Physical Activity and Exercise

—THIS EBOOK IS UNDER REVISION—

• Physical inactivity is the most common cardiometabolic risk factor and the easiest one to eliminate.
• Up to 60 minutes of moderate-intensity endurance exercise on most days of the week can significantly reduce abdominal fat, visceral fat in particular (~30%).
• Both an acute bout of exercise and chronic endurance exercise can significantly improve insulin sensitivity. The effect is equal to or greater than that achieved with pharmacotherapy (~20% improvement with acute and 30-85% improvement with chronic exercise).
• Regular endurance exercise can lead to modest but significant improvements in HDL cholesterol (~5%) and triglyceride (~15%) levels. It has less of an effect on LDL cholesterol levels. The lack of change in LDL cholesterol may be misleading, as physical activity can produce a beneficial increase in LDL particle size from small to large.
• While regular, moderate-intensity endurance exercise can reduce the risk of cardiovascular events by improving an individual’s hemostatic and fibrinolytic profile, intense acute exercise may trigger myocardial infarction, especially in at-risk individuals, by inducing a hypercoaguable state.
• Endurance exercise has consistently been shown to modestly reduce both systolic and diastolic blood pressure by ~4 mmHg in lean, overweight, hypertensive, and normotensive patients.
• Although acute exercise can cause elevated systemic inflammation, regular endurance exercise of fairly vigorous intensity appears to reduce levels of inflammatory markers by ~30%.
• Although the metabolic improvements achieved through regular endurance exercise are generally greater when body weight is reduced, increasing physical activity can dramatically improve visceral fat, insulin resistance, lipid levels, and blood pressure, even when body weight does not change.

In the past 20 years, awareness has increased of the complex relationship between individual metabolic abnormalities and subsequent risk of cardiovascular disease (CVD) and type 2 diabetes. Yet our knowledge of this relationship is not new. In 1923, a common clustering of risk factors including obesity, hypertension, and gout had already been described [1]. However, it was not until Reaven’s 1988 Banting lecture [2] that the combination of insulin resistance, dyslipidemia, and hypertension was proposed as a unique entity (syndrome X) that increased CVD and diabetes risk. In addition, based on the early observations of Vague [3,4], others recognized the key role of fat distribution, excess abdominal fat in particular, as a mediator of metabolic risk and component of the syndrome [5]. Over the years, the cluster of obesity [particularly abdominal obesity], insulin resistance, hypertension, and dyslipidemia has been given a variety of names, including syndrome X [2], the deadly quartet [5], dysmetabolic syndrome [6], insulin resistance syndrome [7], and more. Major organizations such as the World Health Organization (WHO) [8] and others [9-11] have recently adopted the term “metabolic syndrome” for clinical diagnostic purposes. Although metabolic syndrome clinical criteria and cutoff values vary between organizations, they often include the following: 1) elevated waist circumference, waist-to-hip ratio, or body mass index, 2) elevated triglycerides, 3) low HDL cholesterol levels, 4) elevated blood pressure, and 5) impaired fasting glucose or glucose intolerance [8-11].

A joint statement by the American Diabetes Association (ADA)and the European Association for the Study of Diabetes [EASD] challenged the concept of the metabolic syndrome and questioned its clinical utility above and beyond individual risk factors [12]. The statement also concluded that “the metabolic syndrome has been imprecisely defined, there is a lack of certainty regarding its pathogenesis, and there is considerable doubt regarding its value as a CVD risk marker” [12]. Following the publication of the critical review of the metabolic syndrome, the International Chair on Cardiometabolic Risk [13], the ADA, and the American Heart Association [AHA] introduced the concept of global cardiometabolic risk, which goes beyond the earlier meaning of the metabolic syndrome to encompass a broader cluster of risk factors associated with CVD and type 2 diabetes [14]. Cardiometabolic risk includes the features of the metabolic syndrome as well as traditional CVD risk factors [13]. Among Canadian adults, physical inactivity is the most prevalent cause of abdominal obesity and the metabolic syndrome [15], and along with smoking is one of the factors that is easiest to target. In addition, physical activity and/or exercise have consistently been recommended for the reduction of many individual cardiometabolic risk factors [9,10,16]. Prospective studies have shown that increasing physical activity seems to protect against the development of diabetes and CVD in a dose-response manner [17,18]. Exercise’s specific role in reducing abdominal obesity, visceral fat in particular, and improving insulin sensitivity, lipid levels (triglycerides, HDL cholesterol, LDL size), blood pressure, thrombosis, and inflammation is examined below.

