Ecological data on temporal trends suggest that the rising prevalence of obesity is, at least in part, attributable to declining population energy expenditure. However, population-level data on trends in physical activity are scarce. In longitudinal cohort studies individuals who report higher levels of leisure-time physical activity tend to be less likely to gain weight, but studies vary in their conclusions because of issues of confounding, reverse causality and measurement error. The majority of studies suggest that low levels of activity are only weakly associated with future weight gain. Questions about dose–response can only be properly addressed by studies including objective measures of activity with known measurement error. The observational studies leave uncertainties about the direction of causality, as individuals who are overweight are less likely to stay active. Adjustment for confounding can diminish the impact of known confounders, but only randomisation can deal with issues of unmeasured confounding. Although there are a large number of clinical trials on the treatment of individuals with obesity or the prevention of weight regain among weight losers, the updated review of trials to prevent weight gain de novo only reveals six trials published since 2000 in adults and eleven in children. Not only are these trials relatively few in number but, for various methodological reasons, they are uncertain in their conclusions about whether increasing activity will be effective in preventing obesity. Whilst efforts should continue to enhance the evidence base it is wise, in the meantime, to stick to the consensus public health advice of advocating 45–60 min moderate intensity activity daily to prevent obesity.

Currently, in many European countries more than half the adult population is overweight; it hass become ‘abnormal’ to be of ‘normal weight’. The risk of type 2 diabetes, CVD, hypertension and certain forms of cancer increase with increasing weight. Biological evolution has produced body-fat-regulating mechanisms that are more powerful in protecting against weight loss than against weight gain. The current environment offers constant availability of affordable palatable energy-rich foods, with no need to consume the energy through physical activity. The ‘obesogenic’ environment is to some extent a political issue, but it has been shown that the healthcare system can also have a role in preventing obesity-related morbidity. The Finnish Diabetes Prevention Study was the first controlled randomised study to show that individualised lifestyle counselling of individuals with high risk of developing type 2 diabetes can influence diet, physical activity and body weight, and that type 2 diabetes can be prevented, or at least postponed. Most importantly, lifestyle changes do not have to be extreme. If the population would adopt a lifestyle in line with the official nutrition recommendations, the obesity and diabetes trend could at least be stabilised.

The prevalence of obesity, overweight and type 2 diabetes are increasing in all regions of Europe. Obesity is already commonplace, affecting 10–20% of men and 10–25% of women, and by 2010 approximately 31 million of the population will require treatment for diabetes and its related complications, including the ‘metabolic syndrome’ (a cluster of cardiovascular risk factors). Associated health and social welfare costs are expected to rise to economically unsustainable levels in Europe as a direct result of these trends. Effective strategies are needed to tackle this major public health problem and to decrease dependence on medical management. These issues are the focus of LIPGENE (FOOD-CT-2003-505944), funded by the European Commission, which will investigate the interactions between dietary constituents and the genome in the development of chronic diseases, such as the metabolic syndrome, and will utilise new technologies to identify novel solutions. The LIPGENE consortium comprises twenty-five research centres across Europe. Features of the 5-year work programme include a major human nutrition intervention study in eight European cities, development of a sustainable vegetable oil product naturally rich in long-chain n-3 fatty acids, and identification of a protocol for feeding dairy cows that will result in milk with a more favourable fatty acid composition. Other work packages will provide a detailed economic analysis of the current and future healthcare costs associated with the metabolic syndrome, and an analysis of consumer attitudes. There is also a dissemination programme associated with the project that features conferences, workshops and associated publications.

Concerns have been expressed that the introduction of novel foods into the diet might lead to the development of new food allergies in consumers. Novel foods can be conveniently divided into GM and non-GM categories. Decision-tree approaches (e.g. International Life Sciences Institute-International Food Biotechnology Council and WHO/FAO) to assess the allergenic potential of GM foods were developed following the discovery, during product development, of the allergenic potential of GM soyabean expressing a gene encoding a storage protein from Brazil nut (Bertolletia excelsa). Within these decision trees considerations include: the source of the transgene; amino acid homology with known allergens; cross-reactivity with IgE from food-allergic individuals; resistance to proteolysis; prediction using animal models of food allergy. Such decision trees are under constant review as new knowledge and improved models emerge, but they provide a useful framework for the assessment of the allergenic potential of GM foods. For novel non-GM foods the assessment of allergenic potential is more subjective; some foods or food ingredients will need no assessment other than a robust protein assay to demonstrate the absence of protein. Where protein is present in the novel non-GM food, hazard and risk assessments need to be made in terms of the quantity of protein that might be consumed, the identity of individual protein components and their relationships to known food allergens. Where necessary, this assessment would extend to serum screening for potential cross-reactivities, skin-prick tests in previously-sensitised individuals and double-blind placebo-controlled food challenges.

