1 Department of Prevention, The aim of the study was to examine the effects
of weight reduction by exercise and diet on metabolic control in obese
subjects with insulin resistance, particularly investigating if changes in serum leptin concentrations were directly associated with
improvements in metabolic control. Twenty obese men (48 ± 8 yr;
body mass index 32.1 ± 3.9 kg/m2) with previously diagnosed
type II diabetes mellitus were assigned to a 4-wk intervention program
of exercise (2,200 kcal/wk) and diet (1,000 kcal/day; 50%
carbohydrates, 25% protein, 25% fat; polyunsaturated-to-saturated
fatty acid ratio 1.0). Intervention induced significant reductions in
body weight and serum leptin levels, and improvements in lipoprotein
profile and glucose control. Reductions in leptin levels were directly
associated with reductions in serum triglycerides and cholesterol, a
finding that was independent of improvements in glucose control. These
data show that serum leptin concentrations can be reduced with caloric
restriction and exercise in male patients with type II diabetes, and
they suggest a direct relationship between leptin and lipoprotein
metabolism that is not solely due to weight reduction.
lipoprotein; insulin resistance; exercise; weight
reduction
LEPTIN, THE PRODUCT OF the
ob gene, is an adipocyte-derived
hormone that has been shown to regulate body weight and thermogenesis in rodent models of obesity (4, 11, 28). It has been reported that
diet-induced weight loss is accompanied by significant reductions in
circulating leptin levels in humans (6). However, the effect of
exercise on systemic leptin levels in humans has only recently been
reported in healthy individuals (13, 31), an effect, however, that
could only be demonstrated in females (13, 31) but not in male subjects
(13). Although chronic alterations in energy balance induced by
exercise or weight loss have a profound effect on carbohydrate and
lipid metabolism (9, 15, 21), reductions in fasting insulin
concentrations by exercise training have only recently been linked to
reductions in serum leptin levels (13), and the association between
serum leptin levels and lipids is virtually unknown. Thus the purpose
of this investigation was to determine the influence of a 4-wk
intervention program of exercise and low-caloric diet on body
weight, systemic leptin levels, and metabolic control in male obese
subjects with insulin resistance, particularly focusing on the
relationship between serum leptin levels and lipoproteins.
Patients with type II diabetes mellitus were referred by their general
practitioners or diabetic specialists to the hospital for improvement
of metabolic control. Upon reporting to the hospital, these patients
were asked whether they were willing to participate in an intervention
study. The patients had to fulfill the following criteria: age between
30 and 60 yr, stable weight, body mass index (BMI) >27
kg/m2, sedentary lifestyle, and
diagnosis of diabetes mellitus that at the time of inclusion in the
study was not treated with oral antidiabetic medication. Exclusion
criteria were medication with insulin, oral antidiabetic medication or
lipid-lowering drugs, hypertension resistant to pharmacological
treatment, history of proliferative retinopathy, ischemic heart
disease, peripheral vascular disease, or orthopedic problems limiting
exercise training. Before the intervention program, an exercise stress
test was performed for detecting possible exclusion criteria for the
study, such as signs of ischemic heart disease, a low exercise capacity
of <100 W, hypertension, or arrhythmias during exercise. In addition, maximal heart rate was registered. Laboratory screening parameters (white and red blood cell count, platelet count, sodium, potassium, creatinine, aspartate, and alanine aminotransferase) had to be within
normal limits. In addition, a thorough physical examination was
performed before the patients were assigned for participation in the
study. The study had been approved by an institutional review
committee, and all subjects gave informed consent before participating
in the study.
The Intervention Program
ABSTRACT
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
METHODS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
Exercise program. The exercise program included individual exercise performed on a bicycle ergometer for 30 min on 5 days/wk at an individual intensity of 70% maximal heart rate (1,100 kcal/wk). Heart rate during the program was monitored by heart rate telemetry (Polar, Pacer). An additional energy expenditure of 1,100 kcal/wk was achieved by exercise in groups [2-h hiking tours one time/wk (800 kcal), swimming, water games, and stretching two times/wk for 30 min (300 kcal)]. A total energy expenditure of 2,200 kcal/wk was achieved by physical exercise. The adherence to the exercise program was reinforced and monitored daily by the exercise staff.
Diet. All patients consumed the same diet, which was especially prepared. Diet consisted of a 1,000-kcal diabetic diet with a carbohydrate content of ~50%, a fat content of 25% and a protein content of 25%. The ratio of polyunsaturated to saturated fatty acids was 1.0. The amount of fiber in the diet was ~10 g/day. The patients were encouraged not to eat additional food and were asked daily regarding this matter.
