Medicine & Science in Sports & Exercise:
Roundtable Consensus Statement
Effects of physical activity on insulin action and glucose tolerance in obesity
KELLEY, DAVID E.; GOODPASTER, BRET H.
Department of Medicine, Division of Endocrinology and Metabolism, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261
Address for correspondence: David E. Kelley, M.D., Associate Professor of Medicine, Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15261. E-mail: email@example.com.
Roundtable held February 4–7, 1999, Indianapolis, IN.
KELLEY, D. E. and B. H. GOODPASTER. Effects of physical activity on insulin action and glucose tolerance in obesity. Med. Sci. Sports Exerc., Vol. 31, No. 11, Suppl., pp. S619–S623, 1999.
Purpose: The purpose of this paper is to examine the effect of physical activity on glucose tolerance in relation to obesity.
Methods: We reviewed current literature, with particular emphasis on randomized clinical trials, to prepare an evidence-based evaluation of the effects of physical activity on glucose intolerance in obesity.
Results: This literature review indicates that physical activity has favorable effects on reducing insulin resistance in obesity and among patients with type 2 diabetes mellitus. Improvement in glucose tolerance is less consistently observed and is related to intensity of exercise, collateral changes in adiposity, the interval between exercise and testing of glucose tolerance, and the baseline severity of glucose intolerance.
Conclusion: A review of currently published clinical trial data supports the conclusion that physical activity can reduce insulin resistance and improve glucose intolerance in obesity.
The purpose of this paper is to review the recent published literature concerning effects of physical activity on insulin sensitivity and or glucose tolerance in relation to obesity. Insulin resistance and glucose intolerance are associated with obesity (11,38). Physical activity is commonly prescribed in conjunction with nutritional recommendations to achieve and maintain weight loss and thereby improve glucose homeostasis. In the review of the literature, the emphasis is placed on data from randomized clinical trials (RCT), with particular emphasis upon studies in which exercise was a direct and monitored intervention. Moreover, studies that examined exercise alone rather than in combination with weight loss were given emphasis. Several important and recent studies have examined the combined effects of exercise and weight loss on insulin action and glucose tolerance (9,50). However, since this review is directed at the effects of physical activity on glucose homeostasis independent of weight loss, the combined intervention data are less helpful to address this issue. Consideration was also given to modality of physical activity (e.g., aerobic vs resistance), intensity of effort, frequency and duration of exercise sessions, and overall length of the period of intervention. In addition to the principal focus, as defined above, recent important epidemiological data on the effects of physical activity upon glucose intolerance are also reviewed along with data on the impact of physical activity in patients with type 2 diabetes mellitus (DM).
In preparing this review, the guidelines set forth for preparation of the recent NIH consensus statement on prevention of obesity (38) have been followed, with the aim of providing a single evidence-based statement. The greatest emphasis has been given to the studies of long duration, but because of a relative lack of such data we have also included studies less than 4 months in duration, weighting these accordingly. Two recently published randomized controlled trials (RCT) of relatively long duration are summarized in Table 1, along with two additional RCT, although the latter examined the effect of physical activity in lean subjects. We have also summarized within Table 2 data from seven additional nonrandomized studies conducted without control groups but that nevertheless provide important information regarding various aspects of the effects of physical activity on glucose tolerance.
CURRENT STATUS OF KNOWLEDGE
Evidence Statement: An increase in physical activity improves insulin action in obesity with or without concomitant changes in weight and/or body composition. (Evidence Category B/C).
The RCT by Dengel et al. (10) and by Katzel et al. (30) examined the effect of exercise training on insulin action in obese men. These research subjects, previously sedentary, performed moderate aerobic exercise over a 9- to 10-month period. Exercise was performed during three sessions weekly at a moderate intensity. At completion, the exercise intervention groups achieved an increase in aerobic capacity but had not changed weight (Table 1). Neither group of subjects were glucose intolerant before intervention, and glucose response during an oral glucose tolerance test (OGTT) at the completion of the intervention had not changed as a result of exercise training. However, in both trials, insulin levels during the OGTT were reduced, indicating improved insulin action as a result of exercise training. Similarly, the two RCT that examined lean subjects also found that exercise training improved insulin action regardless of the absence of weight loss (14,18). Of note, and to be addressed more fully later, postintervention glucose tolerance in these studies was assessed within 2–3 d following the last exercise session. Summarizing the results from these RCT, an increase in physical activity by aerobic exercise improves insulin action even without weight loss.