Obesity is a serious and increasing health issue. Approximately two-thirds of adults in the UK are now overweight or obese. Recent public health reports firmly reinforce the importance of engaging individuals to look after their health, including their weight. They also spell out the need for individuals to be supported more actively, on many levels, to enable this ‘engagement’. Meanwhile, national surveys indicate that approximately two-thirds of adults are concerned about weight control, with one-third actively trying to lose weight. This finding is hardly surprising considering current weight statistics, plus the plethora of popular diets on offer. Weight-loss methods include diet clubs, diet books, exercise, meal replacements, advice from healthcare professionals and following a self-styled diet. Obesity is a multi-factorial problem, and losing weight and, in particular, maintaining weight loss is difficult and often elusive. It is argued that the modern obesogenic or ‘toxic’ environment has essentially taken body-weight control from an instinctive ‘survival’ process to one that needs sustained cognitive and skill-based control. The evidence suggests that health professionals can help individuals achieve longer-term weight control by supporting them in making sustainable lifestyle changes using a range of behavioural techniques. These techniques include: assessing readiness to change; self-monitoring; realistic goal setting; dietary change; increased physical activity; stimulus control; cognitive restructuring; relapse management; establishing ongoing support. Consistently working in a client-centred way is also being increasingly advocated and incorporated into practice to help motivate and encourage, rather than hinder, the individual's progress.

Obesity and overweight are linked with a cluster of metabolic and vascular disorders that have been termed the metabolic syndrome. Although there is not yet a universally-accepted set of diagnostic criteria, most expert groups agree that the syndrome is characterised by impaired insulin sensitivity and hyperglycaemia, dyslipidaemia (elevated blood triacyglycerols with depressed HDL-cholesterol), abdominal obesity and hypertension. Based on existing published criteria estimates suggest that the syndrome affects a substantial percentage of the middle-aged and elderly populations of most European countries (10–20%) and confers increased risk of type 2 diabetes (2–8.8-fold) and CVD (1.5–6-fold), as well as having a marked effect on morbidity. Although the pathophysiology is incompletely understood, insulin resistance and abdominal obesity are central to subsequent abnormalities in circulating glucose and lipoproteins, and vascular function that lead to type 2 diabetes, atherosclerosis and CVD. The link between metabolic syndrome, type 2 diabetes and CVD, as well as inability to reverse the present rising rates of obesity, will lead to economically-unsustainable costs of health care in the next 10–20 years. Preventative strategies for metabolic syndrome are required to slow rates of progression and to reduce dependence on costly medical management. A notable development is recent evidence that shows that diet and exercise are more effective than drug treatment in preventing the development of type-2 diabetes in high-risk individuals. The LIPGENE project will investigate dietary fat quality as a strategy for the prevention of metabolic syndrome and identify food chain approaches that can support consumer attempts to alter their dietary patterns.

Pre-eclampsia is a disorder characterised by pregnancy-induced hypertension and new-onset proteinuria occurring in the second half of pregnancy. Worldwide, approximately 2–3% of all pregnant women develop pre-eclampsia. The condition is a major cause of maternal and fetal morbidity and mortality. Abnormal placentation is an important predisposing factor for pre-eclampsia, while endothelial activation appears to be central to the pathophysiological changes, possibly indicative of a two-stage disorder characterised by reduced placental perfusion and a maternal syndrome. There is increasing evidence that pre-eclampsia is associated with both increased oxidative stress and reduced antioxidant defences, which has led to the hypothesis that oxidative stress may play an important role in the pathogenesis of pre-eclampsia, perhaps acting as the link in a two-stage model of pre-eclampsia. In support of this hypothesis a small, but important, preliminary study has shown a highly significant (P = 0.02) reduction in the incidence of pre-eclampsia in women at risk who were taking a supplement of vitamins C and E from mid-pregnancy. Furthermore, these findings support the hypothesis that oxidative stress is at least partly responsible for the endothelial dysfunction of pre-eclampsia. Several larger multicentre trials are currently underway to evaluate the efficacy, safety and cost benefits of antioxidant supplementation during pregnancy for the prevention of pre-eclampsia in both low- and high-risk women, including women with diabetes. The results of these trials are awaited with interest.

