Acta Med Scand 1985; 217: 3-7

REVIEW ARTICLE

Exercise Treatment in Diabetes Mellitus

PER BJORNTORP and MARCIN KROTKIEWSKI From the Departments of Medicine I and Clinical Rehabilitation, Sahlgren’s Hospital, University of Goteborg, Goteborg, Sweden

Exercise is a long-established part of the treatment of diabetes mellitus. It has been assumed to improve the metabolic balance of the diabetic state, but very few controlled studies have actually been performed to prove this point until recently, when the problem has attracted more attention. Recently obtained information is now facilitating firmer conclusions, and clinical advice can now be given on a sounder scientific basis. This knowledge is briefly reviewed below.

Acute exercise and insulin sensitivity Exercise with large muscle groups, when performed long enough at sufficient intensity, empties a large glycogen depot which is then replenished during the following days. Such replenishment may well consume something of the order of 100 g glucose or its equivalents per day. It is of particular significance that the liver is not capturing carbohydrate to full capacity in this situation, thereby giving muscle glycogen priority to available carbohy- drate for storage (1). This means that in this situation the uptake of glucose in the brain (about 150 g/day) and muscles, for rebuilding of glycogen, constitutes the major disposal of glucose, because other uptake is limited. These considerations emphasize the critical role of muscle and exercise for glucose homeostasis in man (for review, see ref. 2). Recent work has now established that repletion of glucose stores in the post-exercise phase may well be the main determinant of glucose disposal rate in this situation. Furthermore, peripheral insulin sensitivity is increased when this occurs (3). It has already been shown that muscle tissue is more insulin-sensitive after contractions (4, 5). This then probably is the background to lower plasma insulin levels several days after such an exercise (6, 7).

A picture then emerges where muscle glycogen resynthesis after exercise becomes a major determinant of glucose tolerance. Since this replenishment has a duration of a few days, the insulin-sensitive condition in which muscle glycogen is resynthesized will persist more or less continuously in an exercise program typically consisting of three work sessions per week. This means that such an exercise program should actually by itself increase glucose tolerance by continuously increasing muscle insulin sensitivity.

Physical training and insulin sensitivity It is interesting to note the simlarities between this continuous “post-exercise condition” and the physically trained state, defined as the condition where more chronic adaptations to exercise are manifest, as measured in a steady-state condition free from acute post- exercise changes. In the physically trained condition, peripheral insulin sensitivity is elevated (8), particularly in muscle (9). The explanation of this is not established but might be found in adaptations in insulin binding or in critical steps for glucose transport and/or storage in muscle, induced as adaptations to the repeated exercise sessions and/or to the “post-exercise condition” as such. There is evidence to suggest that also in the physically trained condition the liver gives priority to glucose storage in muscle (lo), similar to observations in the post-exercise state.

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Physical training and insulin secretion In the physically trained condition, plasma insulin concentration is diminished, mainly due to a decreased insulin secretion from the pancreas (for review, see ref. 11). It is of course tempting to speculate that this decrease is regulated from the insulin-sensitive muscle to counterbalance hypoglycemic reactions. A major research effort has not revealed any certain other such regulation by known factors including body fat mass, insulin secreta- gogues (glucose and amino acids), anti-insulin hormones or gut factors stimulating insulin secretion (“incretins”) (11). It is of interest in this connection, however, that increases in the sensitivity of the P-adrenergic and cholinergic nervous systems with physical training (12) would tend to increase insulin secretion.

Peripheral insulin concentration is determined not only by insulin secretion, but also by the capture of the secreted insulin by the liver. There is evidence that also this is regulated by physical training, which causes an increased uptake (13).

With this background in the normal regulation of insulin sensitivity, secretion and hepatic uptake of insulin, as well as with recent results from our laboratory, it is possible to see more clearly what is occurring in defined clinical states after physical training.

Obesity without diabetic glucose tolerance It is useful to divide obesity into high and low insulin-secreting groups. In obese subjects secreting increased amounts of insulin, this is inhibited by physical training, hyperinsulin- emia is diminished (13, 14). In obese subjects with low insulin secretion, however, physical training is actually associated with increasing insulin secretion perhaps via stimulation by the sensitized P-adrenergic and cholinergic nervous systems (12). The extra insulin secreted seems to be captured by the liver, peripheral insulin concentrations remaining unchanged. In spite of the increased sensitivity of the trained muscles and unchanged insulin concentrations in the periphery, as well as a better “insulinization” of the liver, glucose tolerance is usually not changed, presumably because it is already normal from the outset.

Diabetes mellitus type II In patients with diabetes mellitus type 11, previous reports have indicated a limited improvement of glucose tolerance after physical training (15, 16) and it has been suggested that subgroups of this condition might be more or less responsive to training. Our recent study of a large group of patients with diabetes mellitus type 11, allowing analysis in subgroups, has elucidated some important points here. On average the whole group showed a limited improvement in glucose tolerance after physical training as described previously. It turned out, however, that only those who had objective signs of physical training in circulatory variables (higher maximal oxygen uptake, lower blood pressure) also improved their glucose tolerance.

