influencing Insulin Sensitivity with Resistance Exercise Exercise Intensity and Training Duration. When prescribing the level of intensity for resistance exercise, a common method is to use a percentage of the 1 RM. As described earlier, 1 RM refers to the maximum amount of weight an individual can lift successfully one time. Owing to safety implications a “true” 1 RM is not usually performed, and instead can be estimated as described by Wathen (74). Briefly, a light weight is initially used and the patient is instructed to perform as many repetitions as safely possible with it. Based on the number of completed repetitions, a predictive 1-RM table can calculate what the patient’s estimated 1 RM load would be for that particular exercise. Once this is achieved, the appropriate load can be selected based on the exercise intensity required. As a general point of reference, resistance exercise of moderate intensity (50–70% 1 RM) usually equates to 8 to 12 repetitions. Chapter 9 / Exercise as an Effective Treatment for Type 2 Diabetes 143 Most studies examining resistance exercise training in type 2 diabetes employ a moderate exercise intensity (50–70% 1 RM) (62,70–72), although it appears that high intensity resistance training (70–85%) is also well- tolerated (61,66,67). Reductions in HbA1c were similar following 4–6 mo of high intensity resistance exercise (approx 9 upper and lower body exercises, 3 d/wk, of progressive resistance at 50–85% 1 RM, using approx 3 sets of 8–10 repetitions) (66,67), and 4 mo of moderate intensity resistance exercise (10 upper and lower body exercises, 3 d/wk, 1–2 sets of 10–15 repetitions of progressive resistance to fatigue) (64). For example, Dunstan et al (67) demonstrated reductions in HbA1c from 8.1% to 6.9%, whereas Cauza et al (64) reported mean reductions in HbA1c from 8.3% to 7.1% with a lower intensity program, although exercise intensity in this latter study was not explicit and may have bordered on high intensity during certain training sessions. The lack of specific criteria for classifying exercise intensity in these studies makes it difficult to ascertain potential differences in intensity-related outcomes. Additionally, no studies have directly compared the effects of different intensities of resistance training in patients with type 2 diabetes; therefore, there is no conclusive evidence that high intensity resistance training provides greater improvement in glucose control. Resistance exercise training has been shown to result in large improvements in insulin sensitivity within 4–6 wk (62). In a controlled study of normal weight (mean BMI of 22 kg/m 2 ) type 2 diabetic patients, moderate intensity resistance exercise (approx 40–50% of 1RM, 5 d/wk) improved insulin sensitivity by 48% during a hyperinsulinemic-euglycemic clamp measurement performed 2 d after the last exercise bout (62). Ibañez et al (61) observed similar improvements in insulin sensitivity (46%) in type 2 diabetic patients using a hyperinsulinemic-euglycemic clamp 24 h after completion of a 16 wk training session. In spite of the longer training session, the latter experiment only employed resistance exercise 2 d/wk, but involved a much higher intensity (70–80% 1RM). The similar outcome between these two studies is likely explained by similar improvements in muscular strength (approx 17%). These data indicate that exercise intensity and the duration of training may be variables affecting the extent of improved glycemic control, secondary to their effects on muscle strength and/or hypertrophy. Duration of Type 2 Diabetes. At present, there are insufficient data to determine the benefits of beginning a resistance training program as early as possible after diagnosis of type 2 diabetes. Most reports of resistance training in type 2 diabetic patients include those who have been diagnosed for at least 3 yr (average of 8 yr) (16,64,66–68,70,71). However, one study of overweight (BMI = 28.3 kg/m 2 ) elderly men (67 yr old) with newly diagnosed type 2 diabetes showed improvements in insulin sensitivity similar to those with a longer history of diabetes (61). Ryan et al (73) have reported that older individuals with more pronounced insulin resistance show greater improvements than those with less severe insulin resistance following resistance exercise training (3 d/wk for 6 mo, performing 1–3 sets of 8–15 repetitions on each day of exercise). This is different from aerobic- oriented exercise training, in which those patients with more severe insulin resistance show little improvement in insulin sensitivity compared with patients having less severe insulin resistance (20). This implies that similar improvements in insulin sensitivity can be achieved in both newly diagnosed patients and those who have had diabetes for many years. This also implies that patients who have had type 2 diabetes for a longer duration may benefit from resistance training, whereas aerobic training has not been consistently successful in improving glycemic control in such patients. In addition, for patients in a prediabetic state (i.e. impaired glucose tolerance) data demonstrating a complete reversal of impaired glucose tolerance following 4 mo of either moderate resistance or aerobic training (60) should encourage practitioners to prescribe resistance and/or aerobic training as soon as diabetes diagnosis takes place, or if possible, when the individual is considered at risk for the development of type 2 diabetes (i.e., relatives of type 2 