There have been only a few controlled studies on the prevention of overweight and obesity in children and adolescents. These studies differ in relation to strategy, setting, duration, focus, variables of outcome and statistical power, and therefore do not allow general conclusions to be made about the value of preventive measures. All school-based interventions aimed at the prevention of overweight and obesity show some improvement of health knowledge and health-related behaviours. Short-term effects on nutritional state seem to be more pronounced in girls than in boys. School-based interventions can reduce the incidence of overweight. There is evidence that families of intermediate and high socio-economic status as well as intact families benefit more from treatment than families sharing other characteristics. Selected prevention in obese children is most successful when children are treated together with their parents. However, there are social barriers limiting the success of family-based interventions. Although some positive effects have been reported, simple interventions in a single area (e.g. a school health education programme) are unlikely to work on their own. The development of effective preventive interventions probably requires strategies that affect multiple settings simultaneously. At present there is no concerted action, rather many strategies in health promotion that are followed in isolation. Faced with the epidemic of overweight there is a need for national campaigns and action plans on childhood overweight and obesity. It is tempting to speculate that this strategy will also increase the value of isolated approaches (e.g. in schools and families).

Obesity is a serious public health problem that has important social, economic and health consequences. The prevalence of obesity is rising rapidly throughout the world in both rich and poor countries, and it affects all sections of society. There are several important reasons for addressing the prevention of obesity, rather than its treatment or management. The prevention of weight gain (or the reversal of small gains) and the maintenance of a healthy weight are likely to be easier, less expensive and potentially more effective than the treatment of obesity after it has fully developed. A structured planning framework for the identification of potential interventions for the promotion of healthy weight and the prevention of weight gain is clearly required. However, detailed reviews of the scientific literature have revealed that the body of research is too small to provide firm guidance on consistently-effective interventions for adults or children. Ultimately, a broader approach to evidence of effectiveness needs to be adopted. The present paper proposes a structured planning approach that utilises the portfolio model and allows the selection of interventions to be based on the best available evidence, while not excluding untried but promising strategies.

The present paper reports on results obtained as part of the economics module of the LIPGENE project. It reviews recent trends in obesity in the fifteen member states of the EU (the member states before enlargement in 2004) and concludes that in 2002 for both adult men and women at least half the fifteen member states of the EU had obesity levels of >20%. In the same year the total direct and indirect annual costs of obesity in the fifteen member states of the EU were euro32 800×106. The provision of ‘healthy’ foods with an adapted lipid profile provides one means of mitigating the impact of obesity. However, there are extra costs associated with the supply of such foods, via additional costs of food ingredients, identity preservation costs for premium-value food products and the penalties caused by the inability to exploit economies of scale. The limited scale of the markets for healthy foods is caused by their high selling prices. Also presented is an analysis of the costs of subsidising, throughout the EU, ingredients that improve the fatty acid profile of beef, eggs, poultry meat and low-fat spreads, so that healthier versions of these products sell at the same price as traditional alternatives. The total costs of such subsidies for these four food products would have been euro10×109/year in 2002, which was 30% of the direct and indirect costs of obesity.

Obesity is often difficult to tackle in primary care. Pressure of time in the consultation, a lack of appropriately-trained primary care staff, a shortage of community dietitians or nutritionists, the potentially enormous caseload, language or cultural barriers and the sheer intractability of patients' eating habits, exercise behaviour and their clinical condition, all conspire to make general practitioners, other team members and often the patients themselves lose heart and stop even trying. However, there are ways of overcoming these difficulties. Examples of changes that evidence suggests are able to support and enhance basic one-to-one interventions in general practice include: improved clinical guidelines; better training of primary care staff; at-risk patient registers; smarter database search tools; new quality incentives; closer working with dietitians, counsellors and pharmacists; more hospital outreach clinics; designated general practitioner specialists and practice clustering; expanded exercise referral schemes and links with leisure providers; subsidised referral to commercial slimming groups; better use of patient groups and voluntary and community workers. The present paper describes a proposed ‘triple-tier’ pathway for weight management incorporating most of the elements mentioned earlier. With a more joined-up and creative approach to the development and organisation of primary care, more comprehensive training and workforce planning, and better integration with social care, voluntary groups and the commercial sector, weight management in general practice has the potential to be much more effective.

