Over the past decade, we have witnessed the development and the implementation of several landmark clinical trials of type 2 diabetes prevention that took place in the United States and abroad. In fact, we are now reaping the fruits of their efforts as their very encouraging findings are being released. All of these clinical trials incorporated diet, physical activity, and weight loss as part of their intervention strategy for the common goal of preventing type 2 diabetes in individuals who were initially at risk for diabetes. The purpose of this brief review will be to examine the role of physical activity in the prevention of diabetes in light of the findings of these clinical trials. Some of the questions that will be addressed include: 1) What are these clinical trials and what did we learn from them; and 2) What are some of the key unresolved activity issues that still need to be understood in this area?
WHAT DID WE KNOW GOING INTO THESE CLINICAL TRIALS?
We have known for a while that it is physiologically plausible that physical activity can play a role in preventing type 2 diabetes. In general, active individuals have better insulin and glucose profiles than their inactive counterparts, whereas complete inactivity, with detraining and bed rest, results in a deterioration of these metabolic parameters. Most convincingly, training studies have found that exercise improves insulin action or, in other words, decreases insulin resistance. Physical activity has also been shown to be inversely related with obesity and central fat distribution, particularly visceral obesity. In summary, it appears that physical activity may reduce the risk for type 2 diabetes both directly by improving insulin sensitivity and indirectly by producing beneficial changes in body mass and body composition (1,4).
Likewise, over the years, the epidemiology literature has supported this relationship between activity and diabetes. Across the entire gamut of observational study designs from cross-sectional and retrospective to the more powerful prospective epidemiology studies, physical activity has been shown to be significantly inversely associated with type 2 diabetes (1). In addition, for most of these prospective studies, this significant relationship between activity and diabetes was attenuated but persisted when the data was adjusted for body mass index.
WHAT ARE THE LANDMARK CLINICAL TRIALS OF DIABETES PREVENTION?
The following is a brief description of the four landmark clinical trials of type 2 diabetes prevention that were conducted over the past several yrs. Included in each discussion is a general overview of the clinical trial with a primary focus on the exercise and activity goal of the intervention along with some of the highlights of the study results.
The earliest in this series of clinical trials of diabetes prevention was a 6-yr feasibility study in 47- to 49-yr-old men from Malmo, Sweden (3). From a cohort of men identified from a community screening program with impaired glucose tolerance (IGT), 181 men were enrolled in a combined diet and physical activity intervention program and 79 men served as the reference group. The participants were not randomly assigned to the intervention arms, and the two intervention arms differed by medical condition at baseline, a major limitation of this study.
The physical activity goal for the intervention consisted of two 45- to 60-min sessions·wk−1 of moderate intensity activities that included walking, jogging, calisthenics, soccer, and badminton. The more intense physical activities were not a major part of the intervention until late in the training period. During the first yr of the intervention program, the men had the choice of supervised group participation or being on their own after initial instruction. After that time, the participants were asked to continue to follow the protocol either on their own, with previous group partners, or at a local sports club.
Adherence to the physical activity goals
The physical activity goal for the intervention consisted of two 45- to 60-min sessions·wk−1 of moderate intensity activities. During the first yr of the intervention program, the men had the choice of supervised group participation or being on their own after initial instruction. It was reported that 38 % of the men in the IGT intervention group chose to exercise in the supervised group. What happened beyond that was not obtained, or at least not reported. What is known, however, was that the estimated maximal oxygen uptake (estimated from a submaximal bicycle ergometer test) taken over the entire study period was significantly higher (P < 0.001) for the IGT intervention group than for the IGT nonintervention group (see Fig. 1). Because the estimated maximal oxygen uptake values of the two IGT groups were not significantly different at baseline but did substantially improve in the intervention group alone over the intervention yrs, it is reasonable to assume that this difference can be attributed to a successful activity intervention effort.
In addition to higher mean maximal oxygen uptake values, the men who participated in the intervention program had decreased body weight and lower 2-h insulin and glucose concentrations compared with the reference men over the 5-yr follow-up. Most importantly, the percent of men from the intervention group in whom diabetes developed by the 5-yr follow-up was less than half that in the reference group (10.6% vs 28.6%). The relative risk of type 2 diabetes development in the intervention group compared with the reference group was 0.37 (95% confidence interval, 0.20–0.68; P < 0.003).
