OBJECTIVE

To investigate whether associations of common genetic variants recently identified for fasting glucose or insulin levels in nondiabetic adults are detectable in healthy children and adolescents.

RESEARCH DESIGN AND METHODS

A total of 16 single nucleotide polymorphisms (SNPs) associated with fasting glucose were genotyped in six studies of children and adolescents of European origin, including over 6,000 boys and girls aged 9–16 years. We performed meta-analyses to test associations of individual SNPs and a weighted risk score of the 16 loci with fasting glucose.

RESULTS

Nine loci were associated with glucose levels in healthy children and adolescents, with four of these associations reported in previous studies and five reported here for the first time (GLIS3, PROX1, SLC2A2, ADCY5, and CRY2). Effect sizes were similar to those in adults, suggesting age-independent effects of these fasting glucose loci. Children and adolescents carrying glucose-raising alleles of G6PC2, MTNR1B, GCK, and GLIS3 also showed reduced β-cell function, as indicated by homeostasis model assessment of β-cell function. Analysis using a weighted risk score showed an increase [β (95% CI)] in fasting glucose level of 0.026 mmol/L (0.021–0.031) for each unit increase in the score.

CONCLUSIONS

Novel fasting glucose loci identified in genome-wide association studies of adults are associated with altered fasting glucose levels in healthy children and adolescents with effect sizes comparable to adults. In nondiabetic adults, fasting glucose changes little over time, and our results suggest that age-independent effects of fasting glucose loci contribute to long-term interindividual differences in glucose levels from childhood onwards.

Background. Oxygen uptake efficiency slope (OUES) is a reproducible, objective marker of cardiopulmonary function. OUES is reported as being relatively independent of exercise intensity. Practical guidance and criteria for reporting OUES from submaximal tests has not been established. Objective. Evaluate the use of respiratory exchange ratio (RER) as a secondary criterion for reporting OUES. Design. 100 healthy volunteers (53 women) completed a ramped treadmill protocol to exhaustive exercise. OUES was calculated from data truncated to RER levels from 0.85 to 1.2 and compared to values generated from full test data. Results. Mean (sd) OUES from full test data and data truncated to RER 1.0 and RER 0.9 was 2814 (718), 2895 (730), and 2810 (789) mL/min per 10-fold increase in VE, respectively. Full test OUES was highly correlated with OUES from RER 1.0 (r = 0.9) and moderately correlated with OUES from RER 0.9 (r = 0.79). Conclusion. OUES values peaked in association with an RER level of 1.0. Sub-maximal OUES values are not independent of exercise intensity. There is a significant increase in OUES value as exercise moves from low to moderate intensity. RER can be used as a secondary criterion to define this transition.

OBJECTIVE

We examined the independent associations between objectively measured free-living physical activity energy expenditure (PAEE) and the metabolic syndrome in adults in rural and urban Cameroon.

RESEARCH DESIGN AND METHODS

PAEE was measured in 552 rural and urban dwellers using combined heart rate and movement sensing over 7 continuous days. The metabolic syndrome was defined using the National Cholesterol Education Program-Adult Treatment Panel III criteria.

RESULTS

Urban dwellers had a significantly lower PAEE than rural dwellers (44.2 ± 21.0 vs. 59.6 ± 23.7 kJ/kg/day, P < 0.001) and a higher prevalence of the metabolic syndrome (17.7 vs. 3.5%, P < 0.001). In multivariate regression models adjusted for possible confounders, each kJ/kg/day of PAEE was associated with a 2.1% lower risk of prevalent metabolic syndrome (odds ratio 0.98, P = 0.03). This implies a 6.5 kJ/kg/day difference in PAEE, equivalent to 30 min/day of brisk walking, corresponds to a 13.7% lower risk of prevalent metabolic syndrome. The population attributable fraction of prevalent metabolic syndrome due to being in the lowest quartile of PAEE was 26.3% (25.3% in women and 35.7% in men).

