Artikkelit

Physical training in obesity and diabetes mellitus. Regulation of Serum Lipids by Physical Exercis

Katriina Kukkonen, Rainer Rauramaa, and Esko Länsimies
Regulation of Serum Lipids by Physical Exercise

I. Introduction
Disorders of lipid metabolism, which occur in various forms in clinical disease entities such as obesity and diabetes, bear a substantial risk for development of coronary heart disease. Obesity in the middle-aged is fairly common and often associated with impaired glucose tolerance or manifest noninsulin dependent diabetes mellitus as well as with low level of high density lipoproteins in serum. Such an accumulation of several risk factors for coronary heart disease may even be accentuated by the presence of increased blood pressure, which on the other hand, has even been suggested to be mediated through disturbed carbohydrate metabolism(1).

Obesity-associated risk factors are often, however, reversible by reducing the amount of adipose tissue. This may be achieved with the aid of dietary manipulation but it is not always possible to normalize decreased high density lipoprotein (HDL) even if very low density lipoprotein (VLDL) can be decreased(2). Physical training is a physiological approach and is well documented in healthy persons to have a favorable effect as regards body composition(3) as well as serum lipoproteins(4).

II. Obesity
A. General
Obesity means increased amount of adipose tissue. At both extreme ends of body weight (anorexia nervosa and morbid obesity) it is fairly easy to recognize energy imbalance, but in the majority of cases the diagnosis of obesity is based. on statistical or operational (i.e., morbidity and mortality) definitions(5). The implication is that the prevalence of obesity in one population is not necessarily directly comparable to another. therefore, the criteria of obesity applied. also affect the indications for therapy. Physical training is one option among the treatment modalities for obesity and most often used in nonmorbid obesity.

At the cellular level, obesity has been attempted. to be characterized according to size and amount of adipocytes. The existence of two types of obesity, based on fat cell number and size, has been proposed(6-8) and it has also been used for prognosis in obesity treatment(9). However, the concept of hyperplastic obesity has been questioned by Jung et al.(10) and Garrow(11) as well as its prognostic significance(12).

Increased amount of adipocytes is also associated with various endocrine derangements(13-14). Obese persons have often hyperinsulinemia(15) both at rest and during exercise(13) In alignment to animal models Kopelman et al.(14) found. two different types of endocrine responses to symptomatic hypoglycemia (intravenous insulin tolerance test) in humans suggesting for hypothalamic (genetic, obesity starting early in childhood) and acquired obesity. Obesity has also been suggested to be clue to impaired regulation of thermogenesis(16-19).

At this moment, when evaluating different aspects of obesity treatment studies, it is worthwhile to remember the possible different types of obesity and the possible differences in the morphological and biochemical properties in obesity which influence exercise-induced changes in lipid metabolism.

Increased plasma levels of lipoproteins may be due to increased production or decreased clearance(15). Despite the mechanisms, total plasma triglycerides and cholesterol are often increased in obesity;(20) low density lipoprotein (LDL) and very low density lipoprotein (VLDL) are increased while high density lipoprotein (HDL) is decreased.

In many population studies, HDL, has been shown to be inversely correlated with body weight(21-24). LDL cholesterol closely parallels total cholesterol, and VLDL triglycerides bear an inverse relationship to HDL cholesterol. One possible mediator in lipoprotein metabolism is supposed to be composed of different triglyceride lipases (vascular endothelial and hepatic), which hydrolyze plasma triglycerides. This facilitates the transport of fatty acids to, adipose and muscle tissues where they are again stored or used for energy.

In addition to the key role of insulin (25) in the regulation of lipoprotein lipase, nutrition (26) exercise, (27, 28) and training state(29) are important contributors. The lipolytic activity of adipose tissue varies from site to site in human body being highest in gluteal and femoral adipose tissue(30). Acute fasting decreases lipoprotein lipase activity in adipose tissue(31) but after obese people have lost weight and body weight has stabilized, this lipolytic activity has been shown. to increase paradoxically(32).

B. Effect of Exercise on Body Composition and Serum Lipids
In normal weight persons increased physical activity usually decreases adipose tissue and body weight and increases fat-free tissue(33). This has also been found to, take place in obese persons after physical training, the relative changes being even more significant(34-36). However, hyperplastic obese persons do not seem to reduce weight but on the contrary adipose tissue may even increase after training(1, 37-39).

