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Physical Activity/Exercise and Type 2 Diabetes

¹ Department of Medicine, University of Ottawa, Ottawa, Canada
² School of Human Kinetics, University of Ottawa, Ottawa, Canada
³ Clinical Epidemiology Program, Ottawa Health Research Institute, Ottawa, Canada
⁴ Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee
⁵ Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, Boston, Massachusetts

Address correspondence and reprint requests to Ronald J. Sigal, Clinical Epidemiology Program, Ottawa Health Research Institute, 1053 Carling Ave., Ottawa, Ontario, Canada K1Y 4E9. E-mail: rsigal{at}ohri.ca

Abbreviations: ACSM, American College of Sports Medicine • ADA, American Diabetes Association • CAD, coronary artery disease • CVD, cardiovascular disease • DPP, Diabetes Prevention Program • ECG, electrocardiogram • EGP, endogenous glucose production • IGT, impaired glucose tolerance • IRS, insulin receptor substrate • MAP, mitogen-activated protein • MET, metabolic equivalent • NEFA, nonesterified fatty acid • PI, phosphatidylinositol I • RM, repetition maximum

	INTRODUCTION

TOP INTRODUCTION Definitions PHYSIOLOGY OF FUEL METABOLISM... EVALUATION OF THE DIABETIC... PHYSICAL ACTIVITY AND PREVENTION... AEROBIC FITNESS AND AEROBIC... RESISTANCE EXERCISE FLEXIBILITY EXERCISE EXERCISE IN THE PRESENCE... EXERCISE IN THE PRESENCE... COMPARISON BETWEEN THE PROPOSED... References

 
For decades, exercise has been considered a cornerstone of diabetes management, along with diet and medication. However, high-quality evidence on the importance of exercise and fitness in diabetes was lacking until recent years. The last American Diabetes Association (ADA) technical review of exercise and type 2 diabetes (formerly known as non–insulin dependent diabetes) was published in 1990. The present work emphasizes the advances that have occurred since the last technical review was published.

Major developments since the 1990 technical review include:

• Advances in basic science, increasing our understanding of the effects of exercise on glucoregulation.
  
• Large clinical trials demonstrating that lifestyle interventions (diet and exercise) reduce incidence of type 2 diabetes in people with impaired glucose tolerance (IGT).
  
• Meta-analyses of structured exercise interventions in type 2 diabetes showing: 1) effectiveness of exercise in reducing HbA_1c, independent of body weight; and 2) association between exercise training intensity and change in HbA_1c.
  
• Large cohort studies showing that low aerobic fitness and low physical activity level predict increased risk of overall and cardiovascular disease (CVD) mortality in people with diabetes.
  
• Clinical trials showing effectiveness of resistance training (such as weight lifting) for improving glycemic control in type 2 diabetes.
  
• New data on safety of resistance training in populations at high risk for CVD.
  

Based on this new evidence, we have refined the recommendations on the desired types, amounts, and intensities of aerobic physical activity for people with diabetes. Resistance training will now be recommended in a broader group of patients and at a broader range of intensity than done previously. There are other areas in which new evidence is lacking, but we feel that previous recommendations may have been more conservative than necessary. These areas include indications for exercise stress test before beginning an exercise program and precautions regarding exercise in the presence of some specific complications or suboptimal metabolic control. The levels of evidence used are defined by the ADA (see Ref. 1).

A new Handbook of Exercise was published in 2002 by the ADA, including 40 articles by leading experts on specific topics related to exercise and diabetes. Space limitations do not allow the present work to be comprehensive and, where appropriate, we refer the reader to chapters in the Handbook of Exercise and other review articles for additional details. The present review focuses on type 2 diabetes. Issues primarily germane to type 1 diabetes will be covered in a subsequent technical review.

	Definitions

TOP INTRODUCTION Definitions PHYSIOLOGY OF FUEL METABOLISM... EVALUATION OF THE DIABETIC... PHYSICAL ACTIVITY AND PREVENTION... AEROBIC FITNESS AND AEROBIC... RESISTANCE EXERCISE FLEXIBILITY EXERCISE EXERCISE IN THE PRESENCE... EXERCISE IN THE PRESENCE... COMPARISON BETWEEN THE PROPOSED... References

 
The following definitions are based on those outlined in "Physical Activity and Health," the 1996 report of the Surgeon General (2).

Physical activity.
Bodily movement produced by the contraction of skeletal muscle that requires energy expenditure in excess of resting energy expenditure.

Exercise.
A subset of physical activity: planned, structured, and repetitive bodily movement performed to improve or maintain one or more components of physical fitness. In the present review, the terms "physical activity" and "exercise" will be used interchangeably.

Physical fitness.
This includes cardiorespiratory fitness, muscular fitness, and flexibility.

Cardiorespiratory fitness (also known as cardiorespiratory endurance or aerobic fitness).
The ability of the circulatory and respiratory systems to supply oxygen during sustained physical activity. The gold standard for measurement of cardiorespiratory fitness is a test of maximal oxygen uptake (O_2max), typically performed using indirect calorimetry on a treadmill or bicycle ergometer. Cardiorespiratory fitness can be estimated accurately using graded maximal exercise testing on standard treadmill or bicycle ergometer protocols without indirect calorimetry (3).

Aerobic exercise.
This consists of rhythmic, repeated, and continuous movements of the same large muscle groups for at least 10 min at a time. Examples include walking, bicycling, jogging, continuous swimming, water aerobics, and many sports. When performed at sufficient intensity and frequency, this type of exercise increases cardiorespiratory fitness.

Intensity of aerobic exercise.
This will be described as "moderate" when it is at 40–60% of O_2max (50–70% of maximum heart rate) and "vigorous" when it is at >60% of O_2max (>70% of maximum heart rate).

Muscular fitness.
This refers to strength (the amount of force a muscle can exert) and muscular endurance (the ability of the muscle to continue to perform without fatigue).

Resistance exercise.
Activities that use muscular strength to move a weight or work against a resistive load. Examples include weight lifting and exercises using weight machines. When performed with regularity and moderate to high intensity, resistance exercise increases muscular fitness.

Intensity of resistance exercise.
This will be described as "high" if the resistance is 75% of the maximum that can be lifted a single time (75% of 1-RM [repetition maximum]) and "moderate" if resistance is 50–74% of 1-RM.

Flexibility.
This term refers to the range of motion available at joints.

Flexibility exercise.
This is exercise (typically stretching) aimed at increasing or maintaining range of motion at joints.

MET (metabolic equivalent).
A MET is a unit of intensity equal to energy expenditure at rest. Physical activity at 3 METs uses three times as much energy as stationary sitting. MET-hours are units of exercise volume in which intensity in METs is multiplied by duration of the activity in hours.