In the present paper biomarkers of micronutrient status in childhood and some of the factors influencing them, mainly dietary intake, requirements and inflammation will be examined. On a body-weight basis the micronutrient requirements of children are mostly higher than those of an adult, but most biomarkers of status are not age-related. A major factor that is often overlooked in assessing status is the influence of subclinical inflammation on micronutrient biomarkers. In younger children particularly the immune system is still developing and there is a higher frequency of sickness than in adults. The inflammatory response rapidly influences the concentration in the blood of several important micronutrients such as vitamin A, Fe and Zn, even in the first 24 h, whereas dietary deficiencies can be envisaged as having a more gradual effect on biomarkers of nutritional status. The rapid response to infection may be for protective reasons, i.e. conservation of reserves, or by placing demands on those reserves to mount an effective immune response. However, because there is a high prevalence of disease in many developing countries, an apparently-healthy child may well be at the incubation stage or convalescing when blood is taken for nutritional assessment and the concentration of certain micronutrient biomarkers will not give a true indication of status. Most biomarkers influenced by inflammation are known, but often they are used because they are convenient or cheap and the influence of subclinical inflammation is either ignored or overlooked. The objective of the present paper is to discuss: (1) some of the important micronutrient deficiencies in childhood influenced by inflammation; (2) ways of correcting the interference from inflammation.

The present review considers the background to terminology that relates foods, glycaemia and health, including ‘available carbohydrate’, ‘glycaemic index’ (GI), 'glycaemic glucose equivalent', 'glycaemic response index' and 'net carbohydrate', and concludes that central to each of these terms is 'glycaemic load' (GL). GL represents the acute increase in exposure of tissue to glucose determined by foods; it is expressed in ingested glucose equivalents (per 100 g fresh weight or per serving), and is regarded as independent of the state of glucose metabolism from normal to type 2 diabetes mellitus (T2DM). Ad libitum studies in overweight or obese adults and children show that low-GL diets are associated with marked weight benefits, loss of adiposity and reduced food intake. Weight benefits appear on low-glycaemic v. high-glycaemic available carbohydrates, unavailable v. available carbohydrates and protein v. available carbohydrate. Energy intake immediately after lowering of meal GL via carbohydrate exchanges is apparent only after a threshold cumulative intake of >2000 MJ. Various epidemiological and interventional studies are discussed. A relationship between GL and the development of T2DM and CHD is evident. Studies that at first seem conflicting are actually consistent when data are overlaid, such that diets with a GL of >120 glucose equivalents/d would appear to be inadvisable. Whereas certain studies might place GI as being slightly stronger than GL in relationto T2DM risk, this situation appears to be associated with observations in a lower range of GL or when the range of GI is too narrow for accuracy; nevertheless, authors emphasise the importance of GL. Among the studies reviewed, GL offers a better or stronger explanation than GI in various observations including body weight, T2DM in nurses, CHD, plasma triacylglycerols, HDL-cholesterol, high-sensitivity C-reactive protein and protein glycation. Where information is available, the associations between risk factors and GL are either similar or stronger in the overweight or obese, as judged by BMI, and apply to both body weight and blood risk factors. The implications tend to favour a long-term benefit of reducing GL, for which further study is necessary to eliminate any possibility of publication bias and to establish results in clinical trials with overweight and obese patients.

Metabolic syndrome (MS) is more common among socio-economically disadvantaged individuals and is associated with certain risky lifestyle practices. MS also appears to be triggered by adverse social circumstances and chronic stress. The present paper reviews accumulating evidence to imply that individuals who have certain personality and behaviour traits are particularly predisposed to develop MS, and brings together theories that relate to possible psychological mechanisms underlying MS. It considers how such factors might interact causally to encourage the development of MS. As part of the EU-funded LIPGENE Integrated Project, multi-level modelling will be undertaken to explore potential pathways to MS, taking into consideration the interplay between a range of psycho-social, demographic, cultural and lifestyle factors thought to contribute to the development of MS. Data will be gathered for this purpose from a representative sample of >50-year-olds living in Britain (n 1000) and Portugal (n 500). It is anticipated that this information will assist in the development and targetting of future intervention to prevent and treat MS in the normal population.