After weight reduction, the size of fat cells decreases but the number of the cells does not change substantially. Based on a fairly large group of subjects Krotkiewski et al(9) have suggested that fat cell number is a major determinant in the success of weight reduction, at least after dietary treatment. This means that hyperplastic obese persons fare worse when compared to the hypertrophic obese. However, Ashwell et al.(12) emphasize the prognostic importance of basal metabolic rate.

There are few studies concerning the effect of physical training on serum, lipoproteins in the obese. Since all of these studies have been uncontrolled with rather few subjects, conclusions on plasma lipids and physical training in obesity must be very cautious. In addition, one should take into consideration other possible changes in lifestyle (diet, alcohol, smoking) concomitant with inereased leisure time physical activity.

Lewis et al.(40) trained 22 obese middle-aged women for 17 weeks. The training program consisted-of supervised jogging twice a week for 20 min at the intensity of 80% of maximal heart rate as well as calisthenics twice a week for 1 hr. There was a significant decrease in body fat, but no changes in cholesterol or in its lipoprotein fractions. However, HDL-LDL cholesterol ratio increased.

Leon et al.(35) recruited six obese young men who were trained under supervision in laboratory for 16 weeks. The exercise program consisted of vigorous walking (3.2 mil hr) on treadmill for 90 min five times per week. Training had no effect on plasma cholesterol and triglycerides while both HDL, cholesterol and HDL-LDL cholesterol ratio increased significantly. These improvements in cholesterol and its lipoprotein fractions are in agreement with results obtained from nonobese middle-aged men after moderate training(4). The studies of Lewis et al.(40) and Leon et al.(35) are encouraging in indicating the potential effects of physical training in modifying serum lipoproteins with respect to atherosclerosis.

Although muscle work has no effect on either normal or abnormal fasting blood glucose in the obese, it results in increased peripheral insulin sensitivity. This has been clearly demonstrated both during physical exercise and after physical training(37,38,41), suggestive of the beneficial contribution of training to health.

Obesity is often combined with dyslipoproteinemias of which the types II and IV are the most common. Although physical training is accepted as part of the therapy to reduce overweight, there are again few studies available. These are short-term uncontrolled studies with few subjects. In type II dyslipoproteinemia, LDL cholesterol decreased after 10 weeks(42) or 6 months(43) training. HDL cholesterol remained unchanged (43) or increased(42). Originally, normal triglycerides decreased somewhat in both studies.

Lampman et al.(44-46) have applied physical training with varying intensity combined with diet in type IV dyslipoproteinemia. Without exceptions, these regimens have resulted in decreased triglycerides which could not be explained with a concomitant decrease of overweight. Exercise-induced decrease in triglycerides occurred somewhat later than when using only diet but was maintained longer. Similar results of decrease in VLDL triglycerides have also been reported by Oscai et al.(47) Gyntelberg et al.(48), and by Giese et al.(49) after only 4 days of exercise. This implies the potential and rapidly occurring effect of physical activity, which also vanishes in a few days. The beneficial effects of physical training are also advocated by the fact that even if diet normalizes VLD lipoproteins it may not always have effect on low HD lipoproteins in type IV Dyslipoproteinemia(2). Since the ratio of HDL cholesterol and total cholesterol is probably the best parameter to describe the risk of coronary heart disease, the promotion of increased physical activity is also beneficial in various types of dyslipoproteinemias.

III. Diabetes mellitus
A. General
Diabetes mellitus is characterized by chronic elevation of blood glucose concentrations. Accordingly, the diagnosis of diabetes also rests on the determination of blood glucose level, either fasting and/or 2 hr after standard glucose load. For diagnostic purposes, new reference values have been established for diabetes mellitus and also for the so-called impaired glucose tolerance(50-51).

Glucose homeostasis is achieved. by delicate endocrine control of insulin and its counteracting hormones. Insulin is by far the most important hormonal determinant of blood glucose concentration. Human diabetes is characterized by disturbed plasma insulin level. Insulin dependent (IDDM) or type 1 diabetes is clue to diminished endogenous insulin secretion while noninsulin dependent type (NIDDM) or type 2 diabetes is principally described as a state of hyperinsulinism. Type 2 diabetics may be either nonobese or obese, as are also persons with impaired glucose tolerance.

Except for regulating blood glucose homeostasis, insulin plays a major role in the control of lipid metabolism. From many epidemiologic data it is obvious that diabetic subjects are exceptionally prone to macro- or microangiopathic vascular complications. Macroangiopathic lesions are found in coronary, cerebral, and lower limb arteries and are not dependent on the duration or severity of diabetes or on blood glucose concentrations. On the other hand, microangiopathic complications (retinopathy and nephropathy) are closely linked to blood glucose balance over long time periods.

