This is a review of research carried out in Japanese Americans that points towards possible approaches to prevention of type 2 diabetes mellitus. The natural history of type 2 diabetes usually includes both insulin resistance and β-cell dysfunction. Insulin secretion may compensate for insulin resistance. Alternatively, enhanced insulin sensitivity may mask an insulin secretory defect. Epidemiological data support the view that in the vast majority of cases of type 2 diabetes, insulin resistance is essential to the pathogenesis of hyperglycemia. Increased diabetes prevalence as ethnic groups migrate to more urban or westernized regions has been attributed to increased occurrence of insulin resistance. Research among Japanese Americans in Seattle, Washington, showed a higher prevalence of type 2 diabetes than in Japan, which suggested that factors associated with ‘westernization’ might be playing a role in bringing out underlying susceptibility to diabetes. Our research has shown that these impressions were correct and that the abnormalities that characterize the metabolic syndrome play a significant role. Due to increased intra-abdominal fat deposition, Japanese Americans were likely to be ‘metabolically obese’ despite relatively normal BMI. A diet higher in animal fat and lower levels of physical activity were risk factors leading to increased intra-abdominal fat deposition, insulin resistance, and diabetes. Information from epidemiological studies such as these may be used to determine whether diabetes may be prevented through changes in lifestyle or application of specific therapies targeted towards identified metabolic abnormalities.

The aim of this study was to assess the bioequivalence of H13CO-3 and H14CO-3, by administering both labels simultaneously by single infusion and comparing their recovery in breath CO2 and urinary urea. Six healthy male subjects (age range 24–41 years; weight 76·7 (SD, 18·6) KG; HEIGHT 1·79 (sd 0·05) m) were infused with unprimed solutions of HCO3- (110·0 mmol/kg) labelled with 13C (0·76 mmol 13C/h) and 14C (48 Bq/h) at a constant rate for 6 h, in a whole-body calorimeter (1400 litres) for measurement of CO2 production. Samples of breath were collected hourly in a Douglas bag and all urine was collected into two batches (0–4 h and 4–6 h) for estimating recovery of infused label by measurement of enrichment or specific activity. Recovery in breath CO2 of both labels increased from about 25% for the first hour to 88% and above for hours 3–4 onwards. Mean recovery of 13C in breath CO2 was slightly higher than that of 14C for all periods (mean difference always less than 1 % of infused label) but was significant only for the first 3h (P < 0·05). Recovery of 14C in urea was significantly higher (P < 0·01) than 13C, but was confounded by substantial variability and uncertainties concerning 13CO2 background enrichments. These results suggest that there is no compelling need to alter factors currently used for recovery of 14C in breath when using 13C instead, and vice versa.

The effect of two levels of dietary protein energy, moderate (20 %; MP) and high (70 %; HP), on urea kinetics in eleven domestic cats was studied. After a 3-week prefeed, a single dose of [15N15N]urea was administered, and urine and faeces collected over the subsequent 5 d. For each 24 h period, total urea and enrichment of [15N15N]- and [15N14N]urea in urine were determined, and a model applied to calculate urea production, entry into the gastrointestinal tract, recycling to urine or faeces and, by difference, retention by the body and potentially available for anabolism. Urea production and excretion increased with dietary protein level (P<0·05). Most of the urea produced was excreted, with only a small proportion entering the gut, and with the pattern of urea disposal not significantly different between the HP and MP diets. Thus, the percentages of urea production available to the gut were 15 % (MP) and 12 % (HP), of which 57 % (MP) and 59 % (HP) was recycled in the ornithine cycle, 40 % (MP and HP) was potentially available for anabolism and the rest lost as faecal N. As a percentage of urea produced the amount potentially available for anabolism was very low at 6·41 % (MP diet) and 4·79 % (HP diet). In absolute terms urea entering the gut, being recycled in the ornithine cycle and potentially available for anabolism was significantly higher on the HP diet (P<0·05). These results show that cats operate urea turnover, but at a lower rate, and with less nutritional sensitivity than has been reported for other species.

The structure of the iron-binding glycoprotein lactoferrin, present in milk and other exocrine secretions, has been elucidated in great detail, both the three-dimensional protein structure and the attached N-glycans. Structure–function relationships are being established. From these studies a function for lactoferrin in host defence and modulation of iron metabolism emerges. This paper describes in some detail how iron and other cations may be bound by lactoferrins from human or bovine sources and elucidates parts of the molecule that are critical for interactions with cells and biomolecules. Furthermore, the technological aspects, more specifically the heat-sensitivity, of bovine lactoferrin in different matrices are described.