The prevalence of obesity in the general population is high and it is inevitable that artificial feeding will be needed from time to time in the obese patient, particularly in the critical care setting. Against a background of generous endogenous stores of energy as adipose tissue and the ability of obese individuals to survive starvation longer than non-obese individuals, emphasis is placed on preserving lean body mass and optimizing physiological function. Insulin resistance is typical of the obese individual and is exacerbated by stress; overfeeding is dangerous, particularly if it results in hyperglycaemia. Refeeding syndrome also has to be avoided. Weight may be difficult to measure and lean body mass difficult to assess. Calculation of energy requirements is therefore problematic in practice in the obese individual and there is substantial evidence from controlled clinical trials of the safety of feeding at or below resting energy expenditure. If this approach is taken it is wise to provide a more generous than normal protein intake and to beware of patients with a very high baseline urinary N excretion.

The lungs are continually exposed to relatively-high O2 tensions, and as such, in comparison with other organs, they represent a unique tissue for the damaging effects of oxidant attack. At particular times during a lifetime this every day challenge may increase exponentially. The first oxidative insult occurs at birth, when cells are exposed to a sudden 5-fold increase in O2 concentration. Thereafter, the human lung, from infancy through to old age, can be subjected to deleterious oxidative events as a consequence of inhaling environmental pollutants or irritants, succumbing to several pulmonary diseases (including infant and adult respiratory distress syndromes, asthma, chronic obstructive pulmonary disease, cystic fibrosis and cancer) and receiving treatment for these diseases. The present paper will review the concept that consumption of a healthy diet and the consequent ability to establish and then maintain adequate micronutrient antioxidant concentrations in the lung throughout life, and following various oxidative insults, could prevent or reduce the incidence of oxidant-mediated respiratory diseases. Furthermore, the rationale, practicalities and complexities of boosting the antioxidant pool of the respiratory-tract lining fluid in diseases in which oxidative stress is actively involved, by direct application to the lung v. dietary modification, in order to achieve a therapeutic effect will be discussed.

The metabolic syndrome is a very common disease associated with an increased risk of type 2 diabetes mellitus (T2DM) and CVD. The clinical characteristics of the metabolic syndrome include insulin resistance, dyslipidaemia, abdominal obesity and hypertension. The diverse clinical characteristics illustrate the complexity of the disease process, which involves several dysregulated metabolic pathways. Thus, multiple genetic targets must be involved in the pathogenesis and progression of the metabolic syndrome. Nevertheless, the human genome has not changed markedly in the last decade but the prevalence of the metabolic syndrome has increased exponentially, which illustrates the importance of gene–environmental interactions. There is good evidence that nutrition plays an important role in the development and progression of the metabolic syndrome. Indeed, obesity is a key aetiological factor in the development of the metabolic syndrome. Understanding the biological impact of gene–nutrient interactions will provide a key insight into the pathogenesis and progression of diet-related polygenic disorders, including the metabolic syndrome. The present paper will explore the interactions between genetic background and dietary exposure or nutritional therapy, focusing on the role of dietary fatty acids within the context of nutrient regulation of gene expression and individual responsiveness to dietary therapy. Only with a full understanding of gene–gene, gene–nutrient and gene–nutrient–environment interactions can the molecular basis of the metabolic syndrome be solved to minimise the adverse health effects of obesity and reduce the risk of the metabolic syndrome, and subsequent T2DM and CVD.