	PHYSIOLOGY OF FUEL METABOLISM DURING EXERCISE

TOP INTRODUCTION Definitions PHYSIOLOGY OF FUEL METABOLISM... EVALUATION OF THE DIABETIC... PHYSICAL ACTIVITY AND PREVENTION... AEROBIC FITNESS AND AEROBIC... RESISTANCE EXERCISE FLEXIBILITY EXERCISE EXERCISE IN THE PRESENCE... EXERCISE IN THE PRESENCE... COMPARISON BETWEEN THE PROPOSED... References

 
For more detailed reviews of the physiology and basic science of exercise, see Refs. 4–6.

Exercise results in a shift in fuel usage by the working muscle from primarily nonesterified fatty acids (NEFAs) to a blend of NEFAs, glucose, and muscle glycogen. Muscle glycogen is the chief source of energy during the early stages of strenuous exercise, while with increasing exercise duration the contribution of circulating glucose and particularly NEFAs become more important as muscle glycogen gradually depletes. The origin of circulating glucose also shifts from hepatic glycogenolysis to gluconeogenesis. With increasing exercise intensity the balance of substrate usage shifts to greater carbohydrate oxidation. Although the metabolic response to exercise is influenced by numerous factors (e.g., nutrition, age, type of exercise, and physical condition), the most important factors affecting fuel utilization are generally work intensity and duration.

Regulation of fuel mobilization during aerobic exercise
Fuel mobilization is controlled during aerobic exercise largely by the neuroendocrine system. If exercise is sustained, a decrease in insulin secretion and increases in glucagon, catecholamines, cortisol secretion, and other hormones are observed. Postulated signals causing these hormonal and neural changes may be related to deficits in fuel availability, neural feed-forward mechanisms, or increased afferent nerve activity from the working limb, splanchnic bed, or carotid sinus (7,8). In addition to neuroendocrine factors, other parameters such as blood-flow shifts and subtle changes in glycemia or metabolic state play a role in the control of fuel metabolism during exercise.

Endogenous glucose production.
Endogenous glucose production (EGP) is closely coupled to the increase in muscle glucose uptake during moderate exercise. Studies conducted in animal models and human subjects have defined the importance of insulin and glucagon in the stimulation of EGP during light- and moderate-intensity aerobic exercise (7). The exercise-induced increment in glucagon stimulates glycogenolysis and gluconeogenesis (7). Glucagon also stimulates hepatic amino acid metabolism (9) and fat oxidation (7), providing precursors for gluconeogenesis and energy to fuel it. The decrease in insulin during exercise is necessary for the full glycogenolytic response (7). When the decline in portal vein insulin is eliminated, the increase in EGP is reduced by 50%. The importance of the exercise-induced increase in EGP to whole-body glucose homeostasis is illustrated in Fig. 1. If the liver did not release more glucose in response to exercise, hypoglycemia would result.

View larger version (19K): [in this window] [in a new window]   Figure 1— Potential impact of impaired EGP on glucose homeostasis during exercise. If EGP is not coupled to the increase in glucose utilization, hypoglycemia may result.

Type 2 diabetic patients with a mild to moderate elevation in glucose levels may experience a fall in glucose during exercise due to impaired endogenous glucose output. This population, when maintained on diet therapy alone or diet and sulfonylurea therapy with postabsorptive plasma glucose in excess of 200 mg/dl and normal basal insulin, shows a fall in glycemia of 50 mg/dl during a 45-min exercise bout (21). High-intensity intermittent exercise performed in postprandial type 2 diabetic subjects (22) has the same plasma glucose- and insulin-lowering effect as moderate-intensity exercise of equivalent caloric requirement (22).

Fat metabolism.
Moderate exercise is associated with an 10-fold increase in fat oxidation. This is due to increased energy expenditure coupled with greater fatty acid availability. The increase in fatty acid availability is due both to an increase in lipolysis and decreased re-esterification of NEFA to triglycerides (23). Acute NEFA release from adipose tissue is regulated primarily by the actions of insulin and the catecholamines. When the exercise-induced fall in insulin is prevented, the increase in NEFA levels is prevented (7). NEFA levels are diminished during exercise by ß-blockade, presumably due to a suppression of lipolytic activity. Not only are catecholamines increased by exercise, but adipocytes taken following exercise have increased lipolytic responsiveness to ß-adrenergic actions of the catecholamines (24). Besides fat mobilization from adipocytes, there is evidence (25,26) that intramuscular triglycerides represent an important fuel for working muscle. Metabolism of fats during exercise is quantitatively different in obese type 2 diabetic subjects in relation to healthy subjects. In this population, utilization of plasma free fatty acids is reduced, while intramuscular triglyceride utilization is increased (27). Interestingly, lean type 2 diabetic individuals do not have this adaptation to exercise (28).

Muscle glycogenolysis.
Glycogen breakdown is regulated by glycogen phosphorylase. It is interesting that although muscle glycogenolysis increases with increasing work rate, phosphorylase transformation to its active phosphorylated form is not (29). This suggests that allosteric regulators may be important activators of glycogen phosphorylase during exercise (30). ß-Adrenergic receptor stimulation by catecholamines plays a major role in the mobilization of muscle glycogen during exercise (7).

Exercise-induced muscle glucose uptake
Muscle glucose uptake requires three serial steps (Fig. 2). These are the delivery of glucose from the blood to the muscle, transport of glucose across the muscle membrane, and phosphorylation of glucose within the muscle. The effect of exercise on these specific steps that comprise muscle glucose uptake is discussed below and illustrated in Fig. 1.

View larger version (21K): [in this window] [in a new window]   Figure 2— Schematic representation of the control of muscle glucose uptake during exercise. Control of glucose is distributed between three serial steps. These are extracellular glucose delivery from blood to muscle membrane, muscle membrane glucose transport, and intracellular glucose phosphorylation. Below each gear are known mechanisms of regulation. Arrows associated with those mechanisms reflect exercise adaptations. Note that acute exercise increases hexokinase II protein; however, this adaptation is slow in onset. Modified from Wasserman and Halseth (47).

