The provision of food is thought to promote the maintenance of gut integrity. Nutrients are able to elicit and affect both systemic and mucosal immune responses. Enteral diet therapy has long been known to be efficacious in inflammatory bowel disease (IBD), particularly in childhood Crohn's disease. However, the mechanisms of action of these diets are not clear. Nutritional repletion, direct effects on the gut mucosa or decreased intestinal permeability have all been postulated as being important in nutritional therapy. There is some evidence that the enteral diet has a direct effect on the gut mucosa by reducing cytokine production and the accompanying inflammation, thus leading to decreased intestinal permeability. Modifications of enteral diet composition have been evaluated in many studies. Such modifications include fat and/or protein content and the addition of bioactive peptides. The fatty acid composition of the enteral diet seems to have a much greater impact on its efficacy than modification of the N source. As specific fatty acids are precursors of inflammatory mediators derived from arachidonic acid, the reduction in these components may be beneficial in nutritional therapy for IBD. Addition of bioactive peptides to enteral diet formulas may also have a role; such peptides may have specific growth factor or anti-inflammatory actions. There is still much work to be done to define disease-specific enteral diet formulas that are effective as therapies for both Crohn's disease and ulcerative colitis.

Cytokines appear to be major regulators of adipose tissue metabolism. Therapeutic modulation of cytokine systems offers the possibility of major changes in adipose tissue behaviour. Cytokines within adipose tissue originate from adipocyte, preadipocyte and other cell types. mRNA expression studies show that adipocytes can synthesise both tumour necrosis factor a (TNF-a) and several interleukins (IL), notably IL-1b and IL-6. Other adipocyte products with ‘immunological’ actions include complement system products and macrophage colony-stimulating factor. Cytokine secretion within adipocytes appears similar to that of other cells. There is general agreement that circulating TNF-a and IL-6 concentrations are mildly elevated in obesity. Most studies suggest increased TNF-a mRNA expression or secretion in vitro in adipose tissue from obese subjects. The factors regulating cytokine release within adipose tissue appear to include usual ‘inflammatory‘ stimuli such as lipopolysaccaride, but also the size of the fat cells per se and catecholamines. There is conflicting data about whether insulin and cortisol regulate TNF-a. The effects of cytokines within adipose tissue include some actions that might be characterised as metabolic. TNF-a and IL-6 inhibit lipoprotein lipase, and TNF-a additionally stimulates hormone-sensitive lipase and induces uncoupling protein expression. TNF-a also down regulates insulin-stimulated glucose uptake via effects on glucose transporter 4, insulin receptor autophosphorylation and insulin receptor substrate-1. All these effects will tend to reduce lipid accumulation within adipose tissue. Other effects appear more ‘trophic’, and include the induction of apoptosis, regulation of cell size and induction of de-differentiation (the latter involving reduced peroxisome proliferator-activated receptor g). Cytokines are important stimulators and repressors of other cytokines. In addition, cytokines appear to modulate other regulatory systems. Examples of the latter include effects on leptin secretion (probably stimulation followed by inhibition) and reduction of b3-adrenoceptor expression. There seems to be no clear agreement as to which cytokines derived from adipose tissue act as remote regulators, i.e. hormones. Leptin, which is structurally a cytokine, is also a hormone. IL-6 appears to be released systemically by adipose tissue, but TNF-a is probably not. Both leptin and IL-6 appear to act on the hypothalamus, IL-6 acts on the liver, while leptin may have actions on the pancreas. The importance of the immune system in whole-body energy balance provides a rationale for the links between cytokines and adipose tissue. It seems clear that TNF-a is a powerful autocrine and paracrine regulator of adipose tissue. Other cytokines, notably leptin, and possibly IL-6, have lesser actions on adipose tissue. These cytokines act as hormones, reporting the state of adipose tissue stores throughout the body.

