PDM: Metabolic Syndrome (2013)
Straznicky NE, Lambert EA, Nestel PJ, McGrane MT, Dawood T, Schlaich MP, Masuo K, Eikelis N, de Courten B, Mariani JA, Esler MD, Socratous F, Chopra R, Sari CI, Paul E, Lambert GW. Sympathetic neural adaptation to hypocaloric diet with or without exercise training in obese metabolic syndrome subjects. Diabetes. 2010; 59(1): 71-79.PubMed ID: 19833893
- To test the hypothesis that weight loss by combined hypocaloric diet and aerobic exercise training would be associated with greater sympathoinhibition and improvement in MetS components than hypocaloric diet alone
- To examine the interrelationship between reduction in sympathetic tone and concurrent changes in anthropometric, metabolic and cardiovascular parameters.
- Men and post-menopausal women
- Aged 45 to 65 years
- Fulfilling Adult Treatment Panel III criteria for MetS with central obesity (as measured by waist circumference at 102cm or more in men and 88cm or more in women) and two or more MetS parameters
- Sedentary (defined as physical activity less than 20 minutes per session on two or less times per week)
- Stable body weight (±1kg) in previous six months
- Willingness to accept randomized assignment.
- Type 2 diabetes
- History of secondary hypertension or cardiovascular, cerebrovascular, renal, liver, or thyroid disease
- Use of drugs known to affect measured parameters
- Hypertension (monotherapy treated with angiotensin II receptor antagonist) and hypercholesterolemia (HMG-CoA reductase inhibitor) were studied after medication was discontinued for six weeks.
Newspaper advertisements, followed by screening.
A 12-week randomized controlled trial with three groups:
- Weight loss with caloric restriction alone (WL)
- Weight loss by combined caloric restriction and aerobic exercise (WL+EX)
- No treatment (control group).
Implied with measurements.
- WL group: Subjects were provided with a 14-day menu plan with recipes based upon a modified Dietary Approaches to Stop Hypertension (DASH) diet consisting of 30% fat (6% PUFA, 15% MUFA and 9% SFA), 22% protein, and 48% carbohydrate. Energy needs were calculated and the menu plan was accounted for a 600-calorie deficit per day. Meals were prepared in the subjects home, they attended dietary counseling fortnightly, and completed a four-day dietary record to asses compliance at each counseling session.
- WL + EX: Same dietary protocol noted above plus aerobic exercise training comprised of 40 minutes of bicycle riding on alternate days at moderate intensity (defined as 65% of maximum heart rate, which corresponded to 120 to 145 beats per minute). Workload was increased to maintain target heart rate. A cycle test was performed weekly under Alfred Hospital Heart Center supervision. The remaining sessions were conducted in the subject's home (exercise bicycles and heart monitors provided by study staff) and subjects maintained an average heart rate log during each exercise session. Compliance was assessed by measurement of maximal oxygen consumption during a continuous cycle ergometry protocol (workload increased every 20 minutes).
- Control: Instructed to maintain their usual dietary and exercise habits. Also attended the Heart Centre every 3 weeks to measure blood pressure and body weight.
SigmaStat Version 3.5 (Systat Software) was used for statistical analysis. Data were presented as mean ±SE. The following methods were performed: Two-way repeated measures ANOVA to compare baseline and post-test data. Holm-Sidak for post-hoc comparisons. ANCOVA (with baseline adjustments) for primary outcome variables [norepinephrine spillover and muscle sympathetic nerve activity (MSNA)]. Non-parametric data were log-transformed. Two-way repeated measures ANOVA for sub-group analysis by sex. Area under the plasma concentration-time cure (AUC0-120) was used for glucose and insulin. Pearson's and Spearman's rank correlations were used for associations to assess selected variable changes. Forward stepwise regressions were performed with univariate correlations. A sample size of 20 subjects per group was estimated to provide 80% power at a significance level of 5% (two-tailed) to demonstrate 9% or more log norepinephrine spillover and 24% or more in MSNA.
Timing of Measurements
Baseline and 12-week post-test.