Although the terms physical activity and exercise are often used interchangeably, a distinction has been made between them for the purposes of this document. Physical activity is defined as any bodily movement produced by skeletal muscles resulting in increased energy expenditure. It includes both occupational and leisure-time physical activity. Exercise is a component of leisure-time physical activity that is planned, structured, repetitive, and performed for the purpose of improving or maintaining physical fitness. While the evidence presented here mainly addresses the effects of structured and regular exercise, it is well established that increasing physical activity during leisure and non-leisure time yields significant benefits [19].

It has been suggested that abdominal obesity, especially visceral obesity, may be a central component of cardiometabolic risk that is linked to many other individual risk factors [20]. According to recent reviews [21,22], regular exercise appears to readily reduce abdominal and visceral obesity. This evidence is presented below.

The literature suggests that regular exercise causes a wide range of visceral fat changes, from a minor reduction of approximately 5% [23] up to a 50% reduction [24]. These changes in visceral fat also produce a wide range of reductions in body weight. Generally, the highest levels of exercise induce the highest energy deficit, which causes greater weight loss and a greater reduction in visceral fat. For example, approximately 60 minutes of daily exercise over three months is associated with a 1.0 and 0.7 kg (-28 and -26%) reduction in visceral fat and a 7.7 and 6.6 kg weight loss in obese men and women, respectively [25,26]. Approximately 20 to 25 minutes of daily exercise was reported to reduce visceral fat by only 6 to 10%, which corresponded with a modest weight loss (1.4 to 1.8 kg) in overweight women [23] and obese women with diabetes [27]. Illustrating a dose-response relationship between exercise dose, weight loss, and visceral fat loss, Irwin et al. [23] found that women who were highly active (>28 min/day) lost 6.9% of their visceral fat, compared to a 5.9% loss among intermediate active women (19 to 28 min/day), a 3.4% loss in low active women (≤18 min/day), and a 0.1% gain in controls over a year-long intervention.

While weight loss remains the hopeful outcome of chronic exercise in overweight individuals, evidence suggests that even when body weight is unchanged, regular exercise can markedly reduce abdominal fat [25,26,28]. For example, approximately two months of regular, moderate-intensity aerobic exercise significantly reduced visceral fat (-41 to -45%) despite there being no change in weight in samples of type 2 diabetics [29,30]. Even non-obese premenopausal women experienced a significant reduction in visceral fat (-25%) in response to six months of aerobic exercise despite no significant change in weight [31]. Several studies have specifically examined the effect of regular exercise on abdominal adiposity when weight is maintained by having study participants consume compensatory kilocalories equivalent to the amount expended during exercise in an effort to maintain weight [25,26,28]. The length of each intervention was roughly three months, with an energy expenditure of approximately 3,500 kcal/wk. The main findings suggest that in obese Caucasian men and women and men with type 2 diabetes, exercise training can significantly reduce total and abdominal obesity even though there may be little or no change in body weight.

While weight loss remains the hopeful outcome of chronic exercise in overweight individuals, evidence suggests that even when body weight is unchanged, regular exercise can markedly reduce abdominal fat [25,26,28]. For example, approximately two months of regular, moderate-intensity aerobic exercise significantly reduced visceral fat (-41 to -45%) despite there being no change in weight in samples of type 2 diabetics [29, 30]. Even non-obese premenopausal women experienced a significant reduction in visceral fat (-25%) in response to six months of aerobic exercise despite no significant change in weight [31]. Several studies have specifically examined the effect of regular exercise on abdominal adiposity when weight is maintained by having study participants consume compensatory kilocalories equivalent to the amount expended during exercise in an effort to maintain weight [25,26,28]. The length of each intervention was roughly three months, with an energy expenditure of approximately 3,500 kcal/wk. The main findings suggest that in obese Caucasian men and women and men with type 2 diabetes, exercise training can significantly reduce total and abdominal obesity even though there may be little or no change in body weight.