Membrane glucose transport.
Exercise increases glucose transport by stimulating GLUT4 translocation to the muscle cell surface (34). A possible mechanism involves sensing of an increase in muscle AMP, which stimulates AMP kinase, causing a number of metabolic changes, including increased glucose transport (35). Muscle AMP kinase measurements are, in fact, consistent with stimulation by exercise (36,37). Such a role for this enzyme is supported by the demonstration that pharmacological activation of AMP kinase stimulates GLUT4 translocation (38) and glucose uptake (36,39,40) and is linked to other changes in enzyme activities (35,41) and gene transcription (42,43) associated with exercise. AMP kinase activation is not the sole mechanism of contraction-stimulated muscle glucose uptake (40). In addition to AMP kinase activation, data suggest that nitric oxide (NO) may mediate contraction-induced glucose uptake. Electrical stimulation increases muscle NO synthesis, and pharmacologic inhibition of NO synthesis decreases uptake of a glucose analog (44). Another study (45) showed that NO synthase inhibition at the working leg caused a reduction in leg glucose uptake without affecting blood flow. NO synthase has also been implicated as a mediator of AMP kinase–induced glucose uptake (46).

Muscle glucose phosphorylation.
The first step in glucose metabolism is phosphorylation by a hexokinase. There is evidence that glucose phosphorylation is the primary limitation to glucose uptake during exercise (47). Hexokinase II overexpression improves the ability to consume glucose in mice, and reducing the glucose 6-phosphate pool by a glycogen-depleting fast enhances uptake of glucose even further (48). In contrast to the extensive work on glucose transport, very little is known regarding the effects of exercise on hexokinases. The percentage of hexokinase activity associated with mitochondria, where its specific activity is greater, does not appear to be increased with exercise in human muscle (49,50). Exercise has been shown to stimulate muscle hexokinase II gene transcription (51), leading to an increase in its protein (50). The increase in hexokinase activity lags behind the increase in hexokinase II mRNA (51) and may be more significant to the persistent increase in insulin action following exercise or adaptations that occur with training.

Insulin-independent and insulin-sensitive muscle glucose uptake during exercise
The preceding section described the steps required for muscle glucose uptake. The flux through these steps is controlled by insulin-independent signals generated within working muscle, but can be greatly modified by actions of circulating insulin. Exercise increases both insulin-independent muscle glucose uptake and insulin sensitivity. The focus below is on these two important characteristics of exercise.

Insulin-independent glucose uptake.
The cell signaling pathway of contraction-stimulated glucose transport is distinct from that for insulin-stimulated glucose transport (52,53). Although the increase in membrane transporters in response to both insulin and exercise result from an increase in GLUT4 translocation, these stimuli recruit GLUT4 from different intracellular pools (54). Evidence that cell signaling for glucose uptake is different for exercise and insulin is supported by the demonstration that muscle contraction does not increase phosphorylation of insulin receptor substrate (IRS)-1 and -2 or phosphatidylinositol I (PI) 3-kinase (55), all of which are involved in insulin signaling. In addition, wortmannin, an inhibitor of PI 3-kinase, eliminates insulin-stimulated glucose uptake but not glucose transport in isolated contracting muscle (34). The importance of insulin-independent mechanisms in control of exercise-stimulated muscle glucose uptake is further exemplified by studies in type 2 diabetic individuals. Although type 2 diabetic individuals are usually insulin resistant, they are not resistant to the stimulatory effects of exercise on glucose utilization. Type 2 diabetic subjects retain the capacity to translocate GLUT4 to the sarcolemma in response to exercise (56). The functional recruitment of GLUT4 transporters coupled to elevated circulating glucose levels can actually lead to a greater rate of glucose utilization by muscle of people with type 2 diabetes.

Insulin-dependent glucose uptake (insulin sensitivity).
Exercise and insulin stimulate glucose utilization synergistically (7). The primary route of insulin-mediated glucose metabolism at rest and in the postexercise state is nonoxidative metabolism (7). Exercise, however, shifts the route of insulin-stimulated glucose disposal so that all glucose consumed by muscle is oxidized (7). The effects of this increase in insulin action are probably most important in the postprandial state and in the intensively treated diabetic state, when insulin levels are higher than those that normally accompany exercise. Several mechanisms have been proposed to explain how exercise enhances insulin action (6,57,58). Hemodynamic adjustments increase capillary surface area in working muscle, increasing the availability of insulin. Exercise may also increase insulin-stimulated glucose utilization by a mechanism secondary to insulin’s suppressive effect on non-NEFAs. Insulin action is also directly enhanced at working muscle by activation of postinsulin receptor signaling (32).

Carbohydrate ingestion and exercise
Glucose feeding has been shown (7) to improve exercise endurance. The underlying mechanism for this improvement is probably related to increased glucose availability to working muscle. The amount, form, and timing of an oral carbohydrate load, along with the duration and intensity of exercise, will determine how effective glucose ingestion is at sustaining glucose availability to the working muscle.

Carbohydrate ingestion slows the mobilization of endogenous fuels during prolonged exercise. It also slows the rate of fall of circulating glucose that would otherwise occur or leads to an overt increase in circulating glucose (7). At least two important endocrine changes accompany the increase in glucose availability. The exercise-induced fall in insulin and rise in glucagon are attenuated or eliminated altogether. The absence of the fall in insulin attenuates the increases in lipolysis and EGP, whereas a reduction in glucagon will reduce the latter (7). Although insulin acts to suppress glycogen breakdown, multiple signals are present in working muscle, and glycogen is generally not spared by carbohydrate ingestion (59).

The metabolic availability of ingested carbohydrate depends on the composition and quantity of the substrate load. In addition, exercise parameters (i.e., work intensity, duration, and modality) also determine the availability of ingested glucose. As a consequence, it is difficult to ascribe an exact metabolic efficiency of ingested glucose. In any case, a reasonable estimate might be that 40% of a 50-g glucose load, ingested at the start of moderate exercise, is metabolized during the first hour (60). There is probably little difficulty in delivering adequate amounts of ingested glucose to the muscle during light exercise. Because glucose oxidation by muscle increases at higher work rates, it may no longer be possible to absorb adequate amounts of ingested glucose. As a consequence, limitations to the oxidation of ingested glucose may shift at different work intensities: low muscle demand limits glucose oxidation at light work rates, whereas absorption from the gastrointestinal tract limits it at high work rates (61). In humans, the maximum absorption rate of carbohydrate in the gut during exercise is about 1 g/min (62).

Postexercise glucose metabolism
Exercise leads to diverse adaptations that have significant impact on glucoregulation, even after the cessation of exercise. These adaptations largely share the common purpose of replenishing fuel stores, particularly muscle and liver glycogen.