- Dietary intake: Australian Food Composition Tables (FoodWorks Professional v. 3.02)
- Mineral excretion: Urinalysis of 24-hour urine collection to assess sodium, potassium and protein intake
- Anthropometric measures: Body weight measured in light clothing on a digital scale. Waist circumference was measured at midpoint between lowest rib and iliac crest. Hip circumference measured at the greater trochanters. Body composition (total body, truck, abdominal, and peripheral fat and lean masses) was measured with a GE-LUNAR ProdigyAdvanced PA +130510 dual-energy x-ray absorptiometry (DEXA) scan.
- Sympathetic nervous system activity: Performed in a supine position in quiet room after voiding urine. Resting metabolic rate was performed after a 30-minute rest period using breath-by-breath pulmonary gas analysis. Prior to testing, subjects completed a 24-hour urine sample and were instructed to fast for 12 hours; abstain from caffeine for 18 hours and alcohol for 36 hours prior to testing; as well as abstain from exercise the day before testing.
- Norepinephrine kinetics: Isotope dilution method following administering a tracer dose of titrated norepinephrine through intravenous infusion and sampling from the brachial artery
- Muscle sympathetic nerve activity (MSNA): Subcutaneous reference electrode was placed 2 to 3cm from recording site. A tungsten microelectrode was used to collect multi-unit post-ganglionic MSNA following a standard procedure
- Spontaneous cardiac baroreflex sensitivity: Using a sequence method to plot the slope of the regression line between cardiac interval and systolic blood pressure during a 15-minute supine recording
- Metabolic parameters: Standard 75g oral glucose tolerance test (OGTT) with blood sampling every 30 minutes for total of 120 minutes. Whole-body insulin sensitivity was calculated for OGTT with the Matsuda and DeFronzo formula.
- Laboratory measurements: Plasma norepinephrine was determined through HPLC with electrochemical detection. Arterial plasma glucose and lipids were determined by enzymatic methods. Insulin and leptin by radioimmunoassay. High-sensitivity C-reactive protein (hs-CRP) was determined by immunoturbidimetric assay.
- WL group: Subjects were provided with a 14-day menu plan with recipes based upon a modified Dietary Approaches to Stop Hypertension (DASH) diet consisting of 30% fat (6% PUFA, 15% MUFA and 9% SFA), 22% protein and 48% carbohydrate. Energy needs were calculated and the menu plan was accounted for a 600-calorie deficit per day. Meals were prepared in the subjects' home, they attended dietary counseling fortnightly and completed a four-day dietary record to asses compliance at each counseling session.
- WL + EX: Same dietary protocol noted above plus aerobic exercise training comprised of 40-minute bicycle riding on alternate days at moderate intensity (defined as 65% of maximum heart rate, which corresponded to 120 to 145 beats per minute). Workload was increased to maintain target heart rate. A cycle test was performed weekly under Alfred Hospital Heart Center supervision. The remaining sessions were conducted in the subject's home (exercise bicycles and heart monitors provided by study staff) and subjects maintained an average heart rate log during each exercise session. Compliance was assessed by measurement of maximal oxygen consumption during a continuous cycle ergometry protocol (workload increased every 20 minutes).
- Control: Instructed to maintain their usual dietary and exercise habits. Also attended the Heart Centre every three weeks to measure blood pressure and body weight.
- Initial N: 123 screened and 64 eligible and enrolled (gender was not described at baseline; only final N)
- Attrition (final N): 59 (35 males, 24 female)
- Age: 55±1 years for control and WL groups; 54±1 years for WL + EX group
- Anthropometrics: The groups were not statistically different at baseline in anthropometric, metabolic and cardiovascular parameters.
|Body weight (kg)||
|Waist circumference (cm)||109.4±2.5||106.5±1.9||105.1±2.2|
|Total body fat mass (kg)||35.5±2.2||36.4±1.8||35.4±1.5|
|Total body lean mass (kg)||56.8±2.7||53.8±2.2||53.1±2.8|
|Truck fat mass (kg)||21.0±1.2||20.6±0.9||20.1±0.8|
|Abdominal fat mass (kg)||3.3±0.2||3.2±0.2||3.0±0.2|
- Location: Alfred Hospital Heart Center, Melbourne Victoria, Australia.
