Time course over which changes in spontaneous running occurred.
To determine the time course over which diabetic and normal animals diverged in their running performance, data were quantified at three earlier time points after the injection of streptozotocin: day 3, day 6, and the end of week 4. The daily running distance was similar for the diabetic and normal rats during day 3 (Fig. 5). By day 6, the two groups were starting to diverge, although there were still two (of seven) diabetic rats that ran more than 1000 m·d−1 and three (of eight) normal rats that ran less than 1000 m·d−1. By the end of 4 wk, the normal rats as a group had increased their daily running distance approximately threefold compared with values during the first week, and this high distance persisted at the end of week 8. In contrast, the diabetic rats had a gradual decline in running, so that values at 4 and 8 wk were significantly lower than those of normal animals.
The average consecutive running times were similar (albeit slightly lower) in the diabetic compared with the normal rats during the third day after streptozotocin injection (Fig. 6). By day 6, average consecutive running times were diverging for the two groups of animals, and they were significantly different during weeks 4 and 8. The divergence between diabetic and normal rats appeared to be due predominantly to a halving of the consecutive running in the diabetic rats, as the continuous running times of the normal animals was not markedly different at the end of 8 wk compared with day 3.
Several studies have examined total spontaneous running distance of diabetic rodent models. On the one hand, Dubuc et al. (3) found no difference in total running distance between ob/ob (obese) mice with mean glucose values of 320 mg·dL−1 mice and lean mice with mean blood glucose values of 183 mg·dL−1. Woodiwiss et al. (28) found that diabetic rats with blood glucose values of 20.4 mM (368 mg·dL−1) ran the same distance, albeit at a modestly slower average speed, than normal rats with glucose levels of 5.6 mM (101 mg·dL−1). On the other hand, Keller et al. (13) found that nonobese diabetic mice with blood glucose values of ∼25 mM (∼283 mg·dL−1) ran less than half that of normal mice with glucose values of ∼6 mM (∼108 mg·dL−1). In addition, Rowland and Caputo (19) found that streptozotocin-diabetic hamsters with blood glucose values of 398 mg·dL−1 exercised half to two-thirds that of normal animals with glucose values of 116 mg·dL−1 when maintained in a light-dark cycle (14:10), and that the extent of exercise in diabetic animals was reduced even further to ∼25% of control when animals were housed in continuous light. The results of the previous studies along with the present study suggest that mild to moderate degrees of diabetes may or may not diminish exercise activity, whereas animals with more severe hyperglycemia as in the present study exercise less than normal.
Less information is available about the temporal pattern of exercise in diabetes. Dubuc et al. (3) and Woodiwiss et al. (28) did not provide information along these lines. Keller et al. (13) allowed mice access to exercise wheels for only 5 h·d−1, 5 d·wk−1, and noted that both diabetic and normal animals exercised continuously with few interruptions. Rowland and Caputo (19) commented that the diabetic hamsters generally ran less during each hour than the normal animals, but further temporal details were not provided. The present study thus extends previous observations, by demonstrating a marked reduction in the consecutive running time in Type I diabetic compared with normal animals, similar to that described in mdx dystrophic mice (9).
One possible factor that could have contributed to the reduced spontaneous exercise behavior of the diabetic rats in the present study is that they did not eat enough food to maintain a normal rate of weight increase, so that lack of exercise might have been due to relative malnutrition. Arguing against this are two rodent studies indicating that reductions in caloric intake are associated with increases rather than reductions in spontaneous wheel running. Jones et al. (11) found that normal rats that were food restricted (caloric intake one-third to one-half of ad libitum-fed animals) ran 2–4 times as much as normally fed animals (with the exact magnitude of the increase depending on gender). Dubuc et al. (3) found that ob/ob mice that were food restricted (by pair-feeding them to the caloric intake of lean mice) ran almost twice as much as normal.
Several other factors also seem unlikely to have contributed to the altered exercise behavior of diabetic rats. Blood bicarbonate levels were almost identical in diabetic and normal animals, arguing against diabetic ketoacidosis or other types of metabolic acidosis (e.g., due to renal failure) having played a role. Alterations in extracellular sodium and potassium can affect both skeletal and cardiac muscle contractile performance, but blood levels of these ions were similar in the two sets of animals. Blood chloride levels were reduced modestly in the diabetic animals, although probably not sufficiently to impair muscle contractility.