Da Qing, China
The first randomized clinical trial of diabetes prevention was a 6-yr study among Chinese men and women aged 25 yrs and older (8). At the beginning of the study, 577 individuals with impaired glucose tolerance were identified from a city-wide health screening in Da Qing and randomized by clinic into one of four groups: physical activity only, diet only, diet plus physical activity, and a control group.
The individuals who were assigned to the physical activity intervention group were encouraged to increase their daily leisure physical activity level by a minimum of one unit, with a unit specifically defined as 5 min of very strenuous activity (jumping rope, playing basketball, swimming), 10 min of strenuous activity (slow running, climbing stairs, disco dancing for the elderly, playing volleyball or table tennis), 20 min of moderate intensity activity (faster walking or walking down stairs, cycling, doing heavy laundry, slow ballroom dancing), or 30 min of mild intensity activity (slow walking, traveling by bus, shopping, housecleaning). The rate of increase and type of physical activity recommended depended on the age, past physical activity patterns, and the existence of health problems other than IGT, although walking was the primary activity emphasized. Counseling sessions were conducted weekly for 1 month, monthly for 3 mos and then once every 3 mos for the remainder of the study.
Adherence to the physical activity goals
Individuals assigned to the physical activity group were encouraged to increase their daily leisure physical activity by a minimum of one unit. Brisk walking was the most common leisure activity performed in this study. Based on the data shown in Figure 2, it appears that both the physical activity and the diet and physical activity groups increased their units of leisure activity reported per d at follow-up compared with baseline values, whereas the two nonexercising groups did not. Of concern, however, is the fact that the baseline exercise units·d−1 for the two physical activity groups were significantly higher than the control or diet alone group.
The cumulative incidence of diabetes by the 6-yr evaluation was significantly lower in each of the three intervention groups compared with the control group (physical activity, 41%; diet, 44%; diet and physical activity, 46%; control, 68%). In proportional hazards analyses adjusted for differences in baseline body mass index and fasting glucose, the risk reduction associated with the diet and physical activity intervention was 31% for diet (P < 0.03), 46 % for physical activity (P < 0.0005), and 42% for diet and physical activity (P < 0.005).
Finnish Diabetes Prevention Study
The first clinical trial to randomize by individual rather than by clinic (as had been done in the previous trial) was completed in Finland in 523 overweight men and women, 40 to 65 yrs of age, with impaired glucose tolerance (11). Study subjects were recruited at five study centers in Finland primarily through the screening of high-risk groups and, if found eligible, were assigned randomly to either the diet and activity intervention group or the control group.
The physical activity goal for the intervention arm was to perform moderate physical activity for at least 30 min·d−1. Subjects received individual guidance concerning increasing their physical activity levels. The physical activity intervention programs differed slightly between the study centers depending on the facilities available at each site. Endurance exercise (such as walking, jogging, swimming, aerobic ball games, or skiing) was recommended. Supervised, progressive, individually tailored circuit-type resistance training sessions were also offered.
Adherence to the physical activity goals
The physical activity goal for the intervention arm was to perform moderate levels of activity for at least 30 min·d−1. Endurance exercises were recommended, and supervised circuit-type resistance training sessions were offered. Details regarding the amount of activity and the specific types of activity that were actually performed were collected in this study but have not yet been analyzed (Tuomilehto, personal communication). However, it was reported that the participation rates for these supervised sessions ranged from 50% to 85% during the first yr. Beyond that, information about adherence to the physical activity portion of the intervention has to be assumed from data presented at year 1 regarding the self-reported change in physical activity habits at that time point. During the first yr of the intervention, 36% of the intervention arm, compared with 16% of the control arm, reported increasing their physical activity levels (P < 0.001) as determined by a reported shift to a higher physical activity category (see Table 1 for the definitions of the four point physical activity scale). Likewise, the percent of subjects who reported activity levels from this physical activity scale of either 2, 3, or 4 was higher in the intervention group than the control groups (86% vs 71%; P < 0.001).
The cumulative incidence of diabetes after 4 yrs was 11% (95% confidence interval, 6–15%) in the intervention group and 23% (95% confidence interval, 17–29%) in the control group. This resulted in a 58% reduction in diabetes in those individuals who participated in the lifestyle intervention arm of the study (P < 0.001).