World population will reach an estimated nine billion by 2050. Given this factor and continued economic development in today's low-income countries, the total global demand for food will increase approximately threefold over the coming half-century. Meanwhile, against this background, newly-occurring global environmental changes such as climate change are anticipated to affect food production. Other incipient large-scale environmental changes likely to affect food production include stratospheric O3 depletion, the accelerating loss of biodiversity (with knock-on effects on crop and livestock pest species) and the perturbation of several of the great elemental cycles of N and S. The ways in which these various environmental influences affect the production of food (crops and livestock on land, and wild and cultivated fisheries) are complex and interactive. Uncertainties therefore persist about how global climate change is likely to affect world and regional food production. On balance, recent modelling-based estimates indicate that, in the medium to longer term, if not over the next several decades, climate change is likely to affect crop yields adversely, especially in food-insecure regions. The prospect of increased climatic variability further increases the risks to future food production. Given these possible though uncertain adverse impacts of climatic and other environmental changes on world food production, there is a need to apply the Precautionary Principle. There are finite, and increasingly evident, limits to agro-ecosystems and to wild fisheries. Our capacity to maintain food supplies for an increasingly large and increasingly expectant world population will depend on maximising the efficiency and sustainability of production methods, incorporating socially-beneficial genetic biotechnologies, and taking pre-emptive action to minimise detrimental ecologically-damaging global environmental changes.

Metabolism is one of the corner stones of nutritional science. As biology enters the post-genomic era and with functional genomics beginning to take off, we anticipate that the study of metabolism will play an increasingly important role in helping to link advances made via the reductionist paradigm, that has been so successful in molecular and cellular biology, with those emerging from observational studies in animals and human subjects. A reconstructive metabolically-focused approach offers a timely paradigm for enhancing the elegance of nutritional science. Here we give particular attention to the use of tracers as phenotyping tools and discuss the application of our metaprobe concepts with respect to some novel features of metabolism, including ‘underground metabolism’, ‘metabolic hijacking’, ‘catalytic promiscuity’ and ‘moonlighting proteins’. The opportunities for enhancing the study of metabolism by new and emerging technologies, and the importance of the interdisciplinary research enterprise are also touched upon. We conclude that: (1) the metaprobe concepts and approach, discussed herein, potentially yield a quantitative physiological (metabolic) phenotype against which to elaborate partial or focused genotypes; (2) physiological (metabolic) phenotypes which have a whole-body or kinetically-discernible inter-organ tissue-directed metabolic signature are an ideal target for this directed tracer-based definition of the ‘functional’ genotype; (3) metabolism, probed with tracer tool kits suitable for measuring rates of turnover, change and conversion, becomes in the current sociology of the ‘Net’, like AOL, Yahoo, Alta Vista, Lycos or Ask Jeeves, the portal for an exploration of the metabolic characteristics of the ‘Genomics Internet’.

Most food-preservation techniques act by slowing down or completely inhibiting the growth of micro-organisms. Few techniques act by inactivating them. While heat remains the technique most extensively used for inactivation, there has been increasing interest recently in the development of alternative approaches in response to the desires of consumers for products which are less organoleptically and nutritionally damaged during processing and less reliant on additives than previously. The new approaches, therefore, mostly involve technologies that offer full or partial alternatives to heat for the inactivation of bacteria, yeasts and moulds. They include the application to foods of high hydrostatic pressure, high-voltage electric discharges, high-intensity laser and non-coherent light pulses, ‘manothermosonication’ (the combination of mild heating with ultrasonication and slightly-raised pressure), and high-magnetic-field pulses. In addition, a number of naturally-occurring antimicrobials, including lysozyme and low-molecular-weight products of micro-organisms are finding increasing use. High pressure is being used commercially to non-thermally pasteurize a number of foods, while the other physical procedures are in various stages of development and commercial evaluation. Possible nutritional consequences have so far been given little attention compared with microbiological ones.

Before about 1750 there was no substantial secular fall in protein–energy malnutrition (PEM) over large areas, nor reason to expect it. We have since learned that sufficient economic advance (poverty reduction) plus scientific advance (in medicine and food production) are achievable to eliminate mass PEM. The two advances are linked via increased demand for labour, and hence wages and employment, for those formerly too poor to afford adequate food. The extra employment income arises first from smallholder and employee food production, and later, as labour is released, from a wide range of specialised, increasingly non-farm, production, with employment income traded for food. This process eliminated mass hunger in Europe in 1750–1960. Only by 1975 had PEM in the developing world retreated to (very high) 1936–8 levels, but it fell sharply in Asia and Latin America in 1975–1990, due to unprecedented growth in staples yields, smallholder and farm employment income, and hence the poor's purchasing power over food. However, since 1990, poverty reduction has slowed (before reaching most of Africa), alongside much slower-staples yield growth, increasing water shortages, and big shifts of grain and land from man to farm animals. These trends prefigure declining progress against PEM in coming decades, unless there is renewed, employment-intensive food-staples-yield growth. That process requires reorienting crop biotechnology and water science towards the needs of small tropical farmers and their staple food crops, and shifting land towards them. Mass PEM is indeed largely due to inadequate ‘food entitlements’ by the hungry, but will not be remedied without growth in their employment, based on further advances in food-staples yields per unit land and water. Recent evidence suggests that early PEM may increase lifelong risks of infection and/or degenerative disease. This factor would increase the ‘squeeze’ on health resources in low-income countries, between the diseases of poverty and those of old age. That situation increases the need to readdress PEM by renewed progress in food production and land distribution.