Clinical Chemistry
After an overnight fast of 12 h, blood was drawn in the morning on the second day after admission to the hospital for laboratory analysis. An identical procedure was repeated 28 days afterward for comparison of the laboratory values.Lipids and apolipoproteins. Very low density lipoprotein [VLDL; density (d): <1.006 g/ml], intermediate density lipoprotein (IDL; d: 1.006-1.019 g/ml), low-density lipoprotein (LDL; d: 1.019-1.063 g/ml), and high-density lipoprotein (HDL; d: 1.063 to 1.210 g/ml) were prepared by density gradient ultracentrifugation (1, 24). Cholesterol and triglycerides were measured by automated enzymatic methods (Boehringer Mannheim). The apolipoproteins (apo) A-I, B, and A-II were measured by endpoint nephelometry (Boehringer, Marburg, Germany). The within-assay coefficient of variation for lipoproteins was <4% for cholesterol and <4.5% for apolipoproteins.
Insulin, fructosamine, and free fatty acids. Fasting insulin concentrations were determined by an ELISA (Boehringer Mannheim), and free fatty acids were determined by an enzymatic colorimetric method (Wako Chemicals). Fructosamine was also determined by a commercial enzymatic test (Enzymotest; Hoffmann-La Roche). Variation coefficient within assay and between assays was <6%. Glucose was measured during the day before and 2 h after meals, and the "glucose profile" is equivalent to the mean of these six glucose measurements.
Leptin. Serum leptin levels were determined using a commercial RIA (Linco Research, St. Louis, MO). The variation within the assay was <8% and between assays <6%.
Statistical Analysis
Before statistical analyses were performed, each parameter was tested for normality by the Kolmogorov-Smirnov test. In addition, Q-Q plots (expected against observed values) were made. Parameters that were not normally distributed (serum triglycerides, VLDL cholesterol) were logarithmically transformed to reduce the skew of the distribution. To assure a normal distribution, these transformed parameters were then again tested for normality.The data from all 20 patients obtained before the intervention program and 4 wk afterward were compared by the t-test for paired samples.
In addition, Pearson's correlation coefficient was determined between baseline leptin levels and baseline parameters of metabolic control (fasting insulin and fructosamine, glucose profile, lipids, and lipoproteins). For this procedure, logarithmically transformed data were used for triglycerides and VLDL cholesterol. In addition, a stepwise multivariate regression analysis was performed in which baseline values for BMI, leptin, glucose profile, fasting insulin, and fructosamine were entered, with baseline lipids and lipoproteins being the dependent variables.
Pearson's correlation coefficient was also determined for the
relationship between changes of leptin (leptin) and improvements of
glucose control (
glucose profile,
fasting insulin, and
fructosamine) and lipoproteins during intervention. This was
followed by a stepwise multivariate regression analysis in which
changes of obesity parameters (
BMI, leptin) and changes in glucose
control (
glucose profile,
fasting insulin, and
fructosamine)
were entered, with the changes in lipids and lipoproteins being the
dependent variables.
Data were analyzed using the Statistical Package for the Social
Sciences (SPSS, Chicago, IL). Changes of parameters during intervention
were termed values. These were calculated as values after
intervention minus paired values before intervention. Data are
expressed as means ± SD. All P
values of <0.05 were considered to indicate statistical significance.
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RESULTS |
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During the 4 wk, none of the subjects had to be withdrawn from the
study or dropped out because of other reasons. Medication (2 patients
on angiotensin converting-enzyme inhibitors) was not changed during the
study. The daily adherence to the exercise program was >90%, and
adherence was similar for dietary measures (85%). The 4-wk
intervention program induced a reduction of body weight from 96.4 ± 18.5 to 92.3 ± 17.9 kg or expressed as BMI a reduction from 32.1 ± 3.9 to 30.7 ± 3.9 kg/m2. Significant
improvements in carbohydrate and lipid metabolism and serum leptin
concentrations were observed also (Tables 1 and 2).
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|
Correlation analysis between baseline leptin and other parameters before intervention showed a significant relationship to BMI (r = 0.58, P = 0.008), fasting insulin (r = 0.58, P = 0.007), serum cholesterol (r = 0.58, P = 0.007), serum apoB (r = 0.51, P = 0.022), serum triglycerides (r = 0.66, P = 0.002), and VLDL cholesterol (r = 0.59, P = 0.007). Multivariate regression analysis revealed that baseline leptin levels were the only predictor for baseline serum triglycerides (R2 = 0.52, P < 0.001). VLDL cholesterol was determined by leptin only (R2 = 0.47, P = 0.001). For the regression model for baseline serum cholesterol, fructosamine (P = 0.004), glucose (P = 0.019), body weight (P = 0.002), and leptin (P < 0.001) were included as significant predictors (R2 = 0.77). Baseline LDL cholesterol levels were only determined by fructosamine (R2 = 0.24, P = 0.035), and HDL cholesterol levels were determined by BMI only (R2 = 0.44, P = 0.002). Other variables were excluded from the regression models.
