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*Diabetes
The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 2 688-694
Copyright © 2004 by The Endocrine Society

The Effect of a Six-Month Exercise Program on Very Low-Density Lipoprotein Apolipoprotein B Secretion in Type 2 Diabetes

Saima Alam, Michael Stolinski, Claire Pentecost, Massoud A. Boroujerdi, Richard H. Jones, Peter H. Sonksen and A. Margot Umpleby

Department of Diabetes, Endocrinology, and Internal Medicine, St. Thomas’ Hospital, Guys, Kings and St. Thomas’ School of Medicine, Kings College, London SE1 7EH, United Kingdom

Address all correspondence and requests for reprints to: Dr. A. M. Umpleby, Department of Diabetes, Endocrinology, and Internal Medicine, 4th Floor, North Wing, St. Thomas’ Hospital, Lambeth Palace Road, London SE1 7EH, United Kingdom. E-mail: margot.umpleby{at}kcl.ac.uk.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
The dyslipidemia and insulin resistance of type 2 diabetes can be improved by aerobic exercise. The effect of 6 months supervised exercise on very low-density lipoprotein (VLDL) apolipoprotein B metabolism was investigated in patients with type 2 diabetes. Moderately obese patients (n = 18) were randomized into supervised (n = 9) and unsupervised (n = 9) exercise groups. All patients were given a training session and a personal exercise program and asked to exercise four times per week at 70% maximal oxygen uptake for 6 months. Patients in the supervised group had a weekly session with an exercise trainer. VLDL apolipoprotein (apo)B metabolism was measured with an infusion of 1-13C leucine before and after 6 months of the exercise program.

Supervised exercise for 6 months resulted in a significant within-group decrease in percent hemoglobin A1c (P < 0.001), body fat (P < 0.004), nonesterified fatty acid (P < 0.04), and triglycerides (P < 0.05) and an increase in insulin sensitivity (P < 0.01). There was a decrease in VLDL apoB pool size (160.8 ± 42.6 to 84.9 ± 23.2 mg, P < 0.01) and VLDL apoB secretion rate (11.3 ± 2.6 to 5.5 ± 2.0 mg/kg·d, P < 0.05) with no change in fractional catabolic rate. In a between-group comparison, the decrease in VLDL apoB secretion rate in the supervised group did not achieve significance. This study demonstrates that in type 2 diabetes, a supervised exercise program reduces VLDL apoB pool size, which may be due to a decrease in VLDL apoB secretion rate.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
TYPE 2 DIABETES IS associated with a 2- to 4-fold higher risk of cardiovascular disease (CVD), compared with the nondiabetic population. This can be partly attributed to insulin resistance and dyslipidemia (1). The most common lipid abnormalities in type 2 diabetes are increased plasma triglycerides and low levels of high-density lipoprotein (HDL) cholesterol (2). The latter is considered an independent risk factor for CVD (3), whereas elevated triglyceride concentrations are associated with small dense low-density lipoprotein (LDL) particles, which are known to be particularly atherogenic (4).

In insulin-resistant conditions, regular aerobic exercise can increase insulin sensitivity, thereby improving the adverse lipid profile (5, 6). Although patients are advised to exercise as part of their therapy, unless this is part of a supervised exercise program, this is usually unsuccessful. Because current therapeutic strategies are often ineffective in reducing insulin resistance and improving the adverse lipid profile, the use of a supervised exercise program may have a role in the treatment of these patients.

Apolipoprotein B100 (apoB) is a high-molecular-weight protein that is required for the synthesis and hepatic secretion of very low-density lipoprotein (VLDL). Nascent apoB-containing lipoproteins contain mainly triglyceride, free cholesterol, and cholesterol esters. There is evidence that regulation of apoB secretion is governed by the intracellular availability of these lipid substrates for lipoprotein assembly (7, 8). In addition, insulin and the counterregulatory hormones may regulate apoB secretion either directly or indirectly by altering the availability of substrate required for apoB synthesis. We have shown that an acute insulin infusion reduces the secretion of VLDL apoB in both normal and type 2 diabetic subjects, demonstrating the importance of insulin in the control of lipoprotein metabolism (9, 10). We and others have also demonstrated that the secretion of VLDL-apoB is increased in type 2 diabetes, despite elevated insulin levels, compared with age- and weight-matched control subjects, suggesting that there may be loss of sensitivity to the normal insulin mediated suppression of VLDL apoB (11, 12).