- Body weight decreased by 7.6%±0.7% and 8.8%±0.9% in the WL and WL + EX groups, along with concomitant decrease in fat mass. Men lost more weight (8.8±0.8 vs. 6.2±0.8kg), total body fat and trunk fat than women
- Waist circumference had a significant decrease in WL+EX group compared to WL group
- Lean body mass significant decreased in both groups, which was suggested to be associated with the decrease in protein consumption during weight loss. Women in WL+EX group maintained their lean body mass, whereas men tended to lose lean mass.
- Norepinephrine concentration and spillover rates (-22%±6% and -22%±7%) were significantly reduced in WL & WL-EX groups
- MSNA was significantly reduced in WL & WL-EX groups: Burst frequency (25%±9% and 29%±7%) and burst incidence (16%±12% and 27%±5%)
- Waist-to-hip ratio change was strongest correlate to norepinephrine spillover rate for the lifestyle groups.
Anthropometric Variable Change from Baseline to 12-Week Post-Test
|Variables||Control Group||WL Group||WL+EX Group|
|BMI (kg/m2)||0.4±0.1||-2.4±0.2 *||-2.8±0.3 *|
|Body weight (kg)||1.0±0.3||-7.1±0.6 *||-8.4±1.0 *|
|Waist circumference (cm)||-0.1±0.5||-6.7±0.7 *||-9.8±1.2 *+|
|Waist-to-hip ratio||0.0±0.0||-0.02±0.01||-0.03±0.01 *|
|Total body fat mass (kg)||0.3±0.2||-5.2±0.7 *||-6.9±0.9 *|
|Total body lean mass (kg)||0.7±0.2||-1.5±0.5 *||-0.9±0.4 *|
|Trunk fat mass (kg)||0.2±0.2||-3.1±0.5 *||-4.4±0.6 *|
|Abdominal fat mass (kg)||0.1±0.1||-0.05±0.1 *||-0.8±0.1 *|
* P<0.01 vs. control group; + P<0.01 vs. WL group.
Fitness and Blood Pressure Variable Change from Baseline to 12-Week Post-Test
|Variable||Control Group||WL Group||WL+EX Group|
|VO2max (ml x FFM-1 x minute-1)||-1.8±1.0||-0.3±1.0||5.1± 0.1 *+|
|Maximum workload (W)||-7±4||-7±5||38±4 *+|
|Heart rate (bpm)||1±1||-2±2||-5±1 *|
|Systolic blood pressure (mm Hg)||-2±3||-10±2||-10±2|
|Diastolic blood pressure (mm Hg)||0±1||-3±1||-4±1|
* P<0.01 vs. control group; + P<0.05 vs. WL group.
Metabolic Response Change from Baseline to 12-Week Post-Test
|Variable||Control Group||WL Group||WL+EX Group|
|Fasting glucose (mmol per L)||-0.2±0.1||-0.6±0.2 *||-0.6±0.1 *|
|Fasting insulin (mU per L)||2.1±1.3||-5.4±1.2 *||-2.9±0.8 *|
|HOMA-IR||-0.5±0.34||-1.66±0.32 *||-0.89±0.23 *|
|Insulin AUC0-120 (mU·l-1 x minute-1)||99±444||-2,340±819 *||-2,039±606 *|
|ISI||-0.04±0.13||1.00±0.27 *||1.10±0.42 *|
|HDL cholesterol (mmol per L)||-0.02±0.03||-0.07±0.03||-0.09±0.04|
|Triglyceride (mmol per L)||-0.1±0.2||-0.5±0.2 *||-0.7±0.2 *|
|Fasting leptin (ng per ml)||2.0±1.2||-7.5±1.8 *||-5.8±1.5 *|
|hs-CRP (mg per L)||0.0±0.4||-0.2±0.2||-0.9±0.3 *|
|Urinary sodium (mmol per day)||-37±18||-37±10||-22±16|
|RMR (calcium per 24 hours)||-57±86||-136±78||-57±75|
|RMR (calcium per 24 hours)||-0.9±1.3||-1.4±1.5||0.1±1.2|
* P<0.05 vs. control group.