U.S. Diabetes Prevention Program
The Diabetes Prevention Program (DPP) was a randomized clinical trial of diabetes prevention in 3234 overweight men and women aged 25+ yrs with impaired glucose tolerance (2). The study was designed to answer the question of whether lifestyle intervention or treatment with metformin (a biguanide antihyperglycemic agent) would prevent or delay the onset of diabetes in this heterogenous group of individuals from 27 centers across the United States. One of the strengths of this clinical trial was the diversity of the men and women invited to participate. Of the participants enrolled in the DPP, 45% were from minority groups who disproportionately experience type 2 diabetes, including African-Americans, Hispanics, Asian Americans and Pacific Islanders, and Native Americans. Likewise, individuals aged 25 to 85 yrs were eligible to participate, so there was a diversity of age groups as well.
The DPP volunteers who were randomized to the lifestyle arm were asked to reduce their weight by 7% through a low-fat diet and to increase their physical activity levels by 150 min·wk−1 of moderate activity similar to that of a brisk walk. A diet, physical activity, and behavioral modification curriculum was taught to the participants on a one-to-one basis by individual case managers during the first 24 wk of the intervention and was both flexible and culturally sensitive. Subsequent individual sessions (usually monthly) and occasional groups classes with case managers were designed to encourage the maintenance of the behavior changes.
Adherence to the physical activity goals
The participants in the diet and physical activity intervention arm were asked to keep track of their activity each wk via an activity log. The proportion of the lifestyle intervention participants who reported meeting the activity goal of a least 150 min of activity (mostly walking) each wk based on the activity logs was 74% at the completion of the 24-wk curriculum and 58% at the end of the clinical trial. In addition, across all of the intervention arms, self-reported levels of leisure physical activity were assessed annually using the leisure section of the Modifiable Activity Questionnaire (MAQ) (5).
The activity questionnaire, interviewer’s instructions, questionnaire calculations, and testing of both reliability and validity of the instrument have been described previously (5). The physical activity questionnaire assesses both leisure and occupational physical activity over the past yr. For the leisure section of the questionnaire, individuals were presented with a list of nonoccupational activities common to the entire DPP cohort (developed via pilot testing) and asked to identify the specific activities that they had participated in during the past 12 months. They were then asked to estimate the frequency and duration for each activity identified. Estimates for leisure activity were calculated separately as h·wk−1 averaged over the past yr. Each activity was also weighted by its relative metabolic cost (MET), thereby deriving MET h·wk−1 as the final unit of expression.
Past yr leisure physical activity as determined by the MAQ did not differ between the three randomized groups at baseline. As shown in Figure 3, the change in reported leisure physical activity was significantly (P < 0.001) higher over the 4 yrs of intervention for the lifestyle intervention group compared with the other two treatment arms.
With an average follow-up of almost 3 yrs, the incidence of diabetes was 11.0, 7.8, and 4.8 cases per 100 person-yrs in the placebo, metformin, and lifestyle groups, respectively. Participants randomly assigned to the lifestyle intervention reduced their risk of having type 2 diabetes by 58% (95% confidence interval, 48–66%), fairing better than both the placebo group and the metformin group. Most importantly, this decrease in diabetes development in the lifestyle intervention arm held across all age groups, all ethnic groups, and was similar in both men and women.
WHAT DID WE LEARN FROM THESE CLINICAL TRIALS IN REGARDS TO THE ROLE OF PHYSICAL ACTIVITY IN THE PREVENTION OF DIABETES?
Reflecting over the clinical trials presented above, an important question comes to mind regarding the generalizability of these studies. What have we learned from these clinical trials that we can now take out into the communities?
Summarizing the physical activity interventions used in the four clinical trials (see Table 2), a relatively consistent pattern emerges (7). The activity type recommended was aerobic (although the Finnish study also incorporated strength training in the regimen) and was, in general, of moderate intensity. The primary type of aerobic activity adopted by the participants in the DPP and in the Da Qing study was walking, although both the Finnish study and the Malmo study had walking as one of a list of potential activities. Regarding the weekly activity goal, all but the Finnish trial recommended a weekly goal of between 120 and 150 min·wk−1. (Keep in mind that the most prevalent activity in the Da Qing trial was walking, and a brisk walk was to be carried out 20 min·d−1 or 140 min·wk−1.) The Finnish Diabetes Prevention Study, in contrast, recommended 30 min·d−1 (which is 210 min·wk−1), although the actual weekly number of min performed by the participants in this trial have not yet been released.