Insulin resistance has traditionally been cited as the common soil for development of both type 2 diabetes and CVD, and it has been regarded as a key component of cardiometabolic risk [2,32]. The role of insulin resistance in the development of impaired glucose tolerance and overt type 2 diabetes is well established [33,34]. Fortunately, both an acute exercise bout and/or chronic aerobic exercise training have been shown to significantly improve insulin sensitivity and thereby reduce risk of diabetes [35].

Acute Exercise and Insulin Resistance
A single exercise session has been shown to significantly reduce plasma glucose [36,37] and insulin [37] levels in type 2 diabetic subjects. Significant improvements in glucose clearance, as assessed through a euglycemic-hyperinsulinemic clamp, have been achieved in obese diabetics and normoglycemics after one hour of moderate-intensity treadmill exercise [38], insulin-resistant subjects after 50 minutes of moderate-intensity stair climbing exercise [39], diabetic subjects after glycogen-depleting cycle exercise [40], and healthy subjects after 60 minutes of moderate-intensity ergometer exercise [41]. Not only is insulin sensitivity enhanced immediately after the acute exercise bout (38), it appears to last 20 hours after exercise [40] and even up to 48 hours post exercise [39,41], finally dissipating five days post exercise [41]. The degree of improvement in insulin-stimulated whole-body glucose disposal after a single exercise bout ranges from 15 [41) to 24% [38]. These improvements are equal to those achieved through chronic pharmacological intervention [42,43].

Muscle is the main site of insulin-stimulated glucose disposal [44], and the transport of glucose across the plasma membrane appears to be key for glucose disposal in healthy [45] and diabetic [46] subjects. Glucose diffuses into the muscle through glucose transporter proteins (of which GLUT4 is the main isoform), which are translocated to the muscle membrane upon stimulation by insulin [47]. It has been shown that insulin stimulation in diabetic subjects fails to induce normal GLUT4 protein translocation to the muscle membrane [48], thereby limiting glucose diffusion into the muscle. Given this, one potential mechanism underlying enhanced glucose disposal after an acute bout of exercise may be increased translocation of GLUT4 into the sarcolemma and T-tubules of the muscle. Indeed, a single one-hour session of moderate-intensity cycling has been shown to increase the amount of GLUT4 protein in the muscle membrane by almost 75% in a sample of type 2 diabetics and similarly in healthy subjects [49]. Exactly why GLUT4 translocation to the muscle membrane is enhanced post exercise is unclear, but the effect may be due to muscle contraction [50], hypoxia [51], or others [52].

Chronic Endurance Exercise and Insulin Resistance
In addition to the acute effect of exercise, repeated bouts of exercise over an extended period of time appear to cause even bigger improvements in insulin sensitivity. Several excellent reviews have examined the mechanisms behind these exercise-induced improvements in insulin sensitivity [35,53] and suggested a reduction in body fat, visceral fat in particular [25], or increased expression of GLUT4 protein skeletal muscle [54,55].

Approximately three to four months of daily aerobic exercise training inducing a 6 to 8% body weight reduction was shown to improve insulin sensitivity (as assessed by the euglycemic-hyperinsulinemic clamp) by 32 and 60% in middle-aged women and men, respectively [25,26]. In addition, among sedentary and overweight men and women who underwent one of three different exercise interventions 1) low volume/moderate intensity, 2) low volume/high intensity, and 3) high volume/high intensity), all groups experienced significant improvements in insulin sensitivity [56]. While the improvement was lower in the low volume/high intensity group (40%) compared to the other two groups (85%) [56], various combinations of exercise duration and intensity performed on a regular basis will significantly improve insulin sensitivity, and the magnitude of these changes are, on average, greater than those observed after a single exercise bout.

Numerous studies have also shown that chronic exercise can improve insulin sensitivity even without significant weight loss [25,27,57,58]. For example, three months of daily aerobic training in obese men who consumed compensatory kilocalories equivalent to the amount expended during exercise caused a 30% improvement in insulin sensitivity despite no change in weight [25].

The results of the Diabetes Prevention Program have shown that, over a three-year period, a lifestyle modification program featuring a minimum of 150 minutes of exercise per week can reduce the incidence of type 2 diabetes by 58% in at-risk individuals [59]. These results are consistent with other findings [60] and suggest that exercise can prevent diabetes in predisposed patients by improving insulin sensitivity and enhancing glucose disposal acutely and chronically, possibly to a greater degree than what can be achieved through pharmacological interventions [59].