- Daily energy intake decreased by 600±100 and 560±90kcal in WL and WL+EX groups
- Aerobic capacity and workload increased by 19%±4% and 38%±4% in WL+EX group
- Many of the anthropometric, metabolic and cardiovascular parameters decreased by the same magnitude in both lifestyle groups except hs-CRP decreased significant only in WL-EX group.
- Moderate intensity aerobic exercise during weight loss does not confer additional benefits on resting sympathetic neural activity, compared to hypocaloric diet alone
- A body weight reduction of 8% to 9% resulted in 22% reduction in norepinephrine spillover rates and concomitant changes in MSNA in both lifestyle groups
- There were no additional improvement in the MetS components with moderate intensity activity despite a 19% improvement in fitness and reduction in central adiposity
- Weight loss is effective to improve baroreflex function (increased 50% in lifestyle groups)
- Changes in waist-to-hip ratio and abdominal fat mass were strongest predictors of norepinephrine spillover
- Changes in body weight, total body and trunk fat mass, and leptin were strongest predicts of MSNA change.
|Government:||Australian Govt: Heart Foundation Grant-in-Aid and National Health & Medical Research Council Project Grant (472604)|
- Highlighted strengths:
- Randomized controlled trial
- Use of both norepinephrine kinetic methodologies
- Direct measurement of postganglionic MSNA to compute sympathetic neural drive
- Close investigator-participant interaction
- Highlighted limitations:
- Only subset had MSNA data
- Exercise training varied by person
- Did not include resistance training (shown cardiovascular benefits)
- Even though exercise did not provide additional benefit to sympathetic neural adaptation following a hypocaloric diet for 12 weeks, there is ample research to show many other health benefits when exercise is combined with dietary changes. The author's abstract downplays the role of exercise and could be misconstrued by the media.
Quality Criteria Checklist: Primary Research
|1.||Would implementing the studied intervention or procedure (if found successful) result in improved outcomes for the patients/clients/population group? (Not Applicable for some epidemiological studies)||Yes|
|2.||Did the authors study an outcome (dependent variable) or topic that the patients/clients/population group would care about?||Yes|
|3.||Is the focus of the intervention or procedure (independent variable) or topic of study a common issue of concern to dieteticspractice?||Yes|
|4.||Is the intervention or procedure feasible? (NA for some epidemiological studies)||Yes|
|1.||Was the research question clearly stated?||Yes|
|1.1.||Was (were) the specific intervention(s) or procedure(s) [independent variable(s)] identified?||Yes|
|1.2.||Was (were) the outcome(s) [dependent variable(s)] clearly indicated?||Yes|
|1.3.||Were the target population and setting specified?||Yes|
|2.||Was the selection of study subjects/patients free from bias?||Yes|
|2.1.||Were inclusion/exclusion criteria specified (e.g., risk, point in disease progression, diagnostic or prognosis criteria), and with sufficient detail and without omitting criteria critical to the study?||Yes|
|2.2.||Were criteria applied equally to all study groups?||Yes|
|2.3.||Were health, demographics, and other characteristics of subjects described?||Yes|
|2.4.||Were the subjects/patients a representative sample of the relevant population?||???|
|3.||Were study groups comparable?||Yes|
|3.1.||Was the method of assigning subjects/patients to groups described and unbiased? (Method of randomization identified if RCT)||???|
|3.2.||Were distribution of disease status, prognostic factors, and other factors (e.g., demographics) similar across study groups at baseline?||Yes|
|3.3.||Were concurrent controls or comparisons used? (Concurrent preferred over historical control or comparison groups.)||Yes|
|3.4.||If cohort study or cross-sectional study, were groups comparable on important confounding factors and/or were preexisting differences accounted for by using appropriate adjustments in statistical analysis?||N/A|
|3.5.||If case control study, were potential confounding factors comparable for cases and controls? (If case series or trial with subjects serving as own control, this criterion is not applicable.)||N/A|