Although the beneficial effects of exercise on dyslipidemia in type 2 diabetes have been studied extensively, there have been no studies to date on the effect of exercise on the underlying metabolic mechanisms in patients with type 2 diabetes. In this study, using stable isotopic techniques, we investigated the effects of aerobic exercise on VLDL metabolism in a supervised and unsupervised group of patients with type 2 diabetes.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

Moderately obese type 2 diabetic patients (n = 18) were recruited from the Diabetes and Endocrine Day Care Centre at St. Thomas’ Hospital. All the selected patients had failed to show improved glycemic control with diet and tablets [hemoglobin A1c (HbA1c) >7.5%)]. Dyslipidemia was not used as an inclusion criterion. Patients with significant ischemic heart disease, significant diabetic complications, uncontrolled hypertension, lipid-lowering medication, and any joint conditions limiting exercise were excluded from the study. Twenty patients volunteered for the study; two patients withdrew before they had completed the exercise program due to poor health. All patients were on oral hypoglycemic treatment that did not change during the study, 17 patients were on metformin and sulfonylureas, and three patients were on metformin only. In the supervised group, three patients were Afro-Caribbean and six were Caucasian; in the unsupervised group, one patient was Afro-Caribbean and eight were Caucasian. Alcohol intake was similar in the supervised group (0 U/wk, n = 3; 4–14 U/wk, n = 6) and the unsupervised group (0 U/wk, n = 5; 10–14 U/wk, n = 3; 30 U/wk, n = 1). Patients had been diagnosed with diabetes for a minimum of 8 yr. The local ethics committee approved the study, and written informed consent was given by the subjects.

Study protocol

Patients were studied before and after a 6-month exercise program. All patients were given an initial training session and an individualized exercise program based on the American College of Sports Medicine guidelines (13) and were asked to exercise for 20–40 min at 60–85% of maximal oxygen uptake (VO2max) four times per week in a mode of aerobic activity of their choice. Patients were then randomized into a supervised (n = 9) or unsupervised (n = 9) group. In the supervised group, after assessing the patient’s understanding of the relationship between diabetes and exercise, barriers to changing activity habits were identified and addressed (14, 15). Supervised patients saw the exercise trainer once every week for an exercise session and an account of the previous week’s activity. A plan for the activity for the following week was agreed. The exercise trainer did not see patients in the unsupervised group after their initial contact. When patients raised an interest in their diet, questions were answered, but they were not given any formal diet guidelines. All patients had normal access to the nutritionist.

Experimental protocol

The VLDL apoB turnover studies were performed at 0 and 6 months. All patients were asked not to exercise for 3 d before the metabolic study day. Patients were admitted to the metabolic ward at 0800 h after an overnight fast. An iv cannula was placed in a superficial vein of each arm for blood sampling and administration of isotope. 1-13C-leucine (Tracer Technologies, Somerville, MA, 15 mg/ml, 13C enrichment 99%) was administered as a priming dose (1 mg/kg), followed by a constant infusion (1 mg/kg-1·h-1) for 9 h. Baseline blood samples were taken for the measurement of fasting blood glucose, insulin, percent HbA1c, total cholesterol, triglyceride (TG), HDL cholesterol (HDL-C), total apoB, and nonesterified fatty acids (NEFAs). Blood samples were taken at baseline and at 30-min intervals for 9 h for the measurement of VLDL apoB enrichment. Samples were taken every 180 min to measure VLDL-TG, VLDL-cholesterol, and VLDL apoB concentration. Blood samples for {alpha}-ketoisocaproic acid ({alpha}-KIC), the deamination product of leucine, which provides a measure of hepatic intracellular leucine enrichment (16), were taken at regular intervals throughout the study.

Within 5–7 d of the metabolic study, body composition was measured using whole-body dual-energy x-ray absorptiometry [QDR-2000 plus, Hologic, Waltham, MA, intertest coefficient of variation (CV) 0.39%] to measure fat mass and lean mass of the whole body, trunk, and limbs. On the same day, VO2max was measured using a stepwise maximal exercise test on an electromagnetically braked bicycle ergonometer using a computerized open-loop gas analyzer system (Medical Graphics Corp., St. Paul, MN) with electrocardiograph monitoring to ensure patients had no latent ischemic heart disease. Resting heart rate and blood pressure were recorded.

Psychological well-being was assessed at 0 and 6 months using the Well Being Questionnaire (17). The questionnaire includes subscales that cover questions to assess depression, anxiety, energy, and general well being.

Biochemical measurements

VLDL was separated by ultracentrifugation for 16 h at 147,000x g as previously described (9). ApoB-100 within the VLDL fractions was precipitated by the tetramethylurea method, a technique that is highly specific for isolating apoB-100 (>97%) (18). The VLDL precipitate was delipidated and then hydrolyzed with 6 M hydrochloric acid for 24 h at 115 C. The isotopic enrichment of leucine in VLDL apoB was determined by selected ion monitoring of the t-butyldimethylsilyl derivative at mass-charge ratio of 302 and 303 on a gas chromatograph-mass spectrometer (Hewlett Packard 5971A, MSD, Bracknell, UK) in the electron impact ionization mode. The isotopic enrichment of {alpha}-KIC was determined by selected ion monitoring of the quinoxalinol-tert-butyldimethylsilyl derivative at mass-charge ratio of 260 and 259 on gas chromatograph-mass spectrometer (Hewlett Packard 5971A) employing electron impact ionization.