The atherogenic lipid profile (or lipid triad) consisting of hypertriglyceridemia, low levels of HDL cholesterol, and high levels of small and dense LDL particles in particular (61) has been tied to other cardiometabolic risk factors such as abdominal obesity [62] and insulin resistance [63]. Accordingly, this cluster of lipid abnormalities has been shown to predict cardiovascular-related morbidity and mortality [64]. Numerous reviews [65-69] and meta-analyses [7,10,70] have investigated the role of exercise in improving dyslipidemia, and the results are summarized below.

The evidence for exercise-related improvements in lipid status appears to be strongest for HDL cholesterol and triglycerides [65,66,67,70,71]. For example, a meta-analysis of 15 randomized, controlled studies revealed that 30 to 60 minutes of moderate-intensity aerobic exercise three to five times per week produced a mean increase in HDL cholesterol levels of ~4% (0.05 mmol/l) and a decrease in triglyceride levels of ~12% (0.21 mmol/l) [71]. These results generally agree with those of a prior review that concluded that aerobic exercise inducing an energy expenditure of 1,200 to 2,200 kcal/wk can increase HDL cholesterol levels by 4 to 22% (0.05-0.21 mmol/l) and decrease triglyceride levels 4 to 37% (0.01-0.43 mmol/l) [66]. Other analyses [67,70] have echoed these findings, suggesting that only a modest amount of exercise is required to produce significant improvements. However, a dose-response relationship has yet to be established [67]. While some studies have suggested that exercise-induced weight loss is necessary to see lipid improvements [65], others have shown that while HDL cholesterol and triglyceride improvements are generally greater in those who lose weight, these improvements can occur even when weight remains virtually unchanged [66,71,72]. However, these changes may depend on changes to body composition, such as increased skeletal muscle mass or reduced visceral fat [25,26].

While post-exercise improvements in HDL cholesterol and triglyceride levels are reported fairly consistently (as reviewed above), there is scant evidence to suggest that exercise significantly reduces LDL cholesterol levels [65,66,67,70,71]. However, while many authors have concluded that exercise rarely has any effect on LDL cholesterol levels [66,71], some have noted a modest (3%) reduction in response to increased physical activity [67]. High numbers of small, dense LDL particles have been shown to predict incidence of CVD independent of total LDL cholesterol levels [73]. Importantly, exercise has been shown to reduce the concentration of small, dense LDL particles and increase mean LDL particle size without altering total LDL cholesterol levels [72]. Exercise may therefore improve morbidity risk without altering LDL cholesterol levels.

Apolipoprotein B is the apolipoprotein moiety of the atherogenic lipoproteins and represents all non-HDL cholesterol (namely VLDL, IDL, and LDL) in circulation [74]. A number of studies have shown that apolipoprotein B levels predict CVD and related events independent of traditional risk factors [75], including the established lipid risk factors described above [76,77]. Accordingly, some suggest the use of apolipoprotein B in lieu of traditional lipid markers (i.e., LDL cholesterol) for predicting vascular disease [78]. Cross-sectional studies suggest that individuals who are most active tend to have the lowest apolipoprotein B levels [79, 80]. In addition, a number of exercise intervention studies have shown that exercise [81-83] and exercise combined with caloric restriction [84,85] can significantly reduce apolipoprotein B levels. These reductions range from 7 to 20% or 0.10 to 0.20 g/l, and the response to exercise appears to be greater among those with elevated baseline triglyceride concentrations [86].

High blood pressure has been shown to cause stroke, coronary heart disease, and renal disease, and its reduction is associated with a significant drop in the risk of cardiovascular-related morbidity and mortality [87]. Some have also suggested that blood pressure need not drop dramatically to significantly lower associated health risk [88]. Inactivity is a major risk factor for high blood pressure, and sedentary individuals are up to 50% more likely to develop hypertension compared to more active individuals [89]. Many reviews [90-95] have looked at the effect of regular exercise on blood pressure, and their findings are presented below.