Muscle.
Stimulation of muscle glucose uptake persists well after exercise. The added glucose taken up after exercise is channeled into glycogen (32). Glycogen repletion is characterized by a marked and persistent increase in insulin action (32). This increase in insulin action occurs without increasing the tyrosine phosphorylation of the insulin receptor, IRS-1, IRS-2, and shc (63,64). Moreover, PI 3-kinase activity is not increased (65). The presence of the muscle insulin receptor may not even be necessary for the increased effects of insulin on muscle glucose uptake and glycogen synthase after exercise (66). This implies that the effects of prior exercise are mediated by nonmuscle cells or by downstream signaling (66). It has also been proposed that a postreceptor modification may be linked to the glycogen depleting effect of exercise. However, the improved effect of insulin on glucose uptake can persist after exercise, even when pre-exercise glycogen levels have been restored (32). The cellular basis for the persistent increase in insulin sensitivity may, at least in part, relate to increases in skeletal muscle GLUT4 (67), glycogenin (68), and hexokinase II (51) during exercise recovery. It is noteworthy that AMP kinase activation leads to a subsequent increase in insulin sensitivity, much like exercise (69).

Muscle contraction activates a number of signaling pathways, in addition to those involved with glucose transport, in a manner that is influenced by the intensity and duration of work (70,71). These include the activation of the mitogen-activated protein (MAP) kinase (64,72), Akt (71), and p70^s6k (70) pathways. Contraction inhibits the glycogen synthase kinase-3 pathway, at least in rodent muscle (73), promoting glycogen synthesis. It is likely that the activation of some of these signaling cascades are important to the persistent adaptations to exercise and not the acute metabolic response. Activation of MAP kinase, Akt, p70^s6k, and AMP kinase pathways and deactivation of the glycogen synthase kinase-3 pathway all are capable of stimulating gene transcription or protein synthesis (53).

Liver.
It was recently shown (74) that prior exercise increases the capacity of the liver to consume glucose. These data are consistent with studies (75) using ¹³C magnetic resonance spectroscopy that showed that ingestion of glucose immediately after prolonged exercise increased liver glycogen resynthesis. The liver, like muscle, is more insulin sensitive after exercise (76). Also like muscle, a greater fraction of glucose taken up by the liver after exercise is nonoxidatively metabolized (77).

Metabolic adaptations to regular physical activity
Adaptations to chronic exercise depend on the exercise parameters (intensity, duration, frequency, and mode) and the characteristics of the individual (presence of disease, fitness, and genetic determinants). Endurance and resistance exercise lead to biochemical adaptations specific to the training regimen. Adaptations to endurance exercise enable the muscle to use O₂ and blood-borne fuels, whereas those for resistance exercise lead to improved force generation (e.g., hypertrophy, contractile properties). Of specific interest to people with diabetes are those adaptations that directly affect the metabolism of glucose.

The adaptation of the pancreatic ß-cell to exercise training has been the most widely assessed of the endocrine organs. Basal and glucose-stimulated insulin levels are both reduced in response to regular exercise due to reduced secretion (7). Training results in decreases in the mRNA for proinsulin and glucokinase in the pancreas (78). This suggests that there are at least two potential cellular mechanisms for decreased insulin secretion. First, the reduction in proinsulin mRNA suggests that the synthesis of insulin is reduced. Second, because glucokinase is necessary for glucose sensing in the pancreas, the reduction in glucokinase mRNA may explain the decreased sensitivity of the ß-cell to glucose.

Exercise training, whether endurance (79) or resistance (80), leads to increased muscle GLUT4. This increase in GLUT4 probably contributes to the increased capacity for insulin-stimulated glucose transport in trained subjects. This, of course, has important therapeutic implications for people with insulin resistance. Exercise training has been shown to stimulate insulin-stimulated PI 3-kinase in muscle (81–83). There is evidence that this increase is due to IRS-1–associated PI 3-kinase activity (81,83). Because PI 3-kinase is an important step in the recruitment of GLUT4 by insulin to the muscle cell surface, it is reasonable to postulate that this is one site at which regular physical activity may affect insulin signaling. Regular physical activity leads to an increase in basal and insulin-stimulated MAP kinase pathway activity (84). Although an increase in the activity of this signaling pathway is not thought to be necessary for the exercise-induced increase in insulin-stimulated glucose uptake, it may be associated with other adaptive changes in muscle. The mechanisms through which aerobic and resistance exercise increase glucose disposal are similar (85). Although resistance exercise has greater propensity than aerobic exercise to increase muscle mass and thereby glucose storage space (5), this is only one of many factors explaining its effects on glucose disposal (85).

Trained subjects have an increased ability to mobilize and store NEFAs (86). The increased ability to mobilize NEFAs occurs at least in part due to increased adipocyte catecholamine sensitivity and is mediated by an increased formation and/or improved effectiveness of cAMP (87). Training increases the capacity of muscle to extract NEFAs from the blood and oxidize them (7). The mechanism for this adaptation may pertain to the enhanced capacity of trained muscle to oxidize fat (88,89) or to increased number or function of muscle fatty acid transport or binding proteins (89,90). It has been hypothesized that an excess accumulation of intramuscular lipid is associated with insulin resistance. This concept is inconsistent with results from exercise-trained subjects. Compared with sedentary control subjects, athletes with high aerobic fitness have increased intramuscular lipids, but are more insulin sensitive, not less (91).

	EVALUATION OF THE DIABETIC PATIENT BEFORE RECOMMENDING AN EXERCISE PROGRAM

TOP INTRODUCTION Definitions PHYSIOLOGY OF FUEL METABOLISM... EVALUATION OF THE DIABETIC... PHYSICAL ACTIVITY AND PREVENTION... AEROBIC FITNESS AND AEROBIC... RESISTANCE EXERCISE FLEXIBILITY EXERCISE EXERCISE IN THE PRESENCE... EXERCISE IN THE PRESENCE... COMPARISON BETWEEN THE PROPOSED... References

 
For a more detailed review on this subject, see Ref. 92.

Before beginning a program of physical activity more vigorous than brisk walking, people with diabetes should be assessed for conditions that might contraindicate certain types of exercise or predispose to injury (e.g., severe autonomic neuropathy, severe peripheral neuropathy, or preproliferative or proliferative retinopathy), which require treatment before beginning vigorous exercise, or that may be associated with increased likelihood of CVD. The patient’s age and previous physical activity level should be considered.