Sympathetic stimulation has long been recognized to mobilise fatty acids from white adipose tissue. However, it is now apparent that adipose tissue is not only concerned with energy storage as fat, but is a major endocrine and secretory organ. This change has resulted from the identification of leptin as a hormone of energy balance secreted by white adipose tissue. The sympathetic system is a key regulator of leptin production in white fat. Sympathomimetic amines, cold exposure or fasting (which lead to sympathetic stimulation of white fat), decrease ob gene expression in the tissue and leptin production. On the other hand, sympathetic blockade often increases circulating leptin and ob gene expression, and it is postulated that the sympathetic system has a tonic inhibitory action on leptin synthesis. In rodents this action is through stimulation of b3-adrenoceptors. The adrenal medulla (as opposed to the direct sympathetic innervation) has been thought to play only a minor role in the catecholaminergic regulation of white adipose tissue. However, in rodents responses of the leptin system to adrenergic blockade vary with the method used. Changes in leptin and ob gene expression are considerably less using methods of blockade that only effect the terminal adrenergic innervation, rather than medullary secretions as well. Stimulation of the leptin system increases sympathetic activity and hence metabolic activity in many tissues. As well as leptin, other (but not all) secretions from white adipose tissue are subject to sympathetic regulation. In obesity the sympathetic sensitivity of adipose tissue is reduced and this factor may underlie the dysregulation of leptin production and other adipose tissue secretions.

The present review addresses the relative contribution of diet and genotype to variability in human bone growth and mineralisation in the context of the aetiology of osteoporosis. Heritability studies indicate that 60–70 % of the variability in bone mineral mass or bone mineral density (BMD) can be accounted for by genetic variation. Cross-trait analyses suggest that a proportion of this variation reflects genetic influences on bone and body size, such as height and lean body mass. Candidate-gene studies have demonstrated associations between several genetic polymorphisms and bone mineral mass but, as yet, genotype determinations have proved unhelpful in identifying individuals at increased risk of osteoporosis. Variations in diet and other environmental factors contribute 30–40 % to total phenotypic variance in bone mineral mass or BMD. Correlations between intakes of individual nutrients and BMD have been reported, but these relationships are subject to confounding due to size. However, no specific dietary factor has been identified from prospective and twin studies as making a significant contribution to environmental variability in BMD or bone loss. This finding may reflect the difficulties in quantifying environmental exposures, both current and over a lifetime. In addition, the influence of diet on bone health may depend on the genotype of the individual. Optimisation of nutrition and lifestyle remains an attractive strategy for the reduction of fracture risk, but more research is required to fully define optimal dietary requirements.

Population-based studies of human pregnancies show that periconceptional folate supplementation has a significant protective effect for embryos during early development, resulting in a significant reduction in developmental defects of the face, the neural tube, and the cono-truncal region of the heart. These results have been supported by experiments with animal models. An obvious quality held in common by these three anatomical regions is that the normal development of each region depends on a set of multi-potent cells that originate in the mid-dorsal region of the neural epithelium. However, the reason for the sensitive dependence of these particular cells on folic acid for normal development has not been obvious, and there is no consensus about the biological basis of the dramatic rescue with periconceptional folate supplementation. There are two principal hypotheses for the impact of folate insufficiency on development; each of these hypotheses has a micronutrient component and a genetic component. In the first hypothesis the effect of low folate is direct, limiting the availability of folic acid to cells within the embryo itself; thus compromising normal function and limiting proliferation. The second hypothetical effect is indirect: low folate disrupts methionine metabolism; homocysteine increases in the maternal serum; homocysteine induces abnormal development by inhibiting the function of N-methyl-D-aspartate (NMDA) receptors in the neural epithelium. There are three general families of genes whose level of expression may need to be considered in the context of these two related hypotheses: folate-receptor genes; genes that regulate methionine– homocysteine metabolism; NMDA-receptor genes.