Another consideration for the cause of the reduced spontaneous exercise in the diabetic animals is the general malaise and feelings of tiredness that are often associated with chronic disease states. Diabetic humans report a lower quality of life than normal, albeit higher than that of other major chronic diseases (2,6,20). The importance of this factor in determining, or even modulating the present findings, can not be determined definitively from the outcome measures used in the present study. Of note, however, is that the gross behavior of the diabetic animals in terms of moving around the cage, eating and drinking appeared normal, which according to standard animal care guidelines are generally accepted as measures indicating the absence of a substantial amount of distress or discomfort. However, lesser degrees of malaise may have been present, which could have been a factor.
Several physiological factors are more likely to have played a role in the diminished spontaneous running and the reduced duration of running per episode in the diabetic rodents. First, based on the degree of hyperglycemia and polyuria, it is possible that the animals were volume depleted, despite having been provided with ample drinking water, which may adversely affect exercise performance. Serum Na+ values roughly the same for diabetic than normal rats (142 vs 144 mmol·L−1), arguing against a major degree of volume depletion, however.
Second, diabetes impairs skeletal muscle contractile performance, even when tested in vitro (5,8,10,14–17,23,25,26). The reported reductions in muscle force are generally relatively mild, but these measurements were made during very brief contractions. Exercise performance is affected not only by absolute force generating capacity but also the extent to which muscle force declines during repetitive contractions. It has been noted previously that mice with mdx muscular dystrophy (who have diaphragm muscle weakness but relatively well preserved limb muscle function) have both reduced running distance and shortened consecutive running times, which was attributed to a disturbance in muscle endurance (9). In the mdx mouse model, abnormal running behavior most likely is due purely to intrinsic muscle factors, as presumably metabolic derangements are absent. Thus, it is likely that in the present study intrinsic muscle contractile abnormalities also limited running endurance, which could have been due to limb muscle dysfunction affecting spontaneous locomotory performance directly, respiratory muscle dysfunction limiting ventilatory responses to exercise and hence reducing locomotory performance indirectly, or both. A number of mechanisms have been implicated in the pathophysiology of diabetes-induced skeletal muscle dysfunction, including mitochondrial dysfunction and alterations in membrane electrophysiological properties. It is possible that exercise may exert its beneficial effects on diabetic patients by reversing these abnormalities. However, the present study was not designed to determine which of these muscle alterations is the most important in limiting exercise behavior.
In the present study, the diabetic animals had markedly elevated glucose levels, consistent with a Type I diabetic model. The control animals had a mild degree of hyperglycemia, the etiology of which was unclear, although of note is that the animals were not fasted before blood analysis. The glucose values in the present study were comparable to a previous study from our lab in nonexercised streptozotocin-diabetic rats (21), in which the controls and diabetic animals had mean values of 252 and 670 mg·dL−1. The lack of correlation between degree of hyperglycemia and amount of exercise in the animals of the present study could have been due to several factors. First, the glucose values reflect only a single point in time, whereas exercise was quantified over the course of several 1- to 2-d periods spread out over the course of 8 wk. Second, there might be several ongoing relationships between glucose levels and exercise, which could cancel each other out. For example, on the one hand high glucose levels could reduce exercise behavior (i.e, if all animals had an equal propensity toward exercise, those with more extreme hyperglycemia might exercise less), whereas on the other hand high exercise levels could reduce glucose levels (i.e., if all animals had equally high blood glucose levels in the absence of an opportunity to exercise, those with an inherent higher tendency toward exercise might have better glycemic control). Third, it may not be the degree of hyperglycemia per se but rather the secondary consequences of diabetes (e.g., alterations in muscle properties) that determine exercise performance.
Types I and II diabetes differ importantly from each other with respect to pathogenesis, as well as associated metabolic disturbances and end-organ responses. The present study used streptozotocin to induce diabetes, which is a model of Type I diabetes. Although the majority of humans with diabetes have Type II rather than Type I diabetes, it is estimated that of the ∼18 million people in the United States affected by diabetes, up to 10% (or 1.8 million) have Type I diabetes. Furthermore, one in every 400–500 children and adolescents in the United States has Type I diabetes. Thus, there is a sizable proportion of the population for which the present data are relevant and important. Future studies are needed in an animal model of Type II diabetes to determine whether they have a similar temporal deficit in running behavior seen in the Type I diabetic rat and mdx mouse models.
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Keywords:©2004The American College of Sports Medicine
RUNNING; DIABETES; SKELETAL MUSCLE; ENDURANCE; HYPERGLYCEMIA