Total plasma apoB was measured by an immunoturbidimetric method (interassay CV 4.0%), and VLDL apoB concentration was measured using a modified Lowry method as described previously (interassay CV 3.0%) (19). Plasma and VLDL cholesterol and TG concentrations were measured by an enzymatic method (ABX, Chicksands, Shefford, Bedfordshire, UK) using a Cobas Fara II analyzer (Roche, Welwyn Garden City, UK, interassay CV 1.6%). LDL cholesterol was calculated using the Freidwald equation. HDL-C was measured using a stable liquid reagent-immunoinhibition method (HDL-C L-type, {alpha} Labs, Eastleigh, Hampshire, UK). Serum insulin concentrations were measured in duplicate, using an in-house double-antibody RIA (interassay CV 7%). Plasma NEFA concentrations were measured enzymatically (NEFA C, ACS-ACOD method, Wako Chemicals GmbH, Neuss, Germany, interassay CV 3.6%). HbA1c was measured by anion exchange liquid chromatography (Primus Corp., Kansas City, MO) (interassay CV 8%).

Data analysis

Insulin resistance was calculated using the homeostasis assessment model (HOMAIR) (20). The VLDL apoB fractional catabolic rate (FCR) was estimated by a compartmental model using SAAM II software (SAAM, Seattle, WA). A total of 17 time points were included in the compartmental analysis. Briefly, compartment 1 is the precursor compartment, compartment 2 is an intrahepatic delay, and compartment 3 is a plasma compartment for VLDL apoB secreted by the liver as previously described by Riches et al. (21). The precursor compartment was the steady-state tracer/tracee ratio of {alpha}-KIC, which has been shown to reflect the enrichment of intracellular leucine (16). The intrahepatic delay function was 0.5 h. Patients were in a steady-state in the study as shown by the constant VLDL apoB concentration. In this case the fractional secretion rate (FSR) equals the FCR. The VLDL apoB absolute secretion rate (ASR) (milligram per kilogram per day) was calculated from the product of the FSR and the pool size divided by body weight. The pool size was calculated from the product of mean VLDL apoB concentration (mean concentration of apoB in four pooled VLDL samples) and the plasma volume. Plasma volume was calculated using the formula of Pearson et al. (22).

Results are presented as means ± SEM. For within-group comparisons, a paired t test was used for normally distributed data and a Wilcoxon signed rank test was used for nonnormally distributed data. For between-group comparisons, an unpaired t test was used for normally distributed data and a Mann-Whitney U test for nonnormally distributed data. The change in measurements between 0 and 6 months in the two groups was compared with a t test after establishing that these data were normally distributed. Spearman’s rank correlation test was used to examine the relationship between the change in the hepatic secretion of VLDL ASR and other variables.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Baseline characteristics, body composition, and fitness levels

In the supervised and unsupervised groups at baseline, there was no difference in age, body mass index or percent HbA1c (Table 1Go). In the supervised group, after 6 months of exercise, there was a significant decrease in body mass index (30.6 ± 2.0 to 29.6 ± 2.7, P < 0.03), body weight, total body fat, and trunk fat (P < 0.03, P < 0.004, P < 0.005) (Table 2Go). The decrease in body weight was due to a decrease in body fat. Patients in this group increased their VO2max and power, which are measures of aerobic fitness and muscle strength respectively (P < 0.001, P < 0.003) (Table 2Go). There was no significant change in these measurements in the unsupervised group. The change in these measurements from 0 to 6 months between groups was significant for body fat, trunk fat, VO2max, and power (P < 0.004, P < 0.002, P < 0.05, P < 0.006).


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  		TABLE 1. Physical characteristics of patients in the supervised and unsupervised group

 

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  		TABLE 2. Characteristics of patients in the supervised and unsupervised group at baseline and 6 months

 
Glycemic index, insulin resistance, and well-being

After 6 months of exercise in the supervised group, there was a decrease in percent HbA1c (P < 0.001), fasting insulin concentration (P < 0.03), fasting glucose concentration (P < 0.05), and the HOMA score (P < 0.01) (Table 2Go). There was no change in these measurements in the unsupervised group. The change in well-being measured by the total well-being score also improved (P < 0.02) in the supervised group but not in the unsupervised group (Table 2Go). The questionnaire subscales showed that after 6 months of exercise, there was a significant improvement in energy levels (7.1 ± 1.3 to 8.8 ± 1.2, P < 0.03) and positive well-being (11.4 ± 2.0 to 12.7 ± 1.8, P < 0.05) in the supervised group, with no change seen in the depression score and anxiety score. Patients in the unsupervised group showed no significant improvements in the questionnaire subscales. The change in these measurements from 0 to 6 months between groups was significant for percent HbA1c and HOMA score.