Se is an unusual trace element in having its own codon in mRNA that specifies its insertion into selenoproteins as selenocysteine (SeCys), by means of a mechanism requiring a large SeCys-insertion complex. This exacting insertion machinery for selenoprotein production has implications for the Se requirements for cancer prevention. If Se may protect against cancer, an adequate intake of Se is desirable. However, the level of intake in Europe and some parts of the world is not adequate for full expression of protective selenoproteins. The evidence for Se as a cancer preventive agent includes that from geographic, animal, prospective and intervention studies. Newly-published prospective studies on oesophageal, gastric-cardia and lung cancer have reinforced previous evidence, which is particularly strong for prostate cancer. Interventions with Se have shown benefit in reducing the risk of cancer incidence and mortality in all cancers combined, and specifically in liver, prostate, colo-rectal and lung cancers. The effect seems to be strongest in those individuals with the lowest Se status. As the level of Se that appears to be required for optimal effect is higher than that previously understood to be required to maximise the activity of selenoenzymes, the question has been raised as to whether selenoproteins are involved in the anti-cancer process. However, recent evidence showing an association between Se, reduction of DNA damage and oxidative stress together with data showing an effect of selenoprotein genotype on cancer risk implies that selenoproteins are indeed implicated. The likelihood of simultaneous and consecutive effects at different cancer stages still allows an important role for anti-cancer Se metabolites such as methyl selenol formed from γ-glutamyl-selenomethyl-SeCys and selenomethyl-SeCys, components identified in certain plants and Se-enriched yeast that have anti-cancer effects. There is some evidence that Se may affect not only cancer risk but also progression and metastasis. Current primary and secondary prevention trials of Se are underway in the USA, including the Selenium and Vitamin E Cancer Prevention Trial (SELECT) relating to prostate cancer, although a large European trial is still desirable given the likelihood of a stronger effect in populations of lower Se status.

The glycaemic index (GI) was introduced to guide food exchanges within equicarbohydrate food categories, and it expresses the glycaemic potency of the available carbohydrate component in a food relative to that of glucose. As GI is a relative value based on ‘available carbohydrate’ it cannot guide food choice for glycaemic control unless the foods are equal in available carbohydrate. Furthermore, GI cannot respond to food intake or to effects on food glycaemic potency of replacing glycaemic ingredients with non-glycaemic ingredients. The glycaemic glucose equivalent (GGE) overcomes these limitations of GI. The GGE content of an amount of food is the weight of glucose (g) that would induce a glycaemic response equal to that induced by the food. Few studies have compared GI and GGE as guides to food choice for glycaemic control, but in a direct test of the predictive validity of GGE in a group of foods of differing carbohydrate and GI, GGE predicted glycaemic potency well, whereas GI was unrelated to glycaemic effect. Furthermore, an information-processing model of the use of food information in food choice shows that GI has fundamental flaws when used outside the restriction of equicarbohydrate food exchange categories. As a general guide to food choices for the control of glycaemia GI does not satisfy the criteria predictive validity, accuracy, safety, ease of use, flexibility, sufficiency and compatability, whereas GGE does. GGE is also a scientifically precise and meaningful term with which to express glycaemic potency than is ‘glycaemic load’.

Saturated and trans-fatty acids raise total cholesterol and LDL-cholesterol and are known to increase the risk of CHD, while dietary unsaturated fatty acids play important roles in maintaining cardiovascular health. Replacing saturated fats with unsaturated fats in the diet often involves many complex dietary changes. Modifying the composition of foods high in saturated fat, particularly those foods that are consumed daily, can help individuals to meet the nutritional targets for reducing the risk of CHD. In the 1960s the Dutch medical community approached Unilever about the technical feasibility of producing margarine with a high-PUFA and low-saturated fatty acid composition. Margarine is an emulsion of water in liquid oil that is stabilised by a network of fat crystals. In-depth expertise of fat crystallisation processes allowed Unilever scientists to use a minimum of solid fat (saturated fatty acids) to structure a maximum level of PUFA-rich liquid oil, thus developing the first blood-cholesterol-lowering product, Becel. Over the years the composition of this spread has been modified to reflect new scientific findings and recommendations. The present paper will briefly review the developments in fat technology that have made these improvements possible. Unilever produces spreads that are low in total fat and saturated fat, virtually free of trans-fatty acids and with levels of n-3 and n-6 PUFA that are in line with the latest dietary recommendations for the prevention of CHD. Individuals with the metabolic syndrome have a 2–4-fold increased risk of developing CHD; therefore, these spreads could make a contribution to CHD prevention in this group. In addition, for individuals with the metabolic syndrome the spreads could be further modified to address their unique dyslipidaemia, i.e. elevated blood triacylglycerols and low HDL-cholesterol. Research conducted in the LIPGENE study and other dietary intervention studies will deliver the scientific evidence to justify further modifications in the composition of spreads that are healthy for the heart disease risk factors associated with the metabolic syndrome.