CONCLUSIONS

Urban compared with rural residence is associated with lower PAEE and higher prevalence of metabolic syndrome. PAEE is strongly independently associated with prevalent metabolic syndrome in adult Cameroonians. Modest population-wide changes in PAEE may have significant benefits in terms of reducing the emerging burden of metabolic diseases in sub-Saharan Africa.

Objective:

Lipid accumulation in skeletal muscle and the liver is strongly implicated in the development of insulin resistance and type 2 diabetes, but the mechanisms underpinning fat accrual in these sites remain incompletely understood. Accumulating evidence of muscle mitochondrial dysfunction in insulin-resistant states has fuelled the notion that primary defects in mitochondrial fat oxidation may be a contributory mechanism. The purpose of our study was to determine whether patients with congenital lipodystrophy, a disorder primarily affecting white adipose tissue, manifest impaired mitochondrial oxidative phosphorylation in skeletal muscle.

Research Design and Methods:

Mitochondrial oxidative phosphorylation was assessed in quadriceps muscle using 31P-magnetic resonance spectroscopy measurements of phosphocreatine recovery kinetics after a standardized exercise bout in nondiabetic patients with congenital lipodystrophy and in age-, gender-, body mass index-, and fitness-matched controls.

Results:

The phosphocreatine recovery rate constant (k) was significantly lower in patients with congenital lipodystrophy than in healthy controls (P < 0.001). This substantial (∼35%) defect in mitochondrial oxidative phosphorylation was not associated with significant changes in basal or sleeping metabolic rates.

Conclusions:

Muscle mitochondrial oxidative phosphorylation is impaired in patients with congenital lipodystrophy, a paradigmatic example of primary adipose tissue dysfunction. This finding suggests that changes in mitochondrial oxidative phosphorylation in skeletal muscle could, at least in some circumstances, be a secondary consequence of adipose tissue failure. These data corroborate accumulating evidence that mitochondrial dysfunction can be a consequence of insulin-resistant states rather than a primary defect. Nevertheless, impaired mitochondrial fat oxidation is likely to accelerate ectopic fat accumulation and worsen insulin resistance.

OBJECTIVE

Lower birth weight has been associated with a greater risk of metabolic diseases. The aim of this study was examine whether physical activity and aerobic fitness may modify associations between birth weigh and metabolic risk.

RESEARCH DESIGN AND METHODS

The European Youth Heart Study is a population-based study of 9 and 15 year olds (n = 1,254). Birth weight was maternally reported. Skin fold measures were used to calculate body fat and fat mass index (FMI = fat mass [kilograms]/height2). Insulin was measured using fasting blood samples. Physical activity was measured using a hip-worn accelerometer (MTI Actigraph) for >600 min/day for ≥3 days and is expressed as “average activity” (counts per minute) and time spent in above moderate intensity activity (>2000 cpm). Aerobic fitness was assessed using a maximal cycle ergometry test (watts per kilogram fat-free mass).

RESULTS

Higher birth weight was associated with higher FMI (β = 0.49 [95% CI 0.21–0.80]; P = 0.001) and greater waist circumference (0.90 [0.32–1.47]; P < 0.001), adjusted for sex, age-group, sexual maturity, height, and socioeconomic status. Lower birth weight was associated with higher fasting insulin only after further adjustment for adolescent waist circumference and height (−0.059 [−0.107 to −0.011]; P = 0.016). There was no evidence for any modification of the associations after adjustment for physical activity or aerobic fitness.

CONCLUSIONS

The present study did not find any evidence that physical activity or aerobic fitness can moderate the associations among higher birth weight and increased fat mass and greater waist circumference or between lower birth weight and insulin resistance in healthy children and adolescents.

Background

The prevalence of obesity has increased in societies of all socio-cultural backgrounds. To date, guidelines set forward to prevent obesity have universally emphasized optimal levels of physical activity. However there are few empirical data to support the assertion that low levels of energy expenditure in activity is a causal factor in the current obesity epidemic are very limited.