Lipid profile (Tables 3Go and 4Go)

There was no difference in fasting lipid profile before the exercise program in the two groups, although HDL cholesterol tended to be lower (P = 0.07) in the unsupervised group. After 6 months of exercise, there was a significant decrease in fasting plasma TG concentration (P < 0.05) and NEFA concentration (P < 0.04) in the supervised group but not in the unsupervised group. Plasma total cholesterol and LDL cholesterol levels were not different in the two groups at baseline and showed no significant change after 6 months. HDL-C increased significantly in both groups after 6 months (P < 0.001). In the supervised group, there was a significant decrease in VLDL TG concentration (P < 0.01), VLDL-C concentration (P < 0.007) and VLDL apoB concentration (P < 0.01), but there was no change in the VLDL-TG/apoB, VLDL-TG/cholesterol, or VLDL-C/apoB ratio (Table 4Go). The change in these measurements from 0 to 6 months between groups was significant for VLDL apoB concentration (P < 0.002).


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  		TABLE 3. Lipid profile in the supervised and unsupervised group at baseline and 6 months

 

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  		TABLE 4. Composition of VLDL in the supervised and unsupervised exercise groups

 
Kinetic characteristics of VLDL apoB metabolism

VLDL apoB concentrations did not change significantly throughout the course of the metabolic study protocol, demonstrating that apoB kinetics were in a steady-state. {alpha}-KIC enrichment, a measure of VLDL apoB precursor pool enrichment, was achieved rapidly and remained constant during the study. Steady-state enrichment of VLDL apoB was achieved after 7 h of infusion before and after the 6-month exercise program in the supervised and unsupervised groups. The kinetic measurements were not significantly different in the two groups at baseline (Table 5Go).


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  		TABLE 5. Kinetic characteristics of VLDL apoB in the supervised and unsupervised exercise groups

 
After the 6-month exercise program, patients in the supervised group showed a significant decrease in the VLDL pool size (P < 0.01) and ASR (P < 0.05), but there was no significant change in VLDL FCR. The change in these measurements from 0 to 6 months between groups was significant for VLDL apoB pool size (P < 0.004).

There was a significant correlation in all subjects between the change in VLDL apoB ASR (expressed as milligrams per day) from 0 to 6 months and the change in body fat (rs = 0.486, P < 0.04), but the correlation with the change in trunk fat did not achieve statistical significance (rs = 0.414, P = 0.087). The change in VLDL apoB ASR was also significantly correlated with the change in VLDL triglyceride (rs = 0.64, P < 0.006) but did not correlate with the change in HOMAIR. There was no correlation between the change in insulin resistance index and change in NEFA concentration.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
In this study a within-group analysis demonstrated that a supervised exercise program in type 2 diabetic patients resulted in a decrease in triglyceride concentrations and a decrease in VLDL apoB secretion rate with no change in VLDL apoB catabolism. Insulin resistance improved, NEFA concentrations decreased, and HDL-C levels increased after the supervised exercise program. The change in VLDL apoB secretion rate between the supervised and unsupervised exercise group was not significantly different. This may be due to the large between-subject variation in VLDL apoB secretion rate and the increase in activity levels in some subjects in the unsupervised group.

There is considerable evidence that insulin regulates the secretion of VLDL apoB. Acute hyperinsulinemia decreases the hepatic secretion of VLDL apoB in normal subjects (10, 23) and type 2 diabetic patients (9), whereas chronic hyperinsulinemia, as seen in insulin-resistant conditions, is characterized by an increase in the production rate of VLDL apoB (11, 24). In the present study, the exercise program improved insulin sensitivity, as measured by HOMAIR (which largely reflects hepatic insulin sensitivity) and may, therefore, be an important factor in explaining the decrease in VLDL apoB ASR.

The effect of insulin on VLDL apoB ASR may be direct and/or indirect. Insulin has been shown to have a direct effect on VLDL apoB production rate in primary rat hepatocytes (25) and human hepatocytes (26). The mechanism for this is unclear but may be related to insulin’s effects on microsomal transfer protein (MTP). This protein plays an important role in VLDL assembly and intracellular stabilization of apoB. The promoter region for MTP has a negative insulin response element, and insulin can reduce MTP expression (27). In the fructose-fed hamster, an animal model for insulin resistance, MTP expression is increased (28). Treatment of these hamsters with rosiglitazone reduces insulin resistance, restores MTP expression to normal, and reduces VLDL assembly (28).