diabetics). Additional Benefits of Resistance Exercise Benefits of moderate or high intensity resistance training in patients with type 2 diabetes include improved mobility as well as reduced adiposity (75). Such improvements are generally observed in those who also experience increases in muscle strength and/or size, generally without a change in body weight (61,62,66,71). This can be achieved at intensities of 60–100% of 1 RM (75). Resistance exercise may also be tolerated by untrained or obese individuals who have difficulty performing aerobic exercise (66,76). Several studies have examined the safety and efficacy of resistance training at higher exercise intensities (70–85% 1RM) in older individuals with type 2 diabetes (60–80 yr old). These supervised exercise programs have produced high rates of compliance 144 Consitt et al. (88–99%), improvements in glycemic control (5–15%), and little to no adverse effects (61,66,67). One report found, however, that compliance rates and recorded improvements in HbA1c concentrations may decline when exercise is performed at home or in an unsupervised environment, despite maintenance of muscular strength (77). Overall, when performed on a regular basis, in a supervised environment, resistance exercise may prove at least as, if not more beneficial than other treatment methods (i.e., aerobic exercise, pharmaceutical treatment) for obese and older patients. When accompanied by dietary restriction, resistance exercise training may also help to maintain or even improve muscle mass that is typically lost owing to energy deficit (55). This is of potential benefit, not only by maintaining the mass of tissue available for glucose uptake, but also by maintaining mobility and strength, particularly in older individuals, who tend to lose muscle mass. Additionally, exercise training, when used in conjunction with dietary restriction, is more effective than diet alone for the reduction of fasting blood glucose levels (67). Mechanisms of Improved Insulin Action with Resistance Exercise The improvements of glycemic control following resistance training have often been attributed to the accom- panying muscle hypertrophy, which effectively increases the tissue mass responsible for glucose uptake. Despite a high positive correlation between increases in lean body mass and insulin action, the magnitude of change is much greater for glucose disposal than body composition, indicating that a direct causal relationship does not exist (69). Holten et al (76) have shown that 6 wk of 1-legged resistance training at 70–80% of 1RM in type 2 diabetic patients improved insulin action without a concomitant increase in muscle mass. Blood flow was increased in the trained leg versus the untrained leg, while the rate of glucose uptake remained unchanged. The authors concluded that cellular glucose extraction may have increased; otherwise greater blood flow would have resulted in decreased glucose uptake. Indeed, glycogen stores were elevated in the trained leg compared with the untrained leg. Muscle biopsy analysis revealed increased protein kinase B (PKB) levels in the trained leg, which is involved in glycogen synthase activity and possibly GLUT-4 translocation. Glycogen synthase and GLUT-4 protein contents were also increased with resistance training. Together, these data indicate that, as with aerobic training, there may be a direct effect of resistance training on insulin action at the level of the skeletal muscle cell, independent of changes in muscle mass. It is also important to note that these changes in PKB protein content were independent of changes in the oxidative capacity of the muscle (76). It is thought that aerobic exercise-induced GLUT-4 translocation is mediated, in part, by AMPK and cytosolic calcium levels, which also stimulate muscle oxidative capacity (69). The authors hypothesized that the cellular response that enhance insulin action in skeletal muscle following resistance exercise are distinct from those of aerobic exercise (69). Further research is necessary to determine if this is so and whether the addition of resistance exercise to an aerobic exercise program would provide added improvements to insulin sensitivity via a separate cellular mechanism. Risks and Complications Associated with Resistance Exercise Resistance exercise training introduces additional concerns, including the risk of cardiac ischemia and/or hypertension, but, when carefully supervised, this type of exercise can provide exceptional benefit with little to no adverse effect. Nevertheless, as with aerobic exercise, there are contraindications to resistance exercise for the type 2 diabetic patient. One of the main concerns for diabetic patients is an elevation in blood pressure during or after a resistance training bout. However, although transient increases in blood pressure are often observed during a single repetition, particularly at higher intensities, blood pressure generally returns to baseline values or lower within 1–2 s after activity in healthy individuals (78). In fact, a decrease of 5–15% in both systolic and diastolic blood pressures occurs following 4–6 mo of moderate and high intensity resistance training (16) even in older type 2 patients, averaging 67 yr old (66,67). These decreases in resting and postexercise blood pressures are similar to those following 4 mo of aerobic training (66). For diabetic patients with other clinical manifestations of diabetes, such as cardiovascular disease or retinopathy, there