Methods/Design

The Modeling the Epidemiologic Transition Study (METS) is a cohort study designed to assess the association between physical activity levels and relative weight, weight gain and diabetes and cardiovascular disease risk in five population-based samples at different stages of economic development. Twenty-five hundred young adults, ages 25-45, were enrolled in the study; 500 from sites in Ghana, South Africa, Seychelles, Jamaica and the United States. At baseline, physical activity levels were assessed using accelerometry and a questionnaire in all participants and by doubly labeled water in a subsample of 75 per site. We assessed dietary intake using two separate 24-hour recalls, body composition using bioelectrical impedance analysis, and health history, social and economic indicators by questionnaire. Blood pressure was measured and blood samples collected for measurement of lipids, glucose, insulin and adipokines. Full examination including physical activity using accelerometry, anthropometric data and fasting glucose will take place at 12 and 24 months. The distribution of the main variables and the associations between physical activity, independent of energy intake, glucose metabolism and anthropometric measures will be assessed using cross-section and longitudinal analysis within and between sites.

Discussion

METS will provide insight on the relative contribution of physical activity and diet to excess weight, age-related weight gain and incident glucose impairment in five populations' samples of young adults at different stages of economic development. These data should be useful for the development of empirically-based public health policy aimed at the prevention of obesity and associated chronic diseases.

Ruth Loos and colleagues report findings from a meta-analysis of multiple studies examining the extent to which physical activity attenuates effects of a specific gene variant, FTO, on obesity in adults and children. They report a fairly substantial attenuation by physical activity on the effects of this genetic variant on the risk of obesity in adults.

Background

The FTO gene harbors the strongest known susceptibility locus for obesity. While many individual studies have suggested that physical activity (PA) may attenuate the effect of FTO on obesity risk, other studies have not been able to confirm this interaction. To confirm or refute unambiguously whether PA attenuates the association of FTO with obesity risk, we meta-analyzed data from 45 studies of adults (n = 218,166) and nine studies of children and adolescents (n = 19,268).

Methods and Findings

All studies identified to have data on the FTO rs9939609 variant (or any proxy [r2>0.8]) and PA were invited to participate, regardless of ethnicity or age of the participants. PA was standardized by categorizing it into a dichotomous variable (physically inactive versus active) in each study. Overall, 25% of adults and 13% of children were categorized as inactive. Interaction analyses were performed within each study by including the FTO×PA interaction term in an additive model, adjusting for age and sex. Subsequently, random effects meta-analysis was used to pool the interaction terms. In adults, the minor (A−) allele of rs9939609 increased the odds of obesity by 1.23-fold/allele (95% CI 1.20–1.26), but PA attenuated this effect (pinteraction  = 0.001). More specifically, the minor allele of rs9939609 increased the odds of obesity less in the physically active group (odds ratio  = 1.22/allele, 95% CI 1.19–1.25) than in the inactive group (odds ratio  = 1.30/allele, 95% CI 1.24–1.36). No such interaction was found in children and adolescents.

Conclusions

The association of the FTO risk allele with the odds of obesity is attenuated by 27% in physically active adults, highlighting the importance of PA in particular in those genetically predisposed to obesity.

Please see later in the article for the Editors' Summary

Editors’ Summary

Background

Two in three Americans are overweight, of whom half are obese, and the trend towards increasing obesity is now seen across developed and developing countries. There has long been interest in understanding the impact of genes and environment when it comes to apportioning responsibility for obesity. Carrying a change in the FTO gene is common (found in three-quarters of Europeans and North Americans) and is associated with a 20%–30% increased risk of obesity. Some overweight or obese individuals may feel that the dice are loaded and there is little point in fighting the fat; it has been reported that those made aware of their genetic susceptibility to obesity may still choose a poor diet. A similar fatalism may occur when overweight and obese people consider physical activity. But disentangling the influence of physical activity on those genetically susceptible to obesity from other factors that might impact weight is not straightforward, as it requires large sample sizes, could be subject to publication bias, and may rely on less than ideal self-reporting methods.

Why Was This Study Done?