VLDL apoB secretion is also regulated by intrahepatic lipid substrate availability (29). Insulin indirectly impacts on intrahepatic substrate availability by its antilipolytic effect on adipose tissue (30), thereby decreasing the substrate for TG synthesis. In the present study, the decrease in NEFA concentrations may have contributed to a decrease in the hepatic lipid pool, which, in turn, may have resulted in a decrease in VLDL apoB secretion. In a recent study, however, it was demonstrated that sensitivity to acute insulin-mediated suppression of plasma fatty acids was not associated with fasting VLDL TG secretion in normal subjects (31). Lewis et al. (32) also showed that in the presence of elevated NEFA levels, resulting from a heparin and intralipid infusion, acute hyperinsulinemia decreased VLDL TGs by 32%, suggesting that insulin’s direct effect on the liver is the major determinant of VLDL secretion rate. Malmstrom et al. (33) compared the effect of hyperinsulinemia with the effect of lowering NEFAs to comparable levels with acipimox on VLDL apoB production and showed that insulin decreased VLDL production due to a decrease in VLDL1 particles. The acute lowering of NEFAs did not reduce overall VLDL production but shifted the production of VLDL particles to the smaller VLDL2 particles, indicating that VLDL1 and VLDL2 are independently regulated. The kinetics of the VLDL subfractions were not assessed separately in the present study, but an improvement in insulin sensitivity would be expected to reduce the large TG-rich VLDL1 particles. Assessment of the composition of the VLDL particles demonstrated no change in the ratio of triglyceride/apoB after supervised exercise. This suggests that the composition of VLDL particles remained similar, but the number of VLDL particles decreased after supervised exercise. The correlation between the change in VLDL ASR and VLDL TG from 0 to 6 months further substantiates this hypothesis. However, we cannot rule out the possibility that VLDL1 and VLDL2 are independently regulated by exercise because a large change in VLDL1 may obscure any change or lack of change in VLDL2. Measurement of VLDL1 and VLDL2 kinetics are needed to clarify this.

There is considerable evidence that dyslipidemia and insulin resistance are associated with increased body fat and in particular with visceral adiposity (34). In obesity an association between VLDL apoB secretion and body fat and also with visceral fat has been demonstrated (35). In the current study, the supervised exercise program resulted in a significant decrease in body and trunk fat. At 6 months the change in VLDL apoB ASR was significantly related to the change in body fat but not to the change in trunk fat mass. This may be due to the small sample size in the current study. Alternatively, the different methods used to assess visceral fat mass in our study (DEXA scan) and the latter study (magnetic resonance imaging) may explain the different findings. Because abdominal adipocytes have a high lipolytic capacity, it is possible that an increased flux of NEFAs in the portal vein to the liver may stimulate hepatic secretion of VLDL apoB or may contribute to increased triacylglycerol accumulation in liver, which is associated with hepatic insulin resistance (36). Increased levels of circulating NEFAs, as found in the patients in this study, have also been shown to be associated with insulin resistance (37). Although both NEFAs and insulin resistance decreased with exercise, we were unable to demonstrate a relationship between the change in NEFAs and insulin resistance. The decreased NEFA concentrations in the presence of reduced insulin levels after supervised exercise suggest an improvement in insulin sensitivity in adipose tissue. This has also been demonstrated in a study of obese nondiabetic subjects, which demonstrated that aerobic exercise training for 3 months decreased basal lipolysis and hormone-sensitive lipase activity (38).

VLDL particles are removed from the vascular compartment either by complete hydrolysis to intermediate-density lipoprotein and subsequently LDL particles or by direct removal of the partially delipidated particle via the LDL, LDL-related receptor protein, or VLDL receptor in the liver (23). Lipoprotein lipase activity will determine the rate of VLDL hydrolysis to intermediate-density lipoprotein (39). There is evidence that the ability of insulin to increase lipoprotein lipase activity is impaired in type 2 diabetes and that increased physical exercise in these patients increases lipoprotein lipase activity (40). However, in the current study, the improvement in insulin sensitivity with the supervised exercise program did not impact on VLDL catabolism. In previous studies, in patients with type 2 diabetes, we demonstrated that VLDL apoB FCR was similar to normal subjects (11) and that acute hyperinsulinemia did not affect VLDL apoB FCR in diabetic patients (9). This suggests that the insulin resistance of lipoprotein lipase may not affect VLDL FCR in the fasting state. However, this may be different in the postprandial period.

