Metabolic Syndrome X Clinical Trial
Official title:
Neural Mechanisms Predisposing to Cardiovascular Risk in Individuals With the Metabolic Syndrome: Benefits of Dietary Weight Loss, Weight Loss Maintenance and Aerobic Exercise
An abdominal distribution of fat is associated with the greatest heart disease risk, because
commonly, several risk factors of metabolic origin (high blood pressure, unfavourable
cholesterol profile, elevated blood sugar, impaired insulin action) cluster in these
individuals. When this occurs the condition is called the 'metabolic syndrome' (MetS). The
cause of the MetS is yet to be fully elucidated. Increased activity of the nervous system
resulting in enhanced release of the stress hormone 'norepinephrine', may be one mechanism
by which adverse cardiovascular and metabolic sequelae of the MetS might be mediated.
Dietary weight loss, and exercise are first-line treatments for the MetS and provide an
opportunity to prevent or delay the development of type 2 diabetes and heart disease in this
high risk group. However, there is a paucity of data regarding the effects of these
lifestyle factors on the nervous system. Furthermore, it is also unknown whether active
weight loss ('negative energy balance') or a stable lower weight (weight loss maintenance)
is more important in modifying MetS components and nervous system activity. The aims of the
proposed project are:
1. To determine whether dietary weight loss in combination with aerobic exercise is more
beneficial than dietary weight loss alone in reducing nervous system activity and
improving metabolic and cardiovascular parameters in middle-aged men and women with
abdominal obesity and the MetS.
2. To determine whether weight loss maintenance four months after active weight loss is
associated with a preservation of clinical benefits.
3. To study biological determinants of successful weight loss and weight loss maintenance.
Background:
Autonomic dysfunction, namely increased sympathetic drive and reduced vagal tone, may
participate in the pathogenesis and complications of the MetS. Weight loss and aerobic
exercise are first-line therapeutic strategies that are known to be beneficial in lowering
blood pressure, enhancing insulin action and preventing the development of type 2 diabetes.
However, there is a paucity of data regarding their effects on sympathetic nervous system
(SNS) activity. In a recently completed Pilot study in 22 MS subjects we demonstrated that
moderate dietary weight loss (7% of initial body weight) is associated with marked
reductions in whole-body norepinephrine spillover rate (by 43%, P= 0.005) and muscle
sympathetic nervous activity (MSNA, by 15%, P=0.01). In the proposed project we wish to
extend these observations by evaluating the clinical benefits of aerobic exercise and weight
loss maintenance.
Aims:
1. To determine whether dietary weight loss in combination with aerobic exercise (WL + EX)
is more beneficial than dietary weight loss alone (WL) in reducing SNS activity and
improving cardiovascular and metabolic parameters in middle aged men and women with
abdominal obesity and a diagnosis of the MetS.
2. To investigate the determinants of achieved weight loss, with a focus on the roles of
SNS activity, b2-adrenoceptor polymorphisms, resting metabolic rate, plasma and
interstitial adipocytokines.
3. To determine whether clinical benefits during active weight loss (negative energy
balance) are sustained after a 4-month weight loss maintenance program and to
investigate the determinants of successful weight loss maintenance (as above).
4. To examine the inter-relationships between SNS activity, insulin sensitivity,
metabolic, anthropometric and haemodynamic parameters.
Subjects:
Sedentary men and women (n= 66) aged 45 to 65 years with a body mass index of 26 to 39
kg/m2, who fulfil Adult Treatment Panel III criteria for the MetS.
Study design:
Randomized, controlled, parallel design comparison of:
1. WL;
2. WL + EX; or
3. Control (no treatment).
Investigations will be performed at baseline, and at the end of 3-month lifestyle
intervention, and a 4-month weight-maintenance program (WL and WL + EX groups).
Diets:
A modified version of the 'DASH' diet will be used at different caloric levels.
Exercise:
Bicycle riding, performed for 40 minutes on alternate days at a moderate intensity of 65% of
maximum heart rate. Compliance will be assessed by VO2 max measurements.
Investigations:
SNS activity measurements (multiunit and single-unit microneurographic recordings of MSNA,
whole-body norepinephrine spillover, and abdominal adipose tissue and skeletal muscle
interstitial noradrenaline concentration determined by microdialysis) will be made before
and during an oral glucose tolerance test, together with haemodynamic (calf blood flow
measured by venous occlusion plethysmography) measurements. Changes in fat mass will be
quantitated by DEXA scan. Metabolic measurements will include resting metabolic rate,
insulin sensitivity, lipid profile, non-esterified fatty acids, plasma and interstitial
adipokines/cytokines.
Clinical significance:
The proposed project will provide novel information about whole-body and regional
sympathetic activity; the determinants of sympathetic activity and the relative clinical
benefits of active weight loss, weight loss maintenance and aerobic exercise in middle-aged
MetS subjects.
;
Allocation: Randomized, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
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