One potential area of controversy is the circumstances under which a graded exercise electrocardiogram (ECG) stress test should be considered medically indicated. We unfortunately did not find any randomized trials or large cohort studies evaluating the utility of exercise stress testing specifically in people with diabetes; the lack of such studies is an important gap in the literature. Previous ADA guidelines (93) have suggested that before beginning a vigorous or moderate exercise program, an exercise ECG stress test should be done in all diabetic individuals aged >35 years and in all individuals aged >25 years in the presence of even one additional CVD risk factor (diabetes duration >10 years for type 2 diabetes or >15 years for type 1 diabetes, hypertension, dyslipidemia, smoking, proliferative retinopathy, nephropathy including microalbuminuria, peripheral vascular disease, or autonomic neuropathy). If this previous recommendation were followed strictly, the great majority of people with diabetes, including a large number of younger individuals with very low absolute risk of CVD, would require formal exercise stress testing before beginning even a moderate-intensity exercise program. The costs of such widespread stress testing might be prohibitive (92). The prevalence of both symptomatic and asymptomatic coronary artery disease (CAD) is higher in both type 1 and type 2 diabetic individuals compared with nondiabetic individuals of the same age-group. However, many younger diabetic patients have relatively low absolute risk for a coronary event. For example, a 38-year-old Caucasian nonsmoking man with diabetes for 5 years, HbA_1c 7.5%, systolic blood pressure 130 mmHg, total cholesterol 5.2 mmol/l, and HDL cholesterol 1.1 mmol/l would have a 10-year CAD risk of only 7.3% or 0.7% per year, calculated using the U.K. Prospective Diabetes Study (UKPDS) Risk Engine (94) (www.dtu.ox.ac.uk/riskengine/download.htm). The lower the absolute CAD risk, the higher the likelihood of a false-positive test. A recent systematic review for the U.S. Preventive Services Task Force came to the conclusion that stress tests should usually not be recommended to detect ischemia in asymptomatic individuals at low CAD risk (<10% risk of a cardiac event over 10 years) because the risks of subsequent invasive testing triggered by false-positive tests outweighed the expected benefits from the detection of previously unsuspected ischemia (95,96).

There is, however, some value to performing a maximal aerobic exercise test in a broader range of individuals. In addition to screening for exercise-induced ischemia, a maximal exercise test can provide useful information regarding maximal heart rate and blood pressure responses to different exercise levels, initial performance status, and prognosis, and therefore is potentially of some benefit to any individual, diabetic or otherwise. Without a maximal exercise test, one cannot know a given individual’s maximum heart rate or the heart rate associated with a given percentage of the maximum. Use of the Borg scale (Rating of Perceived Exertion [97]), with target perceived intensities of "moderate," "somewhat hard," or "hard," is sometimes recommended as a possible alternative to heart rate–based targets based on maximal exercise testing. A large long-term cohort study found that exercising habitually at perceived intensity of "moderate," "somewhat strong," "strong," or more intense than "strong" were associated with adjusted relative risks for coronary heart disease of 0.86, 0.69, and 0.72, respectively, compared with exercising at perceived intensity of "weak" or less intense (98). However, there is a great deal of variability among individuals in terms of the perceived exertion associated with performing the same exercise at the same objectively defined exercise intensities (99). Likewise, the same individuals often have different ratings of perceived exertion when performing different exercises at the same intensities (e.g., running or bicycling at the same percentage of heart rate reserve) and even at equivalent stages of different treadmill protocols (Bruce versus Balke) (100).

Therefore, available clinical evidence does not support any specific definitive recommendations regarding which individuals should undergo stress testing. Potential benefits must be weighed against risks and costs. Our recommendations should be considered in this context.

A stress test is most useful in terms of positive predictive value for coronary ischemia when the probability of CAD is at least moderate. When the probability of CAD is low (e.g., <10% over 10 years), the number of false-positive tests is likely to be substantially greater than the number of true-positive tests.

Therefore, we propose the following revised criteria for deciding when a stress test is indicated for detection of ischemia. These criteria would encompass virtually all people with diabetes with a 10-year CAD risk of at least 10% (1% per year).

Recommendations: indications for graded exercise test with ECG monitoring
In the absence of contraindications (101,102), maximal exercise testing could be considered in all diabetic individuals in order to assess maximal heart rate, set exercise intensity targets, and assess functional capacity and prognosis. A graded exercise test with ECG monitoring should be seriously considered before undertaking aerobic physical activity with an intensity exceeding the demands of everyday living (more intense than brisk walking) in previously sedentary diabetic individuals whose 10-year risk of a coronary event is 10%. This risk could be estimated directly using the UKPDS Risk Engine (www.dtu.ox.ac.uk/riskengine/download.htm) (94) and would correspond approximately to meeting any of the following criteria:

• Age >40 years, with or without CVD risk factors other than diabetes
  
• Age >30 years and
  • Type 1 or type 2 diabetes of >10 years’ duration
    
  • Hypertension
    
  • Cigarette smoking
    
  • Dyslipidemia
    
  • Proliferative or preproliferative retinopathy
    
  • Nephropathy, including microalbuminuria
    
  
  
• Any of the following, regardless of age
  • Known or suspected CAD, cerebrovascular disease, and/or peripheral vascular disease
    
  • Autonomic neuropathy
    
  • Advanced nephropathy with renal failure
    
  
  

The above should not be construed as a recommendation against stress testing for individuals without the above risk factors or for those who are planning less-intense exercise.

Level of evidence:
E.

	PHYSICAL ACTIVITY AND PREVENTION OF TYPE 2 DIABETES

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Recent clinical trials, and a number of large cohort studies, provide strong evidence for the value of physical activity in reducing the incidence of type 2 diabetes. The Da Qing IGT and Diabetes Study (103) was the first randomized trial evaluating lifestyle interventions for the prevention of type 2 diabetes. In this study, 577 people with IGT from 33 clinics were randomized, by clinic, to diet only, exercise only, diet plus exercise, or control. After 6 years of follow-up, cumulative incidence of type 2 diabetes was 68% in control, 44% in diet only, 41% in exercise only, and 46% in diet plus exercise groups. This study provides evidence that both diet and exercise can be effective diabetes prevention modalities, although their effects were not additive. The Da Qing study’s subjects were far leaner (mean BMI 23 kg/m²) than most people with IGT in the western world.

More compelling evidence for the effectiveness of lifestyle interventions comes from two randomized controlled trials: the Finnish Diabetes Prevention Study (104,105) and the U.S. Diabetes Prevention Program (DPP) (106,107). In the Finnish Diabetes Prevention Study (104,105), 522 overweight subjects, aged 40–65 years, with IGT were randomly assigned to a lifestyle intervention or control group. The goals were to reduce weight by at least 5%; perform moderate-intensity exercise at least 30 min/day; limit total and saturated fat intake to <30 and <10%, respectively, of energy consumed; and increase fiber intake to 15 g/1,000 kcal. Intervention group subjects had 1-h meetings with a dietitian seven times in the first year and every 3 months subsequently. Subjects in the intervention group were also offered an individualized exercise plan, thrice-weekly supervised facility-based aerobic and resistance exercise for 6–12 months free of charge, but the proportion of subjects participating in this facility-based training was not stated in the publications. The cumulative incidence of type 2 diabetes was 11% in the intervention group and 23% in the control group. In the DPP (106,107), 3,234 individuals with IGT aged 25 years were randomly allocated to intensive lifestyle intervention, metformin, or placebo. (A fourth arm, troglitazone, was terminated early when troglitazone was withdrawn from the market.) Subjects in the intensive lifestyle group followed an individually supervised program aimed at achieving and maintaining a 7% weight loss through a low-calorie, low-fat diet and to engage in physical activity of moderate intensity, such as brisk walking, for 150 min/week. A 16-lesson curriculum was taught by case managers one-on-one during the first 24 weeks, and individual and group sessions occurred at least monthly for the remainder of the program. After a mean of 2.8 years of follow-up, the incidence of diabetes was 11.0, 7.8, and 4.8 cases/100 person-years in the placebo, metformin, and lifestyle groups, respectively. Relative risk reductions in the Finnish Diabetes Prevention Study and the DPP were identical at 58% with lifestyle interventions compared with usual care or placebo. The DPP was notable because it included a large, racially and socioeconomically diverse sample.