In this study the psychological well-being of the patients in both the groups was assessed with the Well-Being Questionnaire (17), which has been designed to minimize the possibility of confusing symptoms of poor diabetes control with symptoms of depression. Few studies have investigated the effect of increasing physical activity and psychological well-being in patients with diabetes. A 6-wk training program in elderly patients with type 2 diabetes has been shown to result in significant improvements in all subscales of the Well-Being Questionnaire except depression (41). This is similar to the findings in the present study in which the positive well-being and energy scores increased significantly in the group exercising under supervision for 6 months.

The increase in HDL-C in the unsupervised patients is surprising. Although some patients in this group increased their activity levels, there was no significant change in any measures of fitness, i.e. VO2max and power. Previous exercise studies have reported an increase in HDL-C with very little change in TGs (42); however, it is more likely that the increase in HDL in the unsupervised group is a type I error.

In conclusion, a within-group analysis suggested that an exercise program reduced VLDL apoB pool size by decreasing VLDL apoB secretion rate. The failure to find a significant difference in the change in VLDL apoB secretion rate between the supervised and unsupervised exercise groups may be due to the large between-subject variation in VLDL apoB secretion rate and the increase in activity levels in some subjects in the unsupervised group. We hypothesize that a decrease in VLDL apoB secretion rate may be due to an increase in hepatic insulin sensitivity. A decrease in NEFA flux from adipose tissue to the liver may indirectly improve hepatic insulin resistance (36) and decrease intrahepatic lipid availability, thereby contributing to the decrease in VLDL apoB secretion rate. Increasing evidence suggests that TG concentrations may be a significant risk factor for CVD (43) and that a decrease in TGs may favorably impact on cardiovascular risk (44). This study suggests that the decrease in TGs with regular exercise in type 2 diabetes may be due to a decrease in VLDL apoB secretion rate.


   Acknowledgments
 
We thank Mr. William Jefferson and Mrs. Premila Croos for their technical assistance. We thank Dr. Emanuel Christ (Bern, Switzerland) for reviewing the manuscript.


   Footnotes
 
This work was supported by a grant from the British Heart Foundation (PG/2000056). S.A. was supported by a grant from the government of Pakistan.

Abbreviations: apoB, Apolipoprotein B; ASR, absolute secretion rate; CV, coefficient of variation; CVD, cardiovascular disease; FCR, fractional catabolic rate; FSR, fractional secretion rate; HbA1c, hemoglobin A1c; HDL, high-density lipoprotein; HDL-C, HDL cholesterol; HOMAIR, insulin resistance calculated using homeostasis assessment model; {alpha}-KIC, {alpha}-ketoisocaproic acid; LDL, low-density lipoprotein; MTP, microsomal transfer protein; NEFA, nonesterified fatty acid; TG, triglyceride VLDL, very LDL; VO2max, maximal oxygen uptake.

Received June 16, 2003.