The millennium promises a dramatic politicisation of the food question. In addition to the prominent issues of food security, hunger and nutrition, bioengineering, food safety and quality, there are related issues of environmental sustainability, power, sovereignty and rights. All these issues are deeply implicated in the current corporate form of globalisation, which is transforming historic global arrangements by subordinating public institutions and the question of food security to private solutions. The present paper questions the self-evident association between globalisation and nutritional improvement.

The development of new functional foods requires technologies for incorporating health-promoting ingredients into food without reducing their bioavailability or functionality. In many cases, microencapsulation can provide the necessary protection for these compounds, but in all cases bioavailability should be carefully studied. The present paper gives an overview of the application of various microencapsulation technologies to nutritionally-important compounds, i.e. vitamins, n-3 polyunsaturated fatty acids, Ca, Fe and antioxidants. It also gives a view on future technologies and trends in microencapsulation technology for nutritional applications.

Redistribution of white adipose tissue is a long-term symptom of several chronic diseases. Although the roles of adipocytes in acute illness have been thoroughly studied, how or why short-term responses of adipose tissue to disease sometimes produce long-term redistribution, and the causal relationship between the anatomical changes and the associated metabolic syndromes are poorly understood. The present paper reviews explanations for the redistribution of adipose tissue after infection with HIV, and in Crohn's disease; both conditions that share the peculiarity of selective expansion of certain adipose depots while others are depleted. HIV adipose tissue redistribution syndrome (HARS) develops gradually after several months of infection with the HIV both in untreated patients and in those taking protease inhibitors and nucleoside reverse transcriptase inhibitors. Some current theories about the causes of HARS are critically assessed, and reasons presented for implicating local interactions between the immune system and perinodal adipocytes. Some evolutionary aspects of conspicuous long-term changes in the distribution of human adipose tissue are discussed. Adipose tissue acts as a social signal, indicating dietary history and previous exposure to pathogens. A distinctive symptom of Crohn's disease is selective enlargement of the mesenteric adipose tissue near the diseased lymph nodes and intestine. Perinodal adipocytes have site-specific properties not found in adipocytes from nodeless depots, such as perirenal and epididymal, that may equip them to interact locally with lymph-node lymphoid cells, making polyunsaturated fatty acids selectively and rapidly available to activated immune cells. Studies of the time course of activation of perinodal adipocytes via the lymph nodes they enclose indicate that prolonged or frequent stimulation recruits more adipocytes to control by immune cells, which may lead to selective enlargement of node-containing depots. These concepts suggest hypotheses about HARS and the anomalous development of mesenteric adipose tissue in Crohn's disease that could form the basis for further investigations.

Nutrition profoundly alters the phenotypic expression of a given genotype, particularly during fetal and postnatal development. Many hormones act as nutritional signals and their receptors play a key role in mediating the effects of nutrition on numerous genes involved in differentiation, growth and metabolism. Polypeptide hormones act on membrane-bound receptors to trigger gene transcription via complex intracellular signalling pathways. By contrast, nuclear receptors for lipid-soluble molecules such as glucocorticoids (GC) and thyroid hormones (TH) directly regulate transcription via DNA binding and chromatin remodelling. Nuclear hormone receptors are members of a large superfamily of transcriptional regulators with the ability to activate or repress many genes involved in development and disease. Nutrition influences not only hormone synthesis and metabolism but also hormone receptors, and regulation is mediated either by specific nutrients or by energy status. Recent studies on the role of early environment on development have implicated GC and their receptors in the programming of adult disease. Intrauterine growth restriction and postnatal undernutrition also induce striking differences in TH-receptor isoforms in functionally-distinct muscles, with critical implications for gene transcription of myosin isoforms, glucose transporters, uncoupling proteins and cation pumps. Such findings highlight a mechanism by which nutritional status can influence normal development, and modify nutrient utilization, thermogenesis, peripheral sensitivity to insulin and optimal cardiac function. Diet and stage of development will also influence the transcriptional activity of drugs acting as ligands for nuclear receptors. Potential interactions between nuclear receptors, including those for retinoic acid and vitamin D, should not be overlooked in intervention programmes using I or vitamin A supplementation of young and adult human populations.