This might at a first glance seem a rather trivial finding. It should be considered, however, that subjects with diabetes mellitus type I1 might have difficulties in arriving at a state of adaptation to physical exercise, because there is evidence that the normal compensatory increase in glucose production from the liver during exercise is not seen in such subjects, perhaps due to a residual plasma insulin concentration which is not normally decreased during exercise (17). This then would tend to cause hypoglycemia, perhaps preventing exercise sessions of sufficient intensity and duration to lead to a physically trained condition. Although no direct evidence of such hypoglycemia was seen during the training period in the subjects with diabetes mellitus type 11, an unusually large

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number of subjects did not show improvement in circulatory variables in this training program, which has been used repeatedly before with regular effectiveness.

Further subgrouping of the trained patients with diabetes mellitus type I1 led to another important finding, namely that the subjects with low insulin secretion were those who improved most in glucose tolerance. The extra insulin secretion obtained by training was probably captured by the liver. Presumably the improvement in glucose tolerance was due to a combination of increased muscle sensitivity to insulin, in the presence of unchanged peripheral insulin, plus a better insulinization of the liver, resulting in a higher uptake rate of glucose in muscle as well as in liver. The reason why glucose tolerance was improved here and not in the analogous situation in obesity (see above) might be that the obese subjects already had a normal (or at least non-diabetic) glucose tolerance. In addition, the insulinization of the liver was more pronounced among the diabetic than the obese subjects.

Further subdivisions did not reveal any differences neither between subjects with or without treatment with sulfonylurea, with or without obesity, nor between the sexes. The findings thus seem to be generally applicable.

Exercise treatment in diabetes mellitus 5

Diabetes mellitus type I Against the background reviewed above, one might predict that physical training would improve glucose homeostasis in diabetes rnellitus type I by reducing the need for exoge- nous insulin. Patients with diabetes mellitus type I show an increase in peripheral insulin sensitivity after physical training similar to other groups (18). Therefore, exogenous insulin should be more effective, as is well known from episodes of hypoglycemia after exercise. It has indeed been shown that less insulin can be given to patients with diabetes mellitus type I after physical training (19). In another study ( I @ , however, no decrease was found in the requirement of exogenous insulin. It seems important to regulate insulin administra- tion precisely during a training program of this sort, a fixed excessive therapeutic insulin dose might well be tolerated by adaptive changes against hypoglycemic episodes during the training program.

Other effects of physical training on diabetic patients These studies have shown that physical exercise programs, resulting in a physically trained condition, are beneficial from the viewpoint of regulation of glucose metabolism in diabetes mellitus. This is particularly the case in diabetes mellitus type I1 with insufficient- ly low insulin production, but probably also in diabetes mellitus type I if insulin adminis- tration is gradually adjusted to the decreasing requirement. In addition, physical training has a number of previously known advantages which are of particular significance to the diabetic patient. These include a diminished hyperinsulinemia when insulin secretion is elevated, as well as reductions of body fat, blood pressure and lipids (for review, see ref. 1 I ) . It should be noted in this connection that the improvement in glucose homeostasis is probably more pronounced when body fat is reduced in physical training programs of longer duration (20). Thus a more solid basis is now available for recommending physical exercise as a part of diabetes therapy.

Finally, it should be stressed from a practical point of view that physical training poses no specific problems in diabetic subjects except those obviously present in terms of poor circulatory responses due to ischemic or hypertensive reactions and tendencies to hypo- glycemia. Poorly controlled diabetes mellitus type I might lead to ketotic reactions, usually easily corrected by adjustments of insulin treatment. Trainability should not be abnormal, both central circulation and peripheral equipment in terms of muscle fibers and enzymes are normal and adapt normally to exercise (16, 21, 22). A thing to be noted might be the

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tendency to hypoglycemia mentioned in patients with diabetes mellitus type 11. Further- more, capillarization of muscle might be abnormal in diabetes mellitus type I both before and after physical training (16, 18, 221, reminiscent of capillary abnormalities in the microangiopathy of diabetes mellitus.

P . Bjorntorp and M . Krotkiewski Acta Med Scand 1985; 217

CONCLUSIONS

Recent studies have shown that glucose tolerance and homeostasis are improved by exercise programs leading to a physically trained condition in patients with diabetes mellitus. This is particularly the case in a subgroup of patients with diabetes mellitus type I1 with low insulin secretion probably by a combination of increased liver "insulinization" and increased peripheral insulin sensitivity. The need of exogenous insulin may be diminished in diabetes mellitus type I. The effects are more pronounced when body fat is diminished owing to physical training for long periods. Earlier documented effects of physical training including reduced body fat, plasma insulin, blood pressure and lipids add to the beneficial effects of physical exercise in diabetes mellitus.

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19. Costill DL, Cleary P, Fink WJ, Foster C, Ivy JL, Witzmann F. 'Ikaining adaptations in skeletal muscle of juvenile diabetics. Diabetes 1979; 28: 818-22.

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Received March 6, 1984

Correspondence: P. Bjorntorp, MD, Department of Internal Medicine 1, Sahlgren's Hospital, S-413 45 Goteborg, Sweden.