The majority of the eight nonrandomized controlled trials (Table 2) that were reviewed also yielded results consistent with an effect of physical activity to improve insulin action (23–37,39–44). In the majority of these studies, the outcome measures were glucose and insulin levels during an OGTT. The designs of these studies were diverse in regard to the overall duration of the exercise program and in regard to the intensity, frequency, modality, and length of individual exercise sessions. However, each study did attempt to prevent weight loss during exercise training. On first appraisal, the impact of exercise training on glucose tolerance was not consistent among these nonrandomized studies. As shown in Table 2, four studies reported reduced glucose levels during OGTT as a result of exercise training (4,12,23,44) while the remainder observed no change in glucose tolerance (6,29,47,48). Part of this disparity in results seemed to be a function of the degree of glucose intolerance of the subjects before intervention. Improvement was generally found in those individuals who had impaired glucose tolerance but not necessarily among those individuals with established type 2 DM, as will be discussed later in this paper in more detail.
One of the key issues brought out in several studies (4,6,29,44) summarized within Table 2 is that exercise training can elicit improvement in insulin action in obesity within 1 wk of intervention. This finding indicates that physical activity can elicit improvements in insulin action without concomitant weight loss and without necessarily evoking a true training adaptation response within skeletal muscle morphology. The finding further raises the question of whether improvement in insulin action during longer duration of exercise intervention programs represents a “training adaptation” (45), the impact of the most recent single bout of exercise, or an interaction of these two processes. Several studies addressed, directly or indirectly, the issue concerning the hiatus from the last exercise session to the determination of insulin action, and in this manner they addressed the interaction between potential training adaptations and insulin action. In the study by Segal et al. (47), despite a fairly robust effect upon fitness, no change in insulin action, as determined during insulin infusion studies, was observed following 12 wk of aerobic exercise training. In that study changes of weight were prevented and post-training assessments of insulin action were performed 4–5 d following the last exercise session. A recent study by King et al. (32) illustrates that beneficial effects of exercise training on insulin action decline within 3–4 d following an exercise session. The findings of Segal et al. (47) seem to indicate that acute effects of exercise are as important, and perhaps more important, than chronic “training” effects on insulin action and also suggest that less effect on insulin action will be obtained in the absence of weight loss. From a clinical perspective, these data reinforce the importance of sustaining a regular frequency of exercise to maintain a beneficial effect on insulin action.
While the majority of studies in this review have focused on the effects of aerobic exercise, one study compared aerobic versus strength training on insulin action (48). In that study it was found that these two exercise modalities resulted in similar improvements in insulin action. This suggests that improvements in insulin action from exercise training can occur without concurrent improvements in cardiorespiratory fitness. This evidence is bolstered by results from shorter-term exercise training interventions in which no improvements in cardiorespiratory fitness were observed (4,6,29,44).
The exercise intensity and duration of the training bouts may also influence improvements in insulin action. In a study determining the effects of exercise intensity and duration on insulin action, Kang et al. (29) found that higher intensity exercise resulted in an improvement in insulin action following seven consecutive days of exercise, while isocaloric bouts of exercise at lesser intensity, despite the equivalent energy expenditure, did not improve insulin action. The higher intensity exercise was associated with a greater utilization of muscle glycogen (28), suggesting that the pattern of substrate utilization and, in particular, the depletion of muscle glycogen may regulate the short-term effects of exercise on insulin action, as has been suggested (26). Another factor that may alter insulin action is the macronutrient composition of the diet. Indeed, many of the studies we have presented in this review have altered the caloric intake and/or the diet composition to maintain body weight during the exercise intervention. However, in the study by Hughes et al. (23), improvements resulting from exercise training were shown to be independent of an increased carbohydrate intake.
There are strong epidemiological data that a program of regular exercise can reduce the risk for developing type 2 DM (19,33,34). These favorable effects appear to be most evident among those at highest risk, although recent weight gain will lessen the protective effect of exercise (19). In a large prospective randomized trial, 577 individuals with impaired glucose tolerance identified from screening a population of more than 110,000 men and women found that exercise lowered the risk of conversion to type 2 diabetes during the ensuing 6 yr (41). Positive effects were also observed for diet alone, or in combination with exercise. Within a trial of this size and design, it is difficult to ascertain clearly the amount of exercise actually performed or the extent of cross-over between arms of treatment. Nevertheless, these data do suggest the potential effectiveness of lifestyle interventions of exercise and diet to lessen the risk of type 2 DM among individuals with IGT. A similar pattern of findings was observed among middle-aged British men (42), among middle-aged Japanese men (49), and among African-Americans (27). Follow-up data from the Malmo preventive trial in men with IGT indicate favorable effects on mortality rates among those engaged in long-term interventions of diet and physical activity (15). Data from the Insulin Resistance Atherosclerosis Study (IRAS) substantiate a link between physical activity and insulin sensitivity, and between the latter and risk for progression of atherosclerosis (36). Several important studies concerning the mechanisms of these favorable effects of exercise upon insulin resistance in skeletal muscle have been published in recent years (21,22,26). Using an NMR method, Perseghian et al. (42) observed that following glycogen depleting exercise previous defects in insulin-stimulated glucose transport and phosphorylation were improved within skeletal muscle of insulin-resistant adult offspring of parents with type 2 DM.