In the Malmo study (108,109), a nonrandomized trial, 161 people with IGT who participated in a diet-and-exercise intervention were compared after 6 years with 56 individuals with IGT who were offered the same intervention and declined. The cumulative 6-year incidence of type 2 diabetes was 11% in the intervention group and 21% in the control group (108). After 12 years of follow-up in the Malmo study, overall mortality among IGT subjects was 6.5 per 1,000 person-years in the lifestyle intervention group, less than one-half of the 14.0 per 1,000 person-years in the IGT/no lifestyle intervention (109). Large cohort studies (110–118) have consistently found that higher levels of physical activity and/or cardiorespiratory fitness were associated with reduced risk of developing type 2 diabetes. This was true in most studies, regardless of the presence or absence of additional risk factors for diabetes such as hypertension, parental history of diabetes, and obesity. Comparable magnitudes of risk reduction were seen with walking compared with more vigorous activity when total energy expenditures are similar (114).

Therefore, there is firm and consistent evidence that programs of increased physical activity and modest weight loss reduce the incidence of type 2 diabetes in individuals with IGT. The two strongest studies, the Finnish Diabetes Prevention Study (104) and the U.S. DPP (106), do not permit one to determine the relative importance of physical activity versus diet.

Recommendations: lifestyle measures for prevention of type 2 diabetes
In people with IGT, a program of weight control is recommended, including at least 150 min/week of moderate to vigorous physical activity and a healthful diet with modest energy restriction.

Level of evidence:
A (104–107).

	AEROBIC FITNESS AND AEROBIC EXERCISE IN TYPE 2 DIABETES

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Effects of structured exercise interventions on glycemic control and body weight in type 2 diabetes
For details of the individual aerobic exercise clinical trials, see Ref. 119.

Most clinical trials on the effects of physical activity interventions in type 2 diabetes have had small sample sizes and therefore inadequate statistical power to determine the effects of exercise on glycemic control and body weight. Boulé et al. (119) undertook a systematic review and meta-analysis on the effects of structured exercise interventions in clinical trials of duration 8 weeks on HbA_1c and body mass in people with type 2 diabetes. Twelve aerobic training studies and two resistance training studies were included (totaling 504 subjects), and the results were pooled using standard meta-analytic statistical methods. The exercise and control groups did not differ at baseline in HbA_1c or body weight. Postintervention HbA_1c was significantly lower in exercise than control groups (7.65 vs. 8.31%, weighted mean difference –0.66%; P < 0.001). In contrast, postintervention body weight did not differ between exercise and control groups. Meta-regression confirmed that the beneficial effect of exercise on HbA_1c was independent of any effect on body weight. Therefore, structured exercise programs had a statistically and clinically significant beneficial effect on glycemic control, and this effect was not mediated primarily by weight loss.

Although the significant effect of exercise on HbA_1c in these studies is encouraging, the lack of overall effect of exercise on body weight in these studies is disappointing but not surprising. The exercise volumes and program durations (mean 53 min/session, mean 3.4 sessions/week, mean duration 15 weeks) may have been insufficient to achieve the energy deficit necessary for major weight loss. Most of these studies did not examine body composition, and loss of fat might have been partially offset by increased lean body mass (119a).

Boulé et al. (120) later undertook a meta-analysis of the interrelationships among exercise intensity, exercise volume, change in cardiorespiratory fitness, and change in HbA_1c. This analysis was restricted to aerobic exercise studies in which O_2max was either directly measured or estimated from a maximal exercise test using a validated equation. Exercise intensities during training ranged from 50% of O_2max to >75% of O_2max, exercise volume 8.75–24.75 MET-hours/week. Meta-analysis revealed a clinically significant 11.8% increase in O_2max in exercising groups, compared with a 1% decrease in control groups. Exercise intensity predicted postintervention weighted mean difference in HbA_1c (r = –0.91, P = 0.002) to a larger extent than exercise volume (r = –0.46, P = 0.26).

Consistent with the above, the greatest effect of exercise on HbA_1c (mean absolute postintervention HbA_1c difference of 1.5% between exercise and control groups) was seen in the single study with the highest exercise intensity (121). In this study, subjects exercised at 75% of O_2max, with intervals at even higher intensity, for 55 min three times a week, including 5 min of warm-up and 5 min of cool down. O_2max increased 41% in the exercising subjects versus 1% in control subjects. Abdominal visceral fat assessed by magnetic resonance imaging was reported to decline by 48% and abdominal subcutaneous fat by 18% in the exercising group in this study, which are much larger fat losses than seen in most exercise studies and surprising in light of the relatively moderate total energy expenditure on exercise.

This meta-analysis provides support for higher-intensity aerobic exercise in people with type 2 diabetes as a means of improving HbA_1c. The analysis, however, is limited by the fact that only one study (121) featured an unequivocally high-intensity exercise program at 75% of O_2max. This intensity might be difficult to sustain or even hazardous for many previously sedentary people with type 2 diabetes. Nevertheless, there was a strong dose-response relationship between exercise intensity across studies and both cardiorespiratory fitness and HbA_1c change. These results would provide support for encouraging type 2 diabetic individuals who are already exercising at moderate intensity to consider increasing the intensity of their exercise to obtain additional benefits in both aerobic fitness and glycemic control.

Physical activity, aerobic fitness, and risk of cardiovascular and overall mortality
The effects of exercise on glycemic control, while statistically and clinically significant, might be perceived as modest in relation to the time and effort involved. After all, a similar degree of glucose lowering could be achieved in many cases by adding a single oral hypoglycemic medication. The effects of aerobic exercise on lipids and blood pressure are also relatively modest. However, large cohort studies have found that higher levels of habitual aerobic fitness and/or physical activity are associated with significantly lower subsequent cardiovascular and overall mortality, to a much greater extent than could be explained by glucose lowering alone.