In population studies, hyperglycemia has been associated with the development of atherosclerosis. In the Whitehall study (52) impaired glucose tolerance nearly doubled coronary heart disease mortality compared with subjects without disturbances in glucose tolerance. Besides increased risk for coronary heart disease in the presence of other risk factors, impaired glucose tolerance may progress to manifest diabetes, even if slowly(53) However, Stamler et al.(54) were unable to find any association between glucose intolerance and coronary heart disease.

Data from the Framingham study suggest that diabetes seems to have some unique effects on the development of coronary heart disease, especially in women, which cannot be explained by the usual risk factors(55). Decreasing blood glucose to the so-called normal level docs not affect the later development of vascular complications. Therefore, it has been suggested that disturbances in plasma insulin level may be associated with vascular complications in a way that is so far undefined. Insulin treated diabetic subjects are not actually insulin deficient but on the contrary have supraphysiological amounts of exogenous insulin in circulation unrelated to instantaneous nutritional requirements(56). Noninsulin dependent diabetic subjects, most of whom are obese, have often increased basal level of insulin.

In population studies, high level of plasma insulin has been shown to be an independent risk factor associated with coronary heart disease(57,58) Physical exercise (13) or physical training(37,38,41) in the obese has been shown to decrease plasma insulin in resting state or during glucose challenge. The present data on insulin and lipid disturbances in diabetes may justify the use of physical training as one method of improving metabolic balance.


B. Serum Cholesterol in Diabetes Mellitus
Generally diabetic patients show increased levels of serum cholesterol and its LDL fraction. Data on HDL, cholesterol are somewhat controversial and in this respect the type of diabetes has to be taken into consideration. This topic has recently been reviewed by Witztum and Schonfeld(59).

In insulin dependent diabetic (IDDM) subjects total cholesterol(60-63) or LDL cholesterol(63,64) are similar to nondiabetic persons. However, VLDL cholesterol, which is a minor fraction of cholesterol, has been reported to be slightly higher in IDDM(63). HDL cholesterol is either equal(61,63,65) or greater(60,66,67) in IDDM compared to nondiabetic subjects. Increased HDL level in diabetics seems to contradict with epidemiologic data on the high prevalence of atheroselerosis in diabetes mellitus. This disparity has been explained by alterations in HDL composition (HDL2 and HDL3 subfractions and apolipoprotein A). Indeed, it has been suggested that elevation of HDL cholesterol in IDDM is due to increased HDL3 subfraction(68), which is not regarded antiatherogenic. Taskinen and Nikkilä(69) did not find abnormal lipoprotein structure. On the other hand, Reckless et al.(70) suggest that HD-lipoproteins are of less importance than LD-lipoproteins in relation to large vessel disease in diabetic subjects.

Actually, to achieve good control of IDDM requires supraphysiologic amounts of exogenous circulating insulin which has-been suggested to be a central factor in atherogenesis(56). Poor control of diabetes is associated with abnormally high levels of total cholesterol as well as of LDL and VLDL, cholesterol(63). Insulin treatment for 2 weeks decreased LD- and VLDL-lipoproteins but had no effect on low HDL cholesterol(69). In some studies HDL cholesterol. has been shown to correlate negatively with glycosylated hemoglobin(71), which reflects glucose balance in blood over several weeks, while Elkeles et al.(72) and Kennedy et al.(61) found, no correlation.

In noninsulin dependent diabetes (NIDDM), when evaluating plasma lipid levels,oral antidiabetic medication and. obesity may be confounding factors(73). Total cholesterol is not different from nondiabetic subjects(60,61,71,74). Respective similarity has also been shown for LDL and VLDL cholesterol(66,74). On the other hand, a disparity exists with HDL cholesterol since it has been shown to be either similar(60,66,74) or decreased(61,71) when compared to nondiabetic subjects. Lopes-Virella et al.(71) found no abnormalities in apolipoprotein A.


C. Serum Triglycerides in Diabetes Mellitus
Hypertriglyceridemia is a common dyslipoproteinemia. Carlson and Böttiger(75) have proposed hypertriglyceridemia to be an independent risk factor for coronary heart disease, but newer analyses of epidemiologic studies(76) do not reveal a causality.