The public health ramifications of understanding the interaction between genetic susceptibility to obesity and physical activity are considerable. Tackling the rising prevalence of obesity will inevitably include interventions principally aimed at changing dietary intake and/or increasing physical activity, but the evidence for these with regards to those genetically susceptible has been lacking to date. The authors of this paper set out to explore the interaction between the commonest genetic susceptibility trait and physical activity using a rigorous meta-analysis of a large number of studies.

What Did the Researchers Do and Find?

The authors were concerned that a meta-analysis of published studies would be limited both by the data available to them and by possible bias. Instead of this more widely used approach, they took the literature search as their starting point, identified other studies through their collaborators’ network, and then undertook a meta-analysis of all available studies using a new and standardized analysis plan. This entailed an extremely large number of authors mining their data afresh to extract the relevant data points to enable such a meta-analysis. Physical activity was identified in the original studies in many different ways, including by self-report or by using an external measure of activity or heart rate. In order to perform the meta-analysis, participants were labeled as physically active or inactive in each study. For studies that had used a continuous scale, the authors decided that the bottom 20% of the participants were inactive (10% for children and adolescents). Using data from over 218,000 adults, the authors found that carrying a copy of the susceptibility gene increased the odds of obesity by 1.23-fold. But the size of this influence was 27% less in the genetically susceptible adults who were physically active (1.22-fold) compared to those who were physically inactive (1.30-fold). In a smaller study of about 19,000 children, no such effect of physical activity was seen.

What Do these Findings Mean?

This study demonstrates that people who carry the susceptibility gene for obesity can benefit from physical activity. This should inform health care professionals and the wider public that the view of genetically determined obesity not being amenable to exercise is incorrect and should be challenged. Dissemination, implementation, and ensuring uptake of effective physical activity programs remains a challenge and deserves further consideration. That the researchers treated “physically active” as a yes/no category, and how they categorized individuals, could be criticized, but this was done for pragmatic reasons, as a variety of means of assessing physical activity were used across the studies. It is unlikely that the findings would have changed if the authors had used a different method of defining physically active. Most of the studies included in the meta-analysis looked at one time point only; information about the influence of physical activity on weight changes over time in genetically susceptible individuals is only beginning to emerge.

Additional Information

Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001116.

This study is further discussed in a PLoS Medicine Perspective by Lennert Veerman

The US Centers for Disease Control and Prevention provides obesity-related statistics, details of prevention programs, and an overview on public health strategy in the United States

A more worldwide view is given by the World Health Organization

The UK National Health Service website gives information on physical activity guidelines for different age groups, while similar information can also be found from US sources

Mitochondrial dysfunction is associated with insulin resistance and type 2 diabetes. It has thus been suggested that primary and/or genetic abnormalities in mitochondrial function may lead to accumulation of toxic lipid species in muscle and elsewhere, impairing insulin action on glucose metabolism. Alternatively, however, defects in insulin signaling may be primary events that result in mitochondrial dysfunction, or there may be a bidirectional relationship between these phenomena. To investigate this, we examined mitochondrial function in patients with genetic defects in insulin receptor (INSR) signaling. We found that phosphocreatine recovery after exercise, a measure of skeletal muscle mitochondrial function in vivo, was significantly slowed in patients with INSR mutations compared with that in healthy age-, fitness-, and BMI-matched controls. These findings suggest that defective insulin signaling may promote mitochondrial dysfunction. Furthermore, consistent with previous studies of mouse models of mitochondrial dysfunction, basal and sleeping metabolic rates were both significantly increased in genetically insulin-resistant patients, perhaps because mitochondrial dysfunction necessitates increased nutrient oxidation in order to maintain cellular energy levels.

Background

The increasing prevalence of type 2 diabetes poses both clinical and public health challenges. Cost-effective approaches to prevent progression of the disease in primary care are needed. Evidence suggests that intensive multifactorial interventions including medication and behaviour change can significantly reduce cardiovascular morbidity and mortality among patients with established type 2 diabetes, and that patient education in self-management can improve short-term outcomes. However, existing studies cannot isolate the effects of behavioural interventions promoting self-care from other aspects of intensive primary care management. The ADDITION-Plus trial was designed to address these issues among recently diagnosed patients in primary care over one year.