For the most part, the physical activity goals of these various trials are similar to the public health recommendations, as described in the U.S. Surgeon General’s Report on Physical Activity and Health (10), which call for an increase in moderate levels of physical activity such as walking for approximately 30 min on most days. Because all of these studies demonstrated a significant decrease in the incidence of type 2 diabetes in the activity intervention groups, their results would suggest that the activity goal for the general public is a reasonable goal to start with in attempting to reduce the risk of developing diabetes (and/or to increase weight loss that, in turn, results in the decreased risk of diabetes developing) in those overweight individuals who are at high risk for diabetes.
The flexibility of this type of activity goal will make it much easier to adopt by community members of all ages and ethnic backgrounds because the specifics of how, when, and where to perform physical activity can be custom fit into an individual’s daily routine in a manner that makes sense to their lifestyle and their life demands. Most importantly, physical activity that is incorporated into one’s lifestyle has the potential for being maintained for yrs, as was suggested by a 10-yr follow-up study of older women who participated in a 3-yr clinical trial of walking. Not only were the women who were originally randomized to the walking intervention group more active at the end of the trial, but also they maintained higher physical activity levels compared with the control women 10 yrs after the closure of the clinical trial (9).
WHERE DO WE GO FROM HERE?
After the release of the findings of these clinical trials, many interesting unanswered questions remain. Questions about the specific physical activity prescription (type of activity, duration of each bout, intensity of the activity) that should be recommended to high-risk individuals is a lingering public health issue. However, an equally important question regards the choice of the components of the lifestyle intervention. Are diet and exercise both necessary for a successful intervention, or can either one stand alone? What is the independent contribution of physical activity in the prevention of type 2 diabetes separate from its effect on weight loss and body composition?
Although these recent clinical trials of type 2 diabetes prevention certainly support a lifestyle approach to the prevention of diabetes, the independent effect of activity intervention alone was, in most cases, not directly tested. With the exception of the Da Qing Study, all of these intervention trials combined physical activity with diet and weight loss in their intervention scheme. In the Da Qing Study (8), it was demonstrated that the decrease in diabetes development in the physical activity intervention arm occurred without a significant change in body mass index and was evident in both initially lean and overweight participants (<25 and >25 body mass index).
To understand the potential contribution of physical activity in the prevention of type 2 diabetes, separate from its effect on weight loss and body composition, the physiological rationale behind this relationship between activity and diabetes must be defined. Regarding the physiological rationale behind an independent effect, exercise training studies have supported the contention that physical activity improves insulin sensitivity independent of any effect of activity on weight loss and fat distribution (4). As an example of this in the epidemiology literature, in a recent cross-sectional study, physical activity was shown to be significantly associated with insulin concentrations in two populations at high risk for diabetes that greatly differed by body mass index (6). The fact that a significant positive relationship between physical activity levels and insulin sensitivity was found in both nondiabetic Pima Indians, among whom the prevalence of obesity is quite high, and in nondiabetic Mauritians, who are relatively much leaner, suggests a beneficial role of physical activity on insulin sensitivity and therefore, perhaps even on the prevention of diabetes, that is separate from any influence of physical activity on body composition (6).
Beyond the effect of activity on body mass and composition, it appears that physical activity may reduce the risk for type 2 diabetes directly through improvements in insulin sensitivity (4). However, a large portion of the effect of physical activity in decreasing insulin resistance is short lived and may last for a few days. Therefore, the frequency of activity participation each wk and consistency throughout the yr is a key issue that needs to be measured before one can hope to separate out the indirect and direct effects of activity on the prevention of diabetes. This identifies the need for more frequent assessments of physical activity (ideally with an objective measure of activity) throughout the follow-up period to partition out the benefits of activity beyond obesity. Fortunately, from a public health point of view, these questions are academic. The important issue, as demonstrated in this and many other studies, is that a physically active lifestyle plays an important role in the prevention of type 2 diabetes. The precise mechanisms behind this benefit, however, have yet to be determined.
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