Accepted October 31, 2003.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. Reaven GM 1988 Banting lecture: role of insulin resistance in human disease. Diabetes 37:1595–1607[Abstract]
  2. Betteridge DJ 1999 Diabetic dyslipidaemia. Eur J Clin Invest 29(Suppl 2):12–16
  3. Turner RC, Millns H, Neil HA, Stratton IM, Manley SE, Matthews DR, Holman RR 1998 Risk factors for coronary artery disease in non-insulin dependent diabetes mellitus: United Kingdom Prospective Diabetes Study (UKPDS: 23) BMJ 316:823–828[Abstract/Free Full Text]
  4. Griffin BA, Freeman DJ, Tait GW, Thompson J, Caslake MJ, Packard CJ, Shepherd J 1994 Role of plasma triglyceride in the regulation of plasma low density lipoprotein (LDL) subfractions: relative contribution of small dense LDL to coronary heart disease. Atherosclerosis 106:241–253[CrossRef][Medline]
  5. Lehmann R, Vokac A, Niedermann K, Agosti K, Spinas GA 1995 Loss of abdominal fat and improvement of the cardiovascular risk profile by regular moderate exercise training in patients with NIDDM. Diabetologia 38:1313–1319[Medline]
  6. Mourier A, Gautier JF, De Kerviler E, Bigard AX, Villette JM, Garnier JP, Duvallet A, Guezennec CY, Cathelineau G 1997 Mobilization of visceral adipose tissue related to the improvement in insulin sensitivity in response to physical training in NIDDM. Effects of branched-chain amino acid supplements. Diabetes Care 20:385–391[Abstract]
  7. Dixon JL, Ginsberg HN 1993 Regulation of hepatic secretion of apolipoprotein B-containing lipoproteins: information obtained from cultured liver cells. J Lipid Res 34:167–179[Abstract]
  8. Sniderman A, Brown BG, Stewart BF, Cianflone K 1992 From familial combined hyperlipidaemia to hyperapoB: unravelling the overproduction of hepatic apolipoprotein B. Curr Opin Lipidol 3:137–142
  9. Cummings MH, Watts GF, Umpleby AM, Hennessey TR, Kelly JM, Jackson NC, Sonksen PH 1995 Acute hyperinsulinaemia decreases the hepatic secretion of very low density lipoprotein B100 in type 2 diabetes mellitus: a stable isotope study. Diabetes 44:1059–1065[Abstract]
  10. Watts GF, Cummings MH, Kelly JM, Umpleby AM, O’Brien SF, Sonksen PH 1996 Acute hyperinsulinaemia decreases hepatic secretion of very low density lipoprotein apolipoprotein B-100 in normolipidaemia non diabetic subjects. Endocrinol Metab 3:253–263
  11. Cummings MH, Watts GF, Umpleby AM, Hennessy TR, Naoumova R, Slavin BM, Thompson GR, Sonksen PH 1995 Increased hepatic secretion of very low density lipoprotein apolipoprotein B100 in NIDDM. Diabetologia 38:959–967[Medline]
  12. Duvillard L, Pont F, Florentin E, Galland-Jos C, Gambert P, Verges B 2000 Metabolic abnormalities of apolipoprotein B-containing lipoproteins in non-insulin-dependent diabetes: a stable isotope kinetic study. Eur J Clin Invest 30:685–694[CrossRef][Medline]
  13. 1998 ACSM resource manual guidelines. 3rd ed. Baltimore: Williams and Wilkins
  14. Miller WR, Rollnick S 1991 Motivational interviewing: preparing to change addictive behaviour. New York: Guilford Press
  15. Rollnick S, Mason P, Butler C 2000 Health behaviour change: a guide for practitioners. Edinburgh: Harcourt Brace, Churchill, Livingstone
  16. Matthews DE, Schwartz HP, Yand RD, Motil KJ, Bier D 1982 Relationship of plasma leucine and {alpha}-ketoisocaproate during L[1–13C] leucine infusion in man: a method for measuring human intracellular leucine tracer enrichment. Metabolism 31:1105–1112[CrossRef][Medline]
  17. Bradley C 1994 The well-being questionnaire. In: Bradley C, Ed. Handbook of psychology and diabetes. Chur, Switzerland: Harwood Academic Publishers; 84–109
  18. Kane JP, Sata T, Hamilton RL 1975 Apoprotein composition of very low density lipoproteins of human serum. J Clin Invest 56:1622–1634
  19. Cummings MH, Watts GF, Lumb PJ, Slavin BM 1994 Comparison of immunoturbidimetric and Lowry methods for measuring concentration of very low density lipoprotein apolipoprotein B-100 in plasma. J Clin Pathol 47:176–178[Abstract/Free Full Text]
  20. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC 1985 Homeostasis model assessment: insulin resistance and ß-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 28:412–419[CrossRef][Medline]
  21. Riches FM, Watts GF, Naoumova RP, Kelly JM, Croft KD, Thompson GR 1998 Hepatic secretion of very-low-density lipoprotein apolipoprotein B-100 studied with a stable isotope technique in men with visceral obesity. Int J Obes Relat Metab Disord 22:414–423[CrossRef][Medline]
  22. Pearson TC, Guthrie DL, Simpson J, Chinn S, Barosi G, Ferrant A, Lewis SM, Najean Y 1995 Interpretation of measured red cell mass and plasma volume in adults: Expert Panel on Radionuclides of the International Council for Standardization in Haematology. Br J Haematol 89:748–756[Medline]
  23. Kissebah AH, Alfarsi S, Evans DJ, Adams PW 1982 Integrated regulation of very low density lipoprotein triglyceride and apolipoprotein-B kinetics in non-insulin-dependent diabetes mellitus. Diabetes 31:217–225[Abstract]