Methods/Design

ADDITION-Plus is an explanatory randomised controlled trial of a facilitator-led, theory-based behaviour change intervention tailored to individuals with recently diagnosed type 2 diabetes. 34 practices in the East Anglia region participated. 478 patients with diabetes were individually randomised to receive (i) intensive treatment alone (n = 239), or (ii) intensive treatment plus the facilitator-led individual behaviour change intervention (n = 239). Facilitators taught patients key skills to facilitate change and maintenance of key behaviours (physical activity, dietary change, medication adherence and smoking), including goal setting, action planning, self-monitoring and building habits. The intervention was delivered over one year at the participant's surgery and included a one-hour introductory meeting followed by six 30-minute meetings and four brief telephone calls. Primary endpoints are physical activity energy expenditure (assessed by individually calibrated heart rate monitoring and movement sensing), change in objectively measured dietary intake (plasma vitamin C), medication adherence (plasma drug levels), and smoking status (plasma cotinine levels) at one year. We will undertake an intention-to-treat analysis of the effect of the intervention on these measures, an assessment of cost-effectiveness, and analyse predictors of behaviour change in the cohort.

Discussion

The ADDITION-Plus trial will establish the medium-term effectiveness and cost-effectiveness of adding an externally facilitated intervention tailored to support change in multiple behaviours among intensively-treated individuals with recently diagnosed type 2 diabetes in primary care. Results will inform policy recommendations concerning the management of patients early in the course of diabetes. Findings will also improve understanding of the factors influencing change in multiple behaviours, and their association with health outcomes.

Trial registration

ISRCTN: ISRCTN99175498

The timing of puberty is highly variable1. We carried out a genome-wide association study for age at menarche in 4,714 women and report an association in LIN28B on chromosome 6 (rs314276, minor allele frequency (MAF) = 0.33, P = 1.5 × 10−8). In independent replication studies in 16,373 women, each major allele was associated with 0.12 years earlier menarche (95% CI = 0.08–0.16; P = 2.8 × 10−10; combined P = 3.6 × 10−16). This allele was also associated with earlier breast development in girls (P = 0.001; N = 4,271); earlier voice breaking (P = 0.006, N = 1,026) and more advanced pubic hair development in boys (P = 0.01; N = 4,588); a faster tempo of height growth in girls (P = 0.00008; N = 4,271) and boys (P = 0.03; N = 4,588); and shorter adult height in women (P = 3.6 × 10−7; N = 17,274) and men (P = 0.006; N = 9,840) in keeping with earlier growth cessation. These studies identify variation in LIN28B, a potent and specific regulator of microRNA processing2, as the first genetic determinant regulating the timing of human pubertal growth and development.

OBJECTIVE

The goal of this study was to investigate whether the effects of common genetic variants associated with fasting glucose in adults are detectable in healthy children.

RESEARCH DESIGN AND METHODS

Single nucleotide polymorphisms in MTNR1B (rs10830963), G6PC2 (rs560887), and GCK (rs4607517) were genotyped in 2,025 healthy European children aged 9–11 and 14–16 years. Associations with fasting glucose, insulin, homeostasis model assessment (HOMA)-insulin resistance (IR) and HOMA-B were investigated along with those observed for type 2 diabetes variants available in this study (CDKN2A/B, IGF2BP2, CDKAL1, SLC30A8, HHEX-IDE, and Chr 11p12).