The perception of healthiness and/or safety, tenderness, juiciness and aroma or flavour are important quality criteria that influence the decision of a consumer to purchase beef. Beef production systems represent the combined and interacting effects of genotype, gender, age at slaughter and nutrition before slaughter. The present paper highlights recent information on how beef production systems can be modified to enhance the tenderness, flavour and healthiness of beef. Carcass management post-slaughter has a larger effect on meat tenderness than gender, genotype or feeding systems. Optimum ‘pasture to plate’ management systems are being established to ensure beef tenderness. The chemistry underlying beef flavour is complex, with in excess of 140 components identified in cooked beef volatiles. Flavour of beef is influenced by cattle diet, but assessment of flavour by a taste panel is subject to the previous experiences and preferences of the panellists. Modern lean beef can have an intramuscular fat concentration of 25–50 g/kg and can be considered a low-fat food. As the quantity of grass in the diet of cattle is increased, there is a decrease in saturated fatty acid concentration, and an increase in the n-3 polyunsaturated fatty acid and conjugated linoleic acid concentrations. It is concluded that there is opportunity to exploit the diet of cattle to produce tender flavoursome beef that has an increased conjugated linoleic acid concentration, a lower fat concentration and a fatty acid profile more compatible with current human dietary recommendations.

Apart from its main functions of digestion, absorption and faecal processing, the human gastrointestinal tract has a complex pattern of muscular activity regulated by a largely autonomous nervous system, and its various organs contain large concentrations of immune and endocrine tissues. Any failure of these closely-integrated systems can lead to diseases ranging from the mildly irritating to the life threatening. Food contains a huge variety of chemical species, many of which are biologically active, and the distal regions of the gut are colonised by a rich and metabolically-active commensal flora that depend on nutrients derived ultimately from the host’s dietary residues. The present paper explores the evidence for significant effects of food ingredients on functional bowel disorders, intestinal infections, and aspects of epithelial cell physiology involved in the development of colo-rectal neoplasia. Various strategies, including the manipulation of the colo-rectal microflora with pre- and probiotics, and the development of new products and plant varieties containing biologically-active constituents, have the potential to underpin the development of novel functional food products. However, these products will need to be based on proven biological principles, and fully tested for efficacy and safety. The rapidly-developing fields of functional genomics and cell biology will open up new experimental strategies to explore these possibilities, and emerging processing technologies seem likely to provide novel methods for their exploitation.

Obesity is associated with insulin resistance. Insulin resistance underlies a constellation of adverse metabolic and physiological changes (the insulin resistance syndrome) which is a strong risk factor for development of type 2 diabetes and CHD. The present article discusses how accumulation of triacylglycerol in adipocytes can lead to deterioration of the responsiveness of glucose metabolism in other tissues. Lipodystrophy, lack of adipose tissue, is also associated with insulin resistance. Any plausible explanation for the link between excess adipose tissue and insulin resistance needs to be able to account for this observation. Adipose tissue in obesity becomes refractory to suppression of fat mobilization by insulin, and also to the normal acute stimulatory effect of insulin on activation of lipoprotein lipase (involved in fat storage). The net effect is as though adipocytes are ‘full up’ and resisting further fat storage. Thus, in the postprandial period especially, there is an excess flux of circulating lipid metabolites that would normally have been ‘absorbed’ by adipose tissue. This situation leads to fat deposition in other tissues. Accumulation of triacylglycerol in skeletal muscles and in liver is associated with insulin resistance. In lipodystrophy there is insufficient adipose tissue to absorb the postprandial influx of fatty acids, so these fatty acids will again be directed to other tissues. This view of the link between adipose tissue and insulin resistance emphasises the important role of adipose tissue in ‘buffering’ the daily influx of dietary fat entering the circulation and preventing excessive exposure of other tissues to this influx.

Like most essential nutrients, Fe needs to be maintained in the body at a defined level for optimal health, with appropriate adaptation to varying Fe needs and supply. The primary mechanism for controlling Fe level is the regulation of Fe absorption. Several different proteins have been identified as contributors to the process. Despite a complex regulatory system, Fe disorders (both Fe deficiency and Fe overload) occur. Fe deficiency is a common problem worldwide, resulting from inadequate dietary Fe and blood loss. Complications include pre-term labour, developmental delay, and impaired work efficiency. No specific genetic syndromes causing isolated Fe deficiency have been described, but animal studies and clinical observations suggest that such a relationship may be a possibility. Conversely, the known causes of Fe overload are genetic. Fe overload is less common than Fe deficiency, but can result in serious medical complications, including cirrhosis, primary liver cancer, diabetes, cardiomyopathy and arthritis. The most common and best characterized syndrome of Fe overload is hereditary haemochromatosis (HHC), an autosomal recessive disorder. Mutations in the HFE protein cause HHC, but the clinical presentation is variable. Of particular interest is the factor that some HFE genotypes appear to be associated with protection from Fe deficiency. Other genetic variants in the regulatory pathway may influence the likelihood of Fe deficiency and Fe overload. Studies of genetic variants in HFE and other regulatory proteins provide important tools for studying the biological processes in Fe regulation. This work is likely to lead to new insights into Fe disorders and potentially to new therapeutic approaches. It will not be complete, however, until coordinated study of both genetic and nutritional factors is undertaken.