|3.6.||If diagnostic test, was there an independent blind comparison with an appropriate reference standard (e.g., "gold standard")?||N/A|
|4.||Was method of handling withdrawals described?||No|
|4.1.||Were follow-up methods described and the same for all groups?||???|
|4.2.||Was the number, characteristics of withdrawals (i.e., dropouts, lost to follow up, attrition rate) and/or response rate (cross-sectional studies) described for each group? (Follow up goal for a strong study is 80%.)||No|
|4.3.||Were all enrolled subjects/patients (in the original sample) accounted for?||Yes|
|4.4.||Were reasons for withdrawals similar across groups?||???|
|4.5.||If diagnostic test, was decision to perform reference test not dependent on results of test under study?||N/A|
|5.||Was blinding used to prevent introduction of bias?||Yes|
|5.1.||In intervention study, were subjects, clinicians/practitioners, and investigators blinded to treatment group, as appropriate?||N/A|
|5.2.||Were data collectors blinded for outcomes assessment? (If outcome is measured using an objective test, such as a lab value, this criterion is assumed to be met.)||Yes|
|5.3.||In cohort study or cross-sectional study, were measurements of outcomes and risk factors blinded?||N/A|
|5.4.||In case control study, was case definition explicit and case ascertainment not influenced by exposure status?||N/A|
|5.5.||In diagnostic study, were test results blinded to patient history and other test results?||N/A|
|6.||Were intervention/therapeutic regimens/exposure factor or procedure and any comparison(s) described in detail? Were interveningfactors described?||Yes|
|6.1.||In RCT or other intervention trial, were protocols described for all regimens studied?||Yes|
|6.2.||In observational study, were interventions, study settings, and clinicians/provider described?||N/A|
|6.3.||Was the intensity and duration of the intervention or exposure factor sufficient to produce a meaningful effect?||Yes|
|6.4.||Was the amount of exposure and, if relevant, subject/patient compliance measured?||Yes|
|6.5.||Were co-interventions (e.g., ancillary treatments, other therapies) described?||Yes|
|6.6.||Were extra or unplanned treatments described?||N/A|
|6.7.||Was the information for 6.4, 6.5, and 6.6 assessed the same way for all groups?||Yes|
|6.8.||In diagnostic study, were details of test administration and replication sufficient?||N/A|
|7.||Were outcomes clearly defined and the measurements valid and reliable?||Yes|
|7.1.||Were primary and secondary endpoints described and relevant to the question?||Yes|
|7.2.||Were nutrition measures appropriate to question and outcomes of concern?||Yes|
|7.3.||Was the period of follow-up long enough for important outcome(s) to occur?||Yes|
|7.4.||Were the observations and measurements based on standard, valid, and reliable data collection instruments/tests/procedures?||Yes|
|7.5.||Was the measurement of effect at an appropriate level of precision?||Yes|
|7.6.||Were other factors accounted for (measured) that could affect outcomes?||Yes|
|7.7.||Were the measurements conducted consistently across groups?||Yes|
|8.||Was the statistical analysis appropriate for the study design and type of outcome indicators?||Yes|
|8.1.||Were statistical analyses adequately described and the results reported appropriately?||Yes|
|8.2.||Were correct statistical tests used and assumptions of test not violated?||Yes|
|8.3.||Were statistics reported with levels of significance and/or confidence intervals?||Yes|
|8.4.||Was "intent to treat" analysis of outcomes done (and as appropriate, was there an analysis of outcomes for those maximally exposed or a dose-response analysis)?||No|
|8.5.||Were adequate adjustments made for effects of confounding factors that might have affected the outcomes (e.g., multivariate analyses)?||Yes|
|8.6.||Was clinical significance as well as statistical significance reported?||Yes|
|8.7.||If negative findings, was a power calculation reported to address type 2 error?||N/A|
|9.||Are conclusions supported by results with biases and limitations taken into consideration?||Yes|
|9.1.||Is there a discussion of findings?||Yes|
|9.2.||Are biases and study limitations identified and discussed?||Yes|
|10.||Is bias due to study's funding or sponsorship unlikely?||Yes|
|10.1.||Were sources of funding and investigators' affiliations described?||Yes|
|10.2.||Was the study free from apparent conflict of interest?||Yes|