While the epidemiological data indicate that physical activity can reduce the risk of type 2 DM (19,27,33,34,41,42,49), the capacity for physical activity to improve metabolic control in the setting of established Type 2 DM is a less consistent finding. There are several recent and excellent reviews on the effect of exercise on glucose control in patients with type 2 DM (1,2,16,26,37,51), that complement earlier important studies (20,46). In general, exercise intervention results in a modest improvement of glucose control, a reduction in need for medication, or some combination of effects. In many patients improvements in glucose tolerance may not occur following exercise, and this is likely a result of a reduced capacity for insulin secretion, although other factors may also contribute. Some of the earlier studies emphasized the impact of relatively high intensity exercise to reverse or improve glucose tolerance in patients with type 2 DM and relatively mild hyperglycemia (20). More recently, several studies indicate the efficacy of milder intensity exercise to ameliorate insulin resistance in type 2 DM (5,7,12,39,52). Also, several studies indicate a favorable effect of circuit resistance training on insulin sensitivity in type 2 DM (14,25). While the insulin resistance of skeletal muscle in patients with type 2 DM is widely recognized, several recent studies find that during exercise rates of glucose utilization are moderately increased compared with nondiabetic subjects exercising at the same intensity (8,17,28,35).
This review has outlined recent research on the effects of physical activity upon glucose tolerance and insulin sensitivity in obesity. The evidence suggests that exercise training does have a beneficial effect on glucose and insulin homeostasis and, most particularly, on insulin resistance. However, several important questions remain. There are not enough data concerning exercise and glucose homeostasis in women and minorities. More information would be useful to examine the interaction of body composition changes and improvements in insulin action as a result of exercise training. Given the strong association between regional adipose tissue depots, fatty acids, and insulin resistance of obesity, this area deserves further investigation with respect to exercise. For example, King et al. (32) showed that insulin action immediately following exercise was impaired because of elevated levels of circulating fatty acids, which have been shown to induce insulin resistance (31). It has also been recently demonstrated that an accumulation of intramuscular triglyceride is associated with insulin resistance in obesity (40). In young lean individuals, exercise training improves the ability to oxidize intramuscular fatty acids (24); however, data regarding the effects of exercise training on substrate selection in obesity and how this may influence insulin action are scarce. Finally, and of greatest importance is how much, at what intensity, and how often should exercise be done to obtain favorable effects on health (3,13).
Therefore, several meaningful questions remain regarding exercise training, insulin action, and obesity:
1. What is the dose-response association between the length of the intervention, the exercise training intensity, and its frequency and duration with effects on insulin action and glucose homeostasis; in other words how much and what type of exercise is needed?
2. How do the improvements in glucose and insulin homeostasis resulting from exercise compare with those induced by diet alone or diet in combination with exercise?
3. What are the optimal yet safest means to reverse impaired glucose tolerance or improve type 2 DM using exercise interventions?
4. What is the interaction between changes in body composition and regional fat distribution and the effects of exercise on glucose homeostasis?
5. What are the effects of exercise on disordered fatty acid metabolism in the setting of insulin resistance and what are the interactive effects of glucose and fatty acid metabolism in response to exercise training?
6. Will a program of regular exercise reduce or delay mortality and morbidity from coronary heart disease (CHD) endpoints (MI, CABG, angioplasty, etc.) in the settings of obesity and glucose intolerance and diabetes and, if so, how much exercise is needed to achieve these effects?
In summary, our assessment of the recent literature suggests that exercise improves glucose homeostasis and insulin action independent of body weight changes. Our perception, however, is that on the whole this body of data is sparse and requires further corroboration. We believe that further studies are required to examine the mechanisms of an altered substrate metabolism in obesity and how these may relate to improved health and prevention of metabolic disease.
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DIABETES MELLITUS; OBESITY; GLUCOSE TOLERANCE; EXERCISE
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