Protected denomination of origin (PDO) cheeses have distinctive sensorial characteristics. They can be made only from raw milk possessing specific features, which is processed through the ‘art’ of the cheesemaker. In general, the distinctive sensorial traits of PDO cheese cannot be achieved under different environmental–production conditions for two main reasons: (1) some milk features are linked to specific animal production systems; (2) cheese ripening is affected by the interaction between milk (specific) and the traditional technology applied to the transformation process (non-specific). Also, the environment for a good ripening stage can be quite specific and not reproducible. With reference to milk, factors of typicality are species and/or breed, pedo–climatic conditions, animal management system and feeding. Other factors that influence cheese quality are milk treatments, milk processing and the ripening procedures. The technology applied to most cheeses currently known as PDO utilizes only raw milk, rennet and natural lactic acid bacteria, so that milk must be, at its origin, suitable for processing. The specific milk characteristics that ensure a high success rate for PDO cheeses are high protein content and good renneting properties, appropriate fat content with appropriate fatty acid composition and the presence of chemical flavours originating from local feeds. Moreover, an appropriate microflora is also of major importance. The factors that contribute to achieving milk suitable for transformation into PDO cheese are genetics, age, lactation stage, season and climate, general management and health conditions, milking and particularly feeding, which affect nutrient availability, endocrine response and health status, and also the presence of microbes and chemical substances which enrich or reduce the milk–cheese quality. Many of these factors are regulated by the Producer Associations. However, the secret of the success of PDO cheeses is the combination of modern technology and tradition, with the objective of adapting the product to market demand, without losing specificity, originality and authenticity.

The present study was funded by the Ministry of Agriculture, Fisheries and Food, its aim being to identify the technical barriers to the development of reduced-fat alternatives for bakery products. Using National Food Survey (Ministry of Agriculture, Fisheries and Food, 1998) statistics on dietary consumption within the home, biscuits, cakes and pastries were identified as contributing significant amounts of fat to the population's dietary intake. Face-to-face interviews were conducted with contacts in the technical community of the baking industry, who were usually working in technical and new-product development functions. A discussion guide was developed to cover the main lines of enquiry. The companies selected were ingredient suppliers (eight), manufacturers (twelve) and retailers (four) and so represented each step of the food supply chain. In brief, results showed that current labelling rules were too stringent, and constrained development of reduced-fat bakery products. Products with lower fat levels are harder to make due to altered handling and processing properties. Their quality is usually poorer than standard products, particularly for flavour, texture and mouthfeel. The perception of freshness is reduced and product shelf-life may consequently be shorter. For the product developer, there are relatively few ingredients that can be used in place of fat, and knowledge of how they work is limited, which inhibits product development. There is no identifiable source of technical knowledge in this field. Consumers perceive reduced-fat bakery products to be of lower quality and are generally unwilling to pay higher prices than for standard products.

Critical illness is associated with a marked increase in metabolic rate and progressive wasting, despite aggressive nutritional support. The metabolic events which are responsible for these phenomena are unclear, but are characterised by marked impairment of the anabolic effects of insulin on glucose metabolism and excessive activation of the sympathetic nervous system. It has been suggested that critical illness may be associated with impaired carbohydrate oxidation and a marked increase in the loss of heat energy associated with glucose administration (glucose-induced thermogenesis). This situation may result in impaired efficiency of nutrient assimilation. Studies employing combinations of nutrient infusions both at clinically-relevant rates and in association with euglycaemic hyperinsulinaemia have, however, demonstrated that nutrient-induced thermogenesis is unaffected in critical illness in human subjects, and that defective glucose utilization occurs as a consequence of impaired insulin-mediated glucose storage rather than oxidation. Although the cellular and molecular mechanisms underlying these changes are controversial, the recent validation of a human model of insulin resistance in critical illness should provide a means of studying this response in future, and allow the identification of therapeutic targets. This information should increase the efficacy of nutritional support in some of our most seriously-ill patients.