Correlation analyses between changes of leptin during intervention
(leptin) were correlated with improvements in serum cholesterol (r = 0.68, P < 0.001; Fig.
1A),
serum triglycerides (r = 0.70, P < 0.001; Fig.
1B), and triglyceride-rich particles
such as VLDL cholesterol (r = 0.72, P < 0.001) but not with changes in
IDL, LDL, and HDL cholesterol or serum apolipoprotein values such as apoB, apoAI, and apoAII. No association was observed between changes of
leptin levels and improvements of glucose control (
glucose profile,
fructosamine, and
insulin).
|
Multivariate regression analysis revealed that changes in serum
triglycerides (log-transformed triglycerides) were only dependent on
changes in leptin (
leptin) concentrations
(P = 0.004) and
fructosamine
(R2 = 0.56;
P = 0.014).
BMI,
glucose
profile, and
fasting insulin were excluded from this model as they
did not add any additional significance to the relationship. The
analysis with original not logarithmically transformed triglyceride
data showed that only
leptin predicted
serum triglyceride levels
(R2 = 0.52, P < 0.001). Changes in
total cholesterol during intervention were also only dependent on
leptin concentrations
(R2 = 0.56, P < 0.001).
VLDL cholesterol (log
transformed) was also only determined by
leptin values
(R2 = 0.52, P < 0.001). The regression model for
changes in untransformed VLDL cholesterol values included
fructosamine in addition to
leptin as an equivalent predictor for
VLDL cholesterol concentrations (R2 = 0.67, P < 0.001).
IDL cholesterol was
only determined by
fructosamine (R2 = 0.49, P = 0.001) and not by
leptin. In
this model,
leptin was excluded as the last variable.
Fructosamine predicted
serum apoB
(R2 = 0.60, P = 0.006), and
glucose profile
determined
serum apoAI (R2 = 0.24, P = 0.027). Change in BMI was always
excluded from the regression models as a predictor for changes in
lipids or lipoproteins.
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DISCUSSION |
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Diet-induced weight loss and exercise training have been shown to reduce systemic leptin concentrations (6, 13, 18). To our knowledge, no study has examined the extent to which systemic leptin levels may be altered by exercise and diet in a group of obese men with type II diabetes mellitus. Our findings support the idea that a nonpharmacological approach in the treatment of type II diabetes is capable of significantly improving glucose and lipid metabolism (8, 10). The results additionally reveal that serum leptin concentrations can be substantially reduced in almost all male diabetic subjects investigated. This is in agreement with observations that reductions of serum leptin levels by ~20% can be induced by exercise training in healthy nonobese subjects (13, 18), although this effect could previously only be documented in females but not in males despite an identical intervention program (13). Therefore, the present study is the first, to our knowledge, indicating that weight loss induced by exercise and diet is associated with reductions of serum leptin levels in males also. Moreover, it is also one of the first two studies investigating patients with metabolic disturbances such as insulin resistance and dyslipoproteinemia with respect to leptin metabolism. Preliminary data by Ryan and Elahi (31) investigating four diabetic women had indicated that reductions in body fat mass and improvements in aerobic capacity by exercise training over 6 mo can reduce leptin concentrations in women with metabolic disturbances (31). The present data confirm this preliminary report in a larger male population.
Four weeks of intervention induced a significant concurrent reduction of serum leptin levels and an improvement of glucose control and dyslipoproteinemia in obese men with type II diabetes. Leptin has been reported to be directly related to fasting plasma insulin concentration and insulin resistance in cross-sectional studies (6, 7, 22). However, in humans, it appears to be relatively stable in response to short-term hyperinsulinemia or hyperglycemia (7, 19, 31). For baseline values, we also observed a close relationship between leptin values and fasting insulin concentrations. However, we found no correlation between changes of serum leptin concentrations and improvements of glucose control during intervention. Instead, we observed a close relationship between leptin and triglyceride-rich lipoproteins. Baseline leptin levels alone predicted baseline serum triglyceride levels by >50%. Moreover, changes of leptin during intervention were closely related to changes in total cholesterol, serum triglycerides, and VLDL cholesterol, relationships that were independent of changes in glucose control or body weight (Fig. 1, A and B). These data suggest that leptin seems to be more closely related to serum triglycerides than to glucose control. Therefore, the relationship between leptin and insulin resistance might be a secondary result of elevated concentrations of serum fatty acids or triglycerides (2, 20). This has not been considered as a confounding factor in previous studies.