RESULTS

Strongest associations were observed for G6PC2 and MTNR1B, with mean fasting glucose levels (95% CI) being 0.084 (0.06–0.11) mmol/l, P = 7.9 × 10−11 and 0.069 (0.04–0.09) mmol/l, P = 1.9 × 10−7 higher per risk allele copy, respectively. A similar but weaker trend was observed for GCK (0.028 [−0.006 to 0.06] mmol/l, P = 0.11). All three variants were associated with lower β-cell function (HOMA-B P = 9.38 × 10−5, 0.004, and 0.04, respectively). SLC30A8 (rs13266634) was the only type 2 diabetes variant associated with higher fasting glucose (0.033 mmol/l [0.01–0.06], P = 0.01). Calculating a genetic predisposition score adding the number of risk alleles of G6PC2, MTNR1B, GCK, and SLC30A8 showed that glucose levels were successively higher in children carrying a greater number of risk alleles (P = 7.1 × 10−17), with mean levels of 5.34 versus 4.91 mmol/l comparing children with seven alleles (0.6% of all children) to those with none (0.5%). No associations were found for fasting insulin or HOMA-IR with any of the variants.

CONCLUSIONS

The effects of common polymorphisms influencing fasting glucose are apparent in healthy children, whereas the presence of multiple risk alleles amounts to a difference of >1 SD of fasting glucose.

OBJECTIVE

Low levels of physical activity appear to be associated with insulin resistance. However, the detailed associations of these complex relationships remain elusive. We examined the prospective associations between self-reported TV viewing time, objectively measured time spent sedentary, at light-intensity activity, and at moderate- and vigorous-intensity physical activity (MVPA) with insulin resistance.

RESEARCH DESIGN AND METHODS

In 192 individuals (81 men and 111 women) with a family history of type 2 diabetes, we measured physical activity and anthropometric and metabolic variables at baseline and after 1 year of follow-up in the ProActive UK trial. Physical activity was measured objectively by accelerometry. Insulin resistance was expressed as fasting insulin and the homeostasis model assessment score (HOMA-IR).

RESULTS

Baseline MVPA was a significant predictor of fasting insulin at follow-up (β = −0.004 [95% CI −0.007 to −0.0001], P = 0.022), and the association approached significance for HOMA-IR (β = −0.003 [−0.007 to 0.000002], P = 0.052), independent of time spent sedentary, at light-intensity activity, sex, age, smoking status, waist circumference, and self-reported TV viewing. Time spent sedentary and at light-intensity activity were not significantly associated with insulin resistance. The change in MVPA between baseline and follow-up was inversely related to fasting insulin (β = −0.003 [−0.007 to −0.0003], P = 0.032) and the HOMA-IR score (β = −0.004 [−0.008 to −0.001], P = 0.015) at follow-up, after adjustment for baseline phenotype in addition to the same confounders as above.

CONCLUSIONS

These results highlight the importance of promoting moderate-intensity activity such as brisk walking for improving insulin sensitivity and possibly other metabolic risk factors to prevent type 2 diabetes.

OBJECTIVE—We examined the cross-sectional association between objectively measured free-living physical activity energy expenditure (PAEE) and glucose tolerance in adult Cameroonians without known diabetes.

RESEARCH DESIGN AND METHODS—PAEE was measured in 34 volunteers using the doubly labeled water method and indirect calorimetry (resting). Fasting blood glucose and 2-h postload blood glucose were measured during a standard 75-g oral glucose tolerance test.

RESULTS—There was a significant negative correlation between PAEE and 2-h glucose (r = −0.43; P = 0.01) but not fasting glucose (r = 0.1; P = 0.57). The inverse association between PAEE and 2-h glucose remained after adjustment for age, sex, smoking, alcohol consumption, and BMI (β = −0.017 [95% CI −0.033 to −0.002]) and was unchanged after further adjustment for waist circumference, body fat percentage, or aerobic fitness.

CONCLUSIONS—PAEE is inversely associated with 2-h glucose independently of adiposity or fitness. Interventions aimed at increasing PAEE could play an important role in diabetes prevention in developing countries.