In untreated(69) and ketotic (77) insulin dependent diabetics, as well as in patients in poor control of the disease(63), elevated levels of triglycerides have been found in all lipoprotein fractions except HDL(69), which carries only a minor proportion of triglycerides. Good control of diabetes evaluated with the aid of glycosylated hemoglobin was accompanied with serum triglycerides concentration not different from nondiabetic siblings(63). In noninsulin dependent diabetes mellitus, serum triglycerides are either similar(74) or increased(64,66,71) when compared to healthy persons.

Several mechanisms have been postulated for the elevation of triglycerides, which seems to be due to a combined effect of increased hepatic secretion of VLDL triglycerides and their decreased removal from plasma(77). The former process is insulin dependent while in the latter the activity of lipoprotein lipase is essential, though at present detailed data are still deficient in human diabetes.

D. Physical Exercise in Diabetes Mellitus
The therapeutic use of physical exercise in diabetes has a tradition of several centuries, extending far before the use of diet, drugs, and exogenous insulin. At present the influence of exercise on glucose homeostasis and substrate utilization in energy metabolism are known rather extensively(78,79). Of crucial importance during physical exercise is the maintenance of glucose homeostasis. In healthy subjects this is achieved with adjustments of insulin secretion(80). Noninsulin dependent patients mostly, respond to exercise not differently from healthy persons.

In insulin dependent diabetic patients in at least moderate glucose balance, exercise alleviates hyperglycemia while in ketotic patients exercise has a tendency to aggravate the disease(81). The first mentioned change is a physiological response but the last mentioned disorder is due to absolute insulin deficiency. In some cases exercise may provoke hypoglycemia in diabetics, because unlike in healthy persons, plasma insulin level, does not decrease during exercise in diabetic patients treated, with exogenous insulin. This leads to a suppression of hepatic output of glucose and an increase in its peripheral utilization. Therefore, in spite of many beneficial effects of increased physical activity, the possible metabolic and cardiovascular risks of physical exercise in diabetic subjects always have to, be taken into consideration.

It has been suggested that the site of exogenous insulin injection is important in connection with its absorption during exercise(82) which has also been acknowledged in practice(83). On the other hand, Kemmer et a1.(84) did not find any increased absorption from, the sites of injection involved in movement during exercise but instead they observed increased plasma insulin level after exercise. Discrepancies regarding insulin absorption during exercise remain to, be clarified, but may be due, at least partly, to differences in experimental protocols used. Anyhow, when evaluating the metabolic responses of exercise and physical training, the effect of circulating insulin has to, be evaluated carefully.

Plasma insulin is also the key regulator of lipolysis. In healthy subjects during exercise, insulin decreases with ensuing increased lipolysis. The same holds true for diabetic patients in good control of the disease(80,85) while due to larger free fatty acids (FFA) availability the leg uptake of FFA is greater in ketotic patients. Therefore, in patients with less good control of the disease the result is accelerated lipolysis and ketogenesis.

Hagan et al(86) observed no changes in plasma triglycerides and FFA after light and moderate exercise in young boys with IDDM. Physical training on the bicycle ergometer for 6 months in subjects with NIDDM decreased significantly both triglycerides and cholesterol, although the study was uncontrolled and included only six subjects(87). In healthy subjects there have been accumulating data from epidemiological studies(88-91) suggesting beneficial effects of increased physical activity on coronary heart disease. This may partly be mediated through increased levels of HDL cholesterol, which can be manipulated by exercise(4). As to diabetic subjects, corresponding data are lacking.

Obviously, as earlier recognized(87) further studies are needed on physical training and plasma lipids in diabetic subjects. More studies are required to define the intensity and type of training to induce and maintain possible favorable changes in plasma lipids. As long as these data are not available, physical training for both insulin dependent and nondependent diabetic patients has to be prescribed individually, remembering the possible metabolic and cardiovascular hazards of exercise.

IV. Conclusions
Lipid disturbances associated with obesity and noninsulin dependent diabetes are additional risks factors for coronary heart disease, while dyslipoproteinemia with other known risk factors in insulin dependent diabetes mellitus does not alone account for the proneness to atherosclerosis(55). Moderate physical training has favorable effects on lipid and carbohydrate metabolism although concomitant weight reduction is often only moderate. However, even if risk factors can be modified. with increased physical activity, there is no evidence of the effect on atherogenesis. On the other hand, when physical training prescription and follow-up are adequately performed, resulting improved physical fitness has concomitant positive influence on psychosocial quality of life which cannot be neglected.

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