The relationship between the concurrent reductions of leptin and lipids cannot be readily explained. As triglyceride-rich particles are directly secreted by the liver and then catabolized by lipases such as hepatic triglyceride lipase or lipoprotein lipase, a direct metabolic influence of leptin on lipoprotein metabolism or lipase activities may be proposed. Very recent data have addressed this issue in leptin-deficient ob/ob mice. The administration of leptin in these animals acutely caused a rapid stimulation of long-chain fatty acid synthesis (5) and an increase of plasma triglycerides by 31% (25). In contrast, long-term administration of leptin markedly decreased fatty acid synthesis in these animals (5). Similarly, overexpression of leptin in normal rats also induced a depletion of triglyceride content in hepatic and skeletal muscle and pancreatic cells (33). This is explained by a leptin-induced increased fat oxidation confined to the intracellular compartment, as serum levels of triglycerides remained unchanged in this setting (33, 34). This effect seems to be directly induced by leptin and has been shown to be independent of caloric intake or hypothalamic regulation (34). In addition to fat oxidation, leptin may also have a direct influence on hepatic lipid metabolism (23). In obese Zucker rats that carry a mutation in the leptin receptor gene, hypertriglyceridemia is one of the phenotypic characteristics. In contrast to lean Zucker rats, these obese animals show a reduced basal expression of the hepatic LDL receptor, which can explain part of the serum lipid abnormalities in these animals (23).
Overall, the data strongly support the notion of a direct influence of
leptin on lipid metabolism. However, so far the studies have primarily
investigated leptin and leptin receptor-deficient animals and have
focused on the intracellular lipid metabolism. Furthermore, data on the
systemic influence of leptin are still equivocal (30, 33). In addition,
other mechanisms such as the influence of exercise and diet on the
expression of tumor necrosis factor- (TNF-
) in adipocytes and
muscle cells have to be considered (12, 14, 17). Both leptin and
TNF-
are directly related and regulated by the same mechanism, the
peroxisome proliferator-activated receptor family, which is also
important for fatty acid metabolism and insulin sensitivity (26, 35). Therefore, the primary mechanisms that account for the simultaneous changes between leptin and lipids during intervention by exercise and
diet observed in our patients with type II diabetes have yet to be elucidated.
Unfortunately, from our study, we cannot differentiate which of the three factors, exercise training, diet, or weight reduction, is the most important factor influencing leptin concentrations. Although previous studies have indicated that weight loss might be the most important factor reducing leptin levels (6, 18, 29), others have also observed a decrease in leptin concentration by exercise training in subjects with stable weight (13). Moreover, it was shown in obese men that the number of endurance exercise hours per week is also directly associated with a reduction in plasma leptin levels independent from changes in body fat percentage and insulin (27). Our results reveal a relationship between BMI and leptin concentration before intervention but fail to show a correlation between changes of leptin and changes of BMI during intervention. This dissociation during the time of intervention has been observed before (27, 32). It has been proposed that long-term hypocaloric diet may uncouple the relationship between body fat and leptin (32). However, this dissociation may also be caused by the fact that body weight and BMI, as measured in the present study, are inaccurate measures of body fat mass. In addition, correlations are always minor when the range for a variable is small, as was the case for BMI and leptin. Furthermore, diet may also play a significant role. Fasting alone has been reported to reduce serum leptin concentration by 64-72% within 1-2 days, despite virtually no change in body fat mass (3). In addition, a hypocaloric diet without additional exercise has also been shown to reduce leptin concentrations by >50% after 4 wk of intervention (16). Future studies may differentiate between short- and long-term diet-induced versus exercise-induced weight reduction, also focusing on the localization of fat depots as well as fat cell size and fatty acid oxidation. Whether the uncoupling of the relationship between body fat mass and serum leptin concentration will be important for the weight course after intervention remains to be shown.
In summary, this study has shown that the assumption that leptin levels can only be reduced by exercise-induced weight loss in females but not in males may only be confined to a healthy population. Our data have shown that the combination of daily exercise and a hypocaloric diet can reduce leptin levels in male obese subjects with insulin resistance. Most interestingly, we found that reductions in leptin levels were closely related to improvements in lipid metabolism, a finding that was mainly independent of changes in glucose control and body weight. This observation is new and certainly worthwhile to be examined in future studies.
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ACKNOWLEDGEMENTS |
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We are indebted to the hospital staff for supervising the exercise and dietary program. The excellent technical assistance of S. Jotterand is greatly appreciated. We also thank Dr. M. W. Baumstark for supervising laboratory analyses.
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: M. Halle, Medizinische Universitätsklinik, Abt. Prävention, Rehabilitation und Sportmedizin, Hugstetter Str. 55, D-79106 Freiburg, Germany (E-mail: mh{at}msm1.ukl.uni-freiburg.de).
Received 22 September 1998; accepted in final form 6 April 1999.
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