Lack of physical activity may be an important etiological factor in the current epidemiological transition characterised by increasing prevalence of obesity and chronic diseases in sub-Sahara Africa. However, there is a dearth of data on objectively measured physical activity energy expenditure (PAEE) in this region. We sought to develop regression equations using body composition and accelerometer counts to predict PAEE. We conducted a cross-sectional study of 33 adult volunteers from an urban (n=16) and a rural (n=17) residential site in Cameroon. Energy expenditure was measured by doubly labelled water over a period of 7 consecutive days. Simultaneously, a hip-mounted Actigraph® accelerometer recorded body movement. PAEE prediction equations were derived using accelerometer counts, age, sex and body composition variables, and cross-validated by the jack-knife method. The Bland and Altman limits of agreement (LOA) approach was used to assess agreement. Our results show that PAEE (kJ·kg−1·day−1) was significantly and positively correlated with activity counts from the accelerometer (r=0.37, p=0.03). The derived equations explained 14 to 40% of the variance in PAEE. Age, sex and accelerometer counts together explained 34% of the variance in PAEE, with accelerometer counts alone explaining 14%. The LOA between DLW and the derived equations were wide, with predicted PAEE being up to 60 kJ·kg−1·day−1 below or above the measured value. In summary, the derived equations performed better than existing published equations in predicting PAEE from accelerometer counts in this population. Accelerometry could be used to predict PAEE in this population and therefore has important applications for monitoring population levels of total physical activity patterns.

BACKGROUND

The endothelial nitric-oxide synthase (NOS3) gene encodes the enzyme (eNOS) that synthesizes the molecule nitric oxide, which facilitates endothelium-dependent vasodilation in response to physical activity. Thus, energy expenditure may modify the association between the genetic variation at NOS3 and blood pressure.

METHODS

To test this hypothesis, we genotyped 11 NOS3 polymorphisms, capturing all common variations, in 726 men and women from the Medical Research Council (MRC) Ely Study (age (mean ± s.d.): 55 ± 10 years, body mass index: 26.4 ± 4.1 kg/m2). Habitual/non-resting energy expenditure (NREE) was assessed via individually calibrated heart rate monitoring over 4 days.

RESULTS

The intronic variant, IVS25+15 [G→A], was significantly associated with blood pressure; GG homozygotes had significantly lower levels of diastolic blood pressure (DBP) (−2.8 mm Hg; P = 0.016) and systolic blood pressure (SBP) (−1.9 mm Hg; P = 0.018) than A-allele carriers. The interaction between NREE and IVS25+15 was also significant for both DBP (P = 0.006) and SBP (P = 0.026), in such a way that the effect of the GG-genotype on blood pressure was stronger in individuals with higher NREE (DBP: −4.9 mm Hg, P = 0.02. SBP: −3.8 mm Hg, P = 0.03 for the third tertile). Similar results were observed when the outcome was dichotomously defined as hypertension.

CONCLUSIONS

In summary, the NOS3 IVS25+15 is directly associated with blood pressure and hypertension in white Europeans. However, the associations are most evident in the individuals with the highest NREE. These results need further replication and have to be ideally tested in a trial before being informative for targeted disease prevention. Eventually, the selection of individuals for lifestyle intervention programs could be guided by knowledge of genotype.

Background

While there are compelling observational data confirming that individuals who exercise are healthier, the efficacy of aerobic exercise interventions to reduce metabolic risk and improve insulin sensitivity in older people has not been fully elucidated. Furthermore, while low birth weight has been shown to predict adverse health outcomes later in life, its influence on the response to aerobic exercise is unknown. Our primary objective is to assess the efficacy of a fully supervised twelve week aerobic exercise intervention in reducing clustered metabolic risk in healthy older adults. A secondary objective is to determine the influence of low birth weight on the response to exercise in this group.

Methods/Design

We aim to recruit 100 participants born between 1931–1939, from the Hertfordshire Cohort Study and randomly assign them to no intervention or to 36 fully supervised one hour sessions on a cycle ergometer, over twelve weeks. Each participant will undergo detailed anthropometric and metabolic assessment pre- and post-intervention, including muscle biopsy, magnetic resonance imaging and spectroscopy, objective measurement of physical activity and sub-maximal fitness testing.

Discussion

Given the extensive phenotypic characterization, this study will provide valuable insights into the mechanisms underlying the beneficial effects of aerobic exercise as well as the efficacy, feasibility and safety of such interventions in this age group.

Trial Registration

Current Controlled Trials: ISRCTN60986572