The evidence appears to be quite consistent regarding the ability of regular aerobic exercise to lower blood pressure [90-95]. Exercise has been shown to reduce both systolic and diastolic blood pressure in lean [90,95], obese [90,95], hypertensive [90,93,94], and normotensive [90,91,93] subjects. Some have also suggested that exercise may have a greater anti-hypertensive effect in women than in men [94,96]. Also, any exercise-related reduction in blood pressure may be greater in Asian than in Caucasian subjects [90]. Although modest weight loss (3 to 9%) has been shown to significantly reduce blood pressure [97], other studies have reported that exercise can significantly improve blood pressure independent of changes to weight [93,95]. With regard to ideal exercise training parameters, most reports have suggested that low- to moderate-intensity exercise is ideal for lowering blood pressure [90,94] and that other exercise program parameters (duration, frequency) generally do not have any impact on the level of improvement [90,95,98].

Regular aerobic exercise is known to reduce blood pressure [90-95]. However, the degree of change reported has been inconsistent. For example, a large meta-analysis of 54 randomized, controlled trials found that aerobic exercise reduces systolic and diastolic blood pressure by approximately 4 and 3 mmHg, respectively [90]. These results agree with some findings [91,92,95], are slightly lower than other findings (6 to 7 mmHg reduction in both systolic and diastolic blood pressure) [93], and are significantly lower than the 11 and 8 mmHg reductions in systolic and diastolic blood pressure attributed to aerobic exercise in another review [94]. These minor discrepancies notwithstanding, exercise can be said to cause a modest reduction in blood pressure. Though physical activity will reduce blood pressure, this decrease is rarely significant enough to return blood pressure to normal levels [96].

Thrombosis (the formation of a blood clot in an intact blood vessel) is a key precursor to stroke, myocardial infarction, and other overt symptoms of blood flow obstruction throughout the circulatory system [99]. While physical inactivity is a major risk factor for thrombosis, an acute bout of strenuous exercise has been reported to cause a prothrombotic state and predispose sedentary and at-risk individuals to cardiovascular events [99,100]. A number of investigations and reviews [99-101] have examined the relationship between acute and chronic exercise. Their findings as well as various hemostatic and fibrinolytic factors that contribute to thrombosis are summarized below.

An acute bout of heavy exercise has long been known as a potential trigger for myocardial infarction [102]. Although there are discrepancies in the literature, a prior systematic review concluded that acute exercise can trigger a cardiovascular event by inducing a prothrombotic state associated with abnormal fibrinolysis and augmented platelet aggregation [99]. However, a number of factors can influence the effect of acute exercise on thrombosis, such as baseline fitness and exercise intensity [99]. For example, a number of studies [103,104] have shown that while acute moderate-intensity (55-65% VO2max) exercise can improve fibrinolysis and reduce platelet adhesiveness and aggregation, high intensity (80% VO2max) exercise can have the opposite effect by increasing blood coagulation and platelet adhesion and aggregation. In addition, while the enhanced fibrinolytic response due to acute exercise is highly transient, the hypercoaguable state appears to be more persistent post exercise, providing an ideal environment for clot formation [105].

Conversely, cross-sectional studies [106,107] consistently document the antithrombotic effect of chronic exercise, which lowers fibrinogen levels (and related coaguability) and increases fibrinolytic capacity (also seen after acute exercise). Numerous exercise intervention studies have also documented enhanced fibrinolytic capacity after regular exercise training, as indicated by an increase in tissue plasminogen activator (a fibrolytic stimulator) and a decrease in plasminogen activator inhibitor type 1 (PAI-1) [108-110]. Regular, moderate-intensity endurance exercise also appears to suppress platelet adhesiveness and aggregation, both at rest and following acute intense exercise [110-112]. However, these thrombotic factors quickly revert to pretraining values upon cessation of chronic exercise training [111,112], suggesting that regular exercise must be maintained for its antithrombotic effects to last.

Overall, it seems that while regular, moderate-intensity exercise can reduce the risk of cardiovascular events by improving an individual’s hemostatic and fibrinolytic profile, intense acute exercise may trigger myocardial infarction, especially in at-risk individuals, by inducing a hypercoaguable state [99,100]. These findings account for the apparent paradox between chronic and acute exercise and thrombosis [113] and provide further support for regular, moderate-intensity exercise as a means to prevent cardiovascular events.