are no consistent data regarding resistance exercise. A pretraining exercise stress test should be performed on those patients with risk factors for CAD to rule out ischemia, arrhythmias, or an exaggerated hypertensive response to exercise (75). Load or weight bearing exercise is contraindicated for patients with peripheral vascular disease or peripheral neuropathy (55). Resistance exercise may provide a beneficial exercise alternative. Patients Chapter 9 / Exercise as an Effective Treatment for Type 2 Diabetes 145 may perform many exercises in a seated position without putting additional pressure on the lower extremities. Nevertheless, it is still necessary to assure that proper footwear is used and that feet are periodically examined for sores and injuries (55). There is no evidence to suggest that resistance exercise exacerbates the blood pressure- induced progression of nephropathy, although, as a precautionary measure, ACSM recommends that systolic blood pressures do not exceed 180–200 mm Hg during or after exercise, as is the case with aerobic exercise (55). Resistance exercise in these patients may even improve muscle mass and nutritional status for those on a low protein diet (75). For patients with cardiovascular disease, resistance exercise may be safer than aerobic exercise because of the lower heart rate and rate-pressure product (indicator of myocardial oxygen consumption: heart rate multiplied by systolic blood pressure) responses to resistance exercise (79). For patients with less severe or moderate retinopathy, exercise intensities should be kept at a minimum (55). Although there are no data proving that exercise of any type will worsen the condition, the ACSM recommends that low intensity aerobic exercise may be performed by some individuals with retinopathy, but for patients with more severe retinopathy, motions that cause large increases in blood pressure, such as putting the head down or the arms over the head, are not advised (55). A general consensus of the resistance training literature is that low intensity resistance exercise may be tolerated by some patients with mild, nonproliferative retinopathy, although the effect of resistance exercise on intraocular pressure is not known (75). All patients should avoid performing the valsalva maneuver or near maximal lifts. COMBINED AEROBIC AND RESISTANCE TRAINING Recent recommendations by the ACSM and the ADA suggest that a combination of aerobic and resistance exercise be included in an exercise prescription (53,55). These recommendations are based on the conclusion that improvements in insulin sensitivity can result from exercise-specific adaptations. Poehlman et al (80) have shown that the increase in lean body mass associated with resistance exercise contributes to increased glucose disposal. In contrast, improvements in glucose disposal observed with aerobic training are owing to improvements in the intrinsic capacity of the muscle because these improvements are independent of changes in lean body mass (80). A combination of aerobic and resistance exercise training might therefore result in the physiological benefits of both types of exercise, and as a consequence the greatest degree of insulin-mediated glucose disposal. There are few studies that have evaluated the benefits of combined exercise training in the diabetic population. Most studies examining the addition of resistance exercise to aerobic exercise programs have found beneficial results over aerobic exercise alone (16,81). However, the majority of these have included greater overall exercise workloads during combined exercise, therefore potentially biasing the results. One randomized 16-wk study controlled for energy expenditure between a combined aerobic and resistance training group and a group only participating in aerobic exercise (24). Although there was no significant change in glycosylated hemoglobin, insulin action was significantly increased in type 2 diabetic subjects participating in combined aerobic and resistance training, but not aerobic training. Tokmakidis et al (82) also reported beneficial results; improvements in glucose tolerance, insulin sensitivity and glycemic control were found in postmenopausal women after only 4 wk of supervised aerobic and resistance exercise, with additional improvements at 16 wk. Although both studies used postmenopausal females, only Tokmakidis et al (82) reported improvements in glycolated hemoglobin after 4 wk of combined training. It is possible that the design of the cross-training program needs to be considered. Subjects in the Cuff et al (24) study completed3daweek of circuit training where both aerobic and resistance exercises were completed on the same day. In contrast, subjects in the Tokmakidis et al (82) study completed2dofresistance exercise and2dofaerobic exercise on separate days. It may be too fatiguing for individuals with a low exercise tolerance to combine both types of exercise within one session, limiting the ability to maintain adequate exercise intensity and therefore minimizing the exercise benefits. In contrast, if individuals are capable of completing a fairly high exercise volume, circuit training has been reported to reduce fasting blood glucose levels as well as glycosylated hemoglobin levels within 8 wk (83). Thus, depending on the specific prescription, improvements in diabetes control may result from a combination of aerobic and resistance exercise. 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