Wei et al. (122) reported on 1,263 type 2 diabetic men, a subsample of >20,000 men in the Aerobics Center Longitudinal Study who underwent a detailed examination, including a maximal treadmill exercise test with ECG monitoring, physical exam, blood tests, and extensive health and lifestyle questionnaires between 1970 and 1993 and followed for mortality through 31 December 1994 using the National Death Index. Cardiorespiratory fitness was classified as low when treadmill time was at the bottom 20% of the overall cohort (including nondiabetic subjects) for the subject’s age-group (30–39 years, 40–49 years, etc.), moderate if performance was in the 21st to 60th percentile for age-group, and high if in the highest 40% for age-group. Among the diabetic subjects, 42% were classified as "low fit" and 58% as "moderate" or "high-fit." The 50% of diabetic subjects who reported any participation in walking, jogging, or other aerobic exercise programs in the previous 3 months were classified as "active," and the other 50% were classified as "inactive." After a mean of 11.7 years of follow-up, there were 180 deaths. Mortality in the moderate-fit men was 60% lower than in low-fit men. Even after adjustment for age, examination year, baseline CVD, hypercholesterolemia, hypertriglyceridemia, BMI, hypertension, parental CVD, smoking, and baseline fasting glucose levels, low-fit diabetic men had a 2.2-fold greater mortality risk compared with men with moderate or high fitness (95% CI 1.6–3.2). Similarly, after adjusting for the same list of confounders, mortality in diabetic men reporting no physical activity participation in the previous 3 months was 1.8-fold higher than in those reporting any participation in such activity (95% CI 1.3–2.5). Low cardiorespiratory fitness was at least as strong a risk factor for mortality as smoking, hypertension, hypercholesterolemia, and any of the other listed risk factors. The same research team has now published an updated study (123) with more subjects and longer follow-up. This later analysis found that moderate or high cardiorespiratory fitness was associated with lower mortality than low fitness independently of body composition and that essentially all of the association between higher BMI and higher mortality was explained by confounding with cardiorespiratory fitness.

Because moderate fitness was associated with vastly lower mortality than low fitness, it is of interest to know the activity levels associated with moderate fitness. Over 17,000 mainly nondiabetic participants in the Aerobic Center Longitudinal Study completed detailed physical activity logs and a maximal exercise test. Among moderately fit subjects (21st to 60th percentile for age) whose only exercise was walking, the mean time spent per week on exercise was 130 min for men and 148 min/week for women. These times are consistent with recommendations from the U.S. Surgeon General (124) and other respected bodies (125–127) to accumulate about 150 min/week of moderate-intensity exercise. Moderately fit subjects whose only exercise was jogging or running reported a mean of 90 min/week for men and 92 min/week for women. These times are consistent with an alternative and equally valid recommendation for vigorous activity 30 min three times a week.

Hu et al. (128) reported on 5,125 female nurses with type 2 diabetes who completed detailed health questionnaires every 2 years, of whom 323 developed new CVD events over 14 years of follow-up. Age-adjusted relative risks according to average hours per week of moderate or vigorous activity were 1.0 for <1 h (reference group), 0.93 for 1–1.9 h, 0.82 for 2–3.9 h, 0.54 for 4–6.9 h, and 0.52 for 7 h. There was little change with adjustment for BMI, smoking, and other CVD risk factors (relative risks 1.0, 1.02, 0.87, 0.61, and 0.55 for <1, 1–1.9, 2–3.9, 4–6.9, and 7 h/week, respectively). Faster usual walking pace was associated with reduced CVD risk, independently of total physical activity score. Therefore, there was some cardioprotection associated with 2–3.9 h/week of physical activity, but a greater degree of cardioprotection associated with at least 4 h/week of such activity.

Myers et al. (129) reported on 6,213 consecutive men referred for treadmill exercise testing for clinical reasons, including 500 with diabetes (J. Myers, e-mail communication, August 2003). They found that in people with and in those without baseline CVD, absolute exercise capacity was a better predictor of mortality risk than percentage of age-predicted exercise capacity. Every 1-MET increment in treadmill performance was associated with 12% greater probability of survival.

To our knowledge, no meta-analysis of the effects of exercise training on lipids or blood pressure in people with diabetes has been published. In the general, predominantly nondiabetic population, the effects of exercise training on blood pressure and lipids are relatively modest. A meta-analysis of the effects of aerobic exercise training on blood pressure (130) (54 trials, total 2,419 participants) found a weighted mean blood pressure change through exercise interventions of –3.84 mmHg systolic and –2.58 mmHg diastolic. A review of the effects of supervised, structured aerobic exercise training on lipids (51 trials of duration 12 weeks, 4,700 subjects) (131) found a mean increase in HDL cholesterol of 4.6% (P < 0.05), and reductions in plasma triglycerides and LDL and total cholesterol of 3.7% (P < 0.05), 5.0% (P < 0.05), and 1.0% (NS), respectively. Greater increases in HDL cholesterol and decreases in plasma triglycerides have been seen with exercise programs that are more rigorous in terms of both volume and intensity than those that have been evaluated in diabetic subjects (132). Aerobic exercise training increases lipoprotein lipase activity and reduces the number of apolipoprotein B–containing particles (133–136).

Potential mechanisms through which exercise could improve cardiovascular health were reviewed recently by Stewart (137). These include decreased systemic inflammation, improved early diastolic filling (reduced diastolic dysfunction), improved endothelial vasodilator function, and decreased abdominal visceral fat accumulation.

Frequency of exercise
The U.S. Surgeon General’s report recommended that most people accumulate 30 min of moderate intensity activity on most, ideally all, days of the week. However, most clinical trials evaluating exercise interventions in people with type 2 diabetes have used a three times per week frequency (119), and many people find it easier to schedule fewer longer sessions rather than five or more weekly shorter sessions. The effect on insulin sensitivity of a single bout of aerobic exercise lasts 24–72 h, depending on the duration and intensity of the activity (138). Because the duration of increased insulin sensitivity is generally not >72 h, we recommend that the time between successive sessions of physical activity be no more than 72 h (i.e., there should not be more than 2 consecutive days without aerobic physical activity). There is some evidence that the effect of resistance exercise training on insulin sensitivity is somewhat longer (139), perhaps because some of its effects are mediated by increases in muscle mass.