  24. Malmstrom R, Packard CJ, Watson TDG, Rannikko S, Caslake M, Bedford D, Stewart P, Yki-Jarvinen H, Shepherd J, Taskinen M-R 1997 Metabolic basis of hypotriglyceridemic effects of insulin in normal men. Arterioscler Thromb Vasc Biol 17:1454–1464[Abstract/Free Full Text]
  25. Sparks JD, Sparks CE, Miller LL 1989 Insulin effects on apolipoprotein B production by normal, diabetic, and treated-diabetic rat liver and cultured rat hepatocytes. Biochem J 261:83–88[Medline]
  26. Salhanick AI, Schwartz SI, Amatruda JM 1991 Insulin inhibits apolipoprotein B secretion in isolated human hepatocytes. Metabolism 40:275–279[CrossRef][Medline]
  27. Lin MC, Gordon D, Wetterau JR 1995 Microsomal triglyceride transfer protein (MTP) regulation in HepG2 cells: insulin negatively regulates MTP gene expression. J Lipid Res 36:1073–1081[Abstract]
  28. Carpentier A, Taghibiglou C, Leung N, Szeto L, Van Iderstine SC, Uffelman KD, Buckingham R, Adeli K, Lewis GF 2002 Ameliorated hepatic insulin resistance is associated with normalization of microsomal triglyceride transfer protein expression and reduction in very low density lipoprotein assembly and secretion in the fructose-fed hamster. J Biol Chem 277:28795–28802[Abstract/Free Full Text]
  29. Sniderman AD, Cianflone K 1993 Substrate delivery as a determinant of hepatic apoB secretion. Arterioscler Thromb 13:629–636[Abstract/Free Full Text]
  30. Coppack SW, Jensen MD, Miles JM 1994 In vivo regulation of lipolysis in humans. J Lipid Res 35:177–193[Abstract]
  31. Carpentier A, Patterson BW, Leung N, Lewis GF 2002 Sensitivity to acute insulin mediated suppression of plasma fatty acids is not a determinant of fasting VLDL triglyceride secretion in healthy humans. Diabetes 51:1867–1875[Abstract/Free Full Text]
  32. Lewis GF, Zinman B, Uffelman KD, Szeto L, Weller B, Steiner G 1995 Interaction between free fatty acids and insulin in acute control of very-low density lipoprotein production in humans. J Clin Invest 95:158–166
  33. Malmstrom R, Packard CJ, Caslake M, Bedford D, Stewart P, Yki-Jarvinen H, Shepherd J, Taskinen MR 1998 Effects of insulin and acipimox on VLDL1 and VLDL2 apolipoprotein B production in normal subjects. Diabetes 47:779–787[Abstract]
  34. Despres JP, Moorjani S, Lupien PJ, Tremblay A, Nadeau A, Bouchard C 1990 Regional distribution of body fat, plasma lipoproteins, and cardiovascular disease. Arteriosclerosis 10:497–511[Abstract/Free Full Text]
  35. Riches FM, Watts GF, Hua J, Stewart GR, Naoumova RP, Barret PH 1999 Reduction in visceral adipose tissue is associated with improvement in apolipoprotein B-100 metabolism in obese men. J Clin Endocrinol Metab 84:2854–2861[Abstract/Free Full Text]
  36. Ryysy L, Hakkinen AM, Goto T, Vehkavaara S, Westerbacka J, Halavaara J, Yki-Jarvinen H 2000 Hepatic fat content and insulin action on free fatty acids and glucose metabolism rather than insulin absorption are associated with insulin requirements during insulin therapy in type 2 diabetic patients. Diabetes 49:749–758[Abstract]
  37. Homko CJ, Cheung P, Boden G 2003 Effects of free fatty acids on glucose uptake and utilization in healthy women. Diabetes 52:487–491[Abstract/Free Full Text]
  38. De Glisezinski I, Crampes F, Harant I, Berlan M, Hejnova J, Langin D, Riviere D, Stich V 1998 Endurance training changes in lipolytic responsiveness of obese adipose tissue. Am J Physiol 275:E951–E956
  39. Eckel RH 1989 Lipoprotein lipase. A multifunctional enzyme relevant to common metabolic diseases. N Engl J Med 320:1060–1068[Abstract]
  40. Lehmann R, Engler H, Honegger R, Riesen W, Spinas GA 2001 Alterations of lipolytic enzymes and high-density lipoprotein subfractions induced by physical activity in type 2 diabetes. Eur J Clin Invest 31:37–44[CrossRef][Medline]
  41. Ligtenberg PC, Godaert GL, Hillenaar EF, Hoekstra JB 1998 Influence of a physical training program on psychological well-being in elderly type 2 diabetes patients. Diabetes Care 21:2196–2197[Medline]
  42. Wilmore JH, Green JS, Stanforth PR, Gagnon J, Rankinen T, Leon AS, Rao DC, Skinner JS, Bouchard C 2001 Relationship of changes in maximal and submaximal aerobic fitness to changes in cardiovascular disease and non-insulin-dependent diabetes mellitus risk factors with endurance training: the HERITAGE Family Study. Metabolism 50:1255–1263[CrossRef][Medline]
  43. Vakkilainen J, Steiner G, Ansquer JC, Aubin F, Rattier S, Foucher C, Hamsten A, Taskinen MR 2003 DAIS Group: relationships between low-density lipoprotein particle size, plasma lipoproteins, and progression of coronary artery disease: the Diabetes Atherosclerosis Intervention Study (DAIS). Circulation 107:1733–1737[Abstract/Free Full Text]
  44. Mack WJ, Krauss RM, Hodis HN 1996 Lipoprotein subclasses in the Monitored Atherosclerosis Regression Study (MARS). Treatment effects and relation to coronary angiographic progression. Arterioscler Thromb Vasc Biol 16:697–704[Abstract/Free Full Text]



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