Exercise for weight loss and weight maintenance
The most successful programs for long-term weight control have involved combinations of diet, exercise, and behavior modification (140). University-based obesity research programs using combinations of diet, exercise, and behavior modification have typically produced weight losses of 9–13.6 kg after 20 weeks, and 60% of this weight loss is maintained over 1 year of follow-up (140). Exercise alone, without concomitant dietary caloric restriction and behavior modification, tends to produce only modest weight loss of 2 kg. Weight loss is typically this small primarily because obese people often have difficulty performing sufficient exercise to create a large energy deficit, and it is relatively easy to counterbalance increased energy expenditure through exercise by eating more or becoming less active outside of exercise sessions (140). However, in a randomized trial, high-volume aerobic exercise (700 kcal/day, about 1 h/day of moderate-intensity aerobic exercise) produced at least as much fat loss as the equivalent degree of caloric restriction (141). Furthermore, exercise-induced weight loss resulted in greater improvements in insulin sensitivity than diet-induced weight loss (141).

The optimal volume of exercise to achieve sustained major weight loss is probably much larger than that needed to achieve improved glycemic control and cardiovascular health. In the National Weight Control Registry (142), a study of individuals who lost at least 13.6 kg (mean 30 kg) and maintained the weight loss for at least 1 year (mean 5 years), the average self-reported energy expenditure on exercise was 2,545 kcal/week among women and 3,293 kcal/week among men. These amounts would correspond to 7 h/week of moderate-intensity exercise. Similarly large amounts of exercise have been associated with long-term maintenance of weight loss in other studies (143–146).

Recommendations: aerobic exercise
The amount and intensity recommended for aerobic exercise vary according to goals.

• To improve glycemic control, assist with weight maintenance, and reduce risk of CVD, we recommend at least 150 min/week of moderate-intensity aerobic physical activity (40–60% of O_2max or 50–70% of maximum heart rate) and/or at least 90 min/week of vigorous aerobic exercise (>60% of O_2max or >70% of maximum heart rate). The physical activity should be distributed over at least 3 days/week and with no more than 2 consecutive days without physical activity.
  
• Performing 4 h/week of moderate to vigorous aerobic and/or resistance exercise is associated with greater CVD risk reduction compared with lower volumes of activity (128).
  
• For long-term maintenance of major weight loss (13.6 kg [30 lb]), larger volumes of exercise (7 h/week of moderate or vigorous aerobic physical activity per week) may be helpful.
  

Levels of evidence:
A, for improved glycemic control (119,120); B, for CVD prevention (122,128); and B, for long-term maintenance of major weight loss (142–146).

	RESISTANCE EXERCISE

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For more detailed reviews on this topic, see Refs. 148 and 149.

The proven value of aerobic exercise notwithstanding, it does have some limitations. Some find aerobic exercise monotonous. Most forms of aerobic exercise would not be advisable with advanced peripheral neuropathy and are challenging in people with severe obesity. Resistance exercise training, by increasing muscle mass and endurance, often causes more rapid changes in functional status and body composition than aerobic training and might therefore be more immediately rewarding. Because each session involves many different resistance exercises, some find it less monotonous than aerobic exercise. Resistance exercise improves insulin sensitivity to about the same extent as aerobic exercise (150).

Because of the increased evidence for health benefits from resistance training during the past 10–15 years, the American College of Sports Medicine (ACSM) now recommends resistance training be included in fitness programs for healthy young and middle-aged adults (125), older adults (151), and adults with type 2 diabetes (127). With increased age, there is a tendency to progressive declines in muscle mass, leading to "sarcopenia," decreased functional capacity, decreased resting metabolic rate, increased adiposity, and increased insulin resistance, and resistance training can have a major positive impact on each of these (151).

Studies of resistance exercise in type 2 diabetes
Notwithstanding the above, the previous ADA Position Statement on physical activity and exercise took a conservative view on resistance exercise, stating that high-intensity resistance training with weights might be appropriate for younger diabetic patients but not for older patients or those with longstanding disease; instead lower-intensity resistance exercise with light weights was endorsed (93). This was due to a lack of published studies on high-intensity resistance exercise in older diabetic individuals and concerns about the safety of this type of exercise in the absence of published data (Table 1).

In recent trial, Cuff et al. (158) randomized 28 well-controlled, obese, postmenopausal type 2 diabetic women to combined aerobic and resistance training, aerobic training alone, or a nonexercising control group. Subjects in the exercising groups participated in three 75-min gym sessions per week for 16 weeks. The aerobic exercise was at 60–75% of heart rate reserve, whereas the resistance training program included two sets of 12 repetitions of five exercises. The aerobic-only group spent additional time on very-low-intensity warm-up and cool-down activity that was not expected to affect glucose metabolism. HbA_1c was excellent in all groups before training (6.3–6.9%) and did not change with exercise training. However, insulin sensitivity assessed with glucose clamp was increased significantly more in the combined aerobic and resistance exercise group than in the aerobic exercise only or control groups. Body fat declined significantly and similarly in both exercise groups, but muscle mass increased significantly only in the combined aerobic and resistance exercise group.

Two clinical trials published in late 2002 (159,160) provided much stronger evidence for the value of resistance training in type 2 diabetes. Dunstan et al. (159) randomized 36 Australian sedentary, overweight, type 2 diabetic subjects aged 60–80 years to 6 months of moderate weight loss plus high-intensity resistance training (RT/WL group; progressing to three sets of 8–10 repetitions of 8–10 exercises three times per week at 75–80% of maximum) or moderate weight loss plus flexibility exercise (control/WL group). Absolute HbA_1c declined 1.2% in the RT/WL group compared with just 0.4% in the control/WL group (P < 0.05 between groups). Mean weight loss and fat loss were similar in both groups, but mean lean body mass increased by 0.5 kg in RT/WL subjects while decreasing 0.4 kg in control/WL subjects (P < 0.05 between groups). Castaneda et al. (160) randomized 62 older sedentary Hispanic adults (40 women and 22 men; mean age 66 years) to 16 weeks of individually supervised high-intensity resistance exercise (RT group, progressing to three sets of eight repetitions of five exercises three times per week at 70–80% of maximum) or sedentary control. Mean HbA_1c declined from 8.7 to 7.6% in RT but did not change in control subjects (P = 0.01 between groups), even though 72% of RT subjects (versus 3% of control subjects) had hypoglycemic medications reduced and 42% of control subjects (versus 7% of RT subjects) had hypoglycemic medications increased. Mean systolic blood pressure declined 9.7 mmHg in RT subjects and rose 7.7 mmHg in control subjects (P = 0.05 between groups). Free fatty acid concentrations declined significantly by 27% in the RT group compared with control subjects, in whom circulating free fatty acids increased by 10% (161). There was a significant positive correlation between the changes in glycosylated hemoglobin and plasma free fatty acid concentrations in the groups combined. The interventions in these two studies involved higher exercise intensity (70–85% of one repetition maximum versus 40–60% of one repetition maximum) and more sets of each exercise (three sets vs. one to two sets) than the other studies described