Eighteen pure-bred steers (live weight 350 kg) from each of two breeds, Aberdeen Angus (AA) and Charolais (CH), were split into three equal groups (six animals each) and offered three planes of nutrition during a 20-week period. The same ration formulation was offered to all animals with amounts adjusted at 3-week intervals to give predicted average weight gains of either 1·0 kg/d (M/M group) or 1·4 kg/d (H/H group). The remaining group (M/H) were offered the same amount of ration as the M/M group until 10 weeks before slaughter when the ration was increased to H. Data on animal performance, carcass characteristics and fibre-type composition in skeletal muscle are presented elsewhere (; ). On three occasions (17, 10 and 2 weeks before slaughter) the animals were transferred to metabolism stalls for 1 week, during which total urine collection for quantification of Nτ-methylhistidine (Nτ-MeH) elimination was performed for 4 d. On the last day, animals were infused for 11 h with [2H5] phenylalanine with frequent blood sampling (to allow determination of whole-body phenylalanine flux) followed by biopsies from m. longissimus lumborum and m. vastus lateralis to determine the fractional synthesis rate of mixed muscle protein. For both breeds, the absolute amount of Nτ-MeH eliminated increased with animal age or weight (P < 0·001) and was significantly greater for CH steers, at all intake comparisons, than for AA (P < 0·001). Estimates of fractional muscle breakdown rate (FBR; calculated from Nτ-MeH elimination and based on skeletal muscle as a fixed fraction of live weight) showed an age (or weight) decline for M/M and H/H groups of both breeds (P < 0·001). FBR was greater for the H/H group (P = 0·044). The M/H group also showed a lower FBR for the first two measurement periods (both at M intake) but increased when intake was raised to H. When allowance was made for differences in lean content (calculated from fat scores and eye muscle area in carcasses at the end of period 3), there were significant differences in muscle FBR with intake (P = 0·012) but not between breed. Whole-body protein flux (WBPF; g/d) based on plasma phenylalanine kinetics increased with age or weight (P < 0·001) and was similar between breeds. The WBPF was lower for M/M compared with H/H (P < 0·001) based on either total or per kg live weight0·75. Muscle protein fractional synthesis rate (FSR) declined with age for both breeds and tended to be higher at H/H compared with M intakes (intake × period effects, P < 0·05). Changing intake from M to H caused a significant increase (P < 0·001) in FSR. The FSR values for AA were significantly greater than for CH at comparable ages (P = 0·044). Although FSR and FBR responded to nutrition, these changes in protein metabolism were not reflected in differences in meat eating quality (Sinclair et al. 2000).

Lactoperoxidase (LP) is one of the most prominent enzymes in bovine milk and catalyses the inactivation of a wide range of micro-organisms in the lactoperoxidase system (LP-s). LP-systems are also identified as natural antimicrobial systems in human secretions such as saliva, tear-fluid and milk and are found to be harmless to mammalian cells. The detailed molecular structure of LP is identified and the major products generated by the LP-s and their antimicrobial action have been elucidated for the greater part. In this paper several aspects of bovine LP and LP-s are discussed, including physico-chemical properties, occurrence in milk and colostrum and mechanisms of action. Since the introduction of industrial processes for the isolation of LP from milk and whey the interest in this enzyme has increased considerably and attention will be paid to potential and actual applications of LP-systems as biopreservatives in food and other products.

The prevalence of obesity is increasing in westernized societies. In the USA the age-adjusted prevalence of BMI ≫30 kg/m2 increased between 1960 and 1994 from 13 % to 23 % for people over 20 years of age. This increase in the prevalence of obesity has been attributed to an increased fat intake and a decreased physical activity. However, the role of the impact of the level of dietary fat intake on human obesity has been challenged. High-fat diets, due to their high energy density, stimulate voluntary energy intake. An increased fat intake does not stimulate its own oxidation but the fat is stored in the human body. When diet composition is isoenergetically switched from low to high fat, fat oxidation only slowly increases, resulting in positive fat balances on the short term. Together with a diminished fat oxidation capacity in pre-obese subjects, high-fat diets can therefore be considered to be fattening. Another environmental factor which could explain the increasing prevalence of obesity is a decrease in physical activity. The percentage of body fat is negatively associated with physical activity and exercise has pronounced effects on energy expenditure and substrate oxidation. High-intensity exercise, due to a lowering of glycogen stores, can lead to a rapid increase in fat oxidation, which could compensate for the consumption of high-fat diets in westernized societies. Although the consumption of high-fat diets and low physical activity will easily lead to the development of obesity, there is still considerable inter-individual variability in body composition in individuals on similar diets. This can be attributed to the genetic background, and some candidate genes have been discovered recently. Both leptin and uncoupling protein have been suggested to play a role in the prevention of diet-induced obesity. Indeed, leptin levels are increased on a high-fat diet but this effect can be attributed to the increased fat mass observed on the high-fat diet. No effect of a high-fat diet per se on leptin levels is observed. Uncoupling proteins are increased by high-fat diets in rats but no data are available in human subjects yet. In conclusion, the increased intake of dietary fat and a decreasing physical activity level are the most important environmental factors explaining the increased prevalence of obesity in westernized societies.

The objectives of this study were to confirm the non-absorbability and the reproducibility of faecal excretion kinetics of orally administered rare earth elements, and to investigate the excretion profiles of rare earth elements and stable isotopic tracers of Fe and Zn to establish the extent to which rare earth element markers duplicate the behaviour of isotopic tracers. Two investigations were performed: (1) six healthy subjects consumed a solution containing five rare earth elements in amounts varying from 1 to 10 mg; (2) seven healthy subjects were given a standard solution labelled with Sm marker and 57Fe tracer, and a meal labelled with Yb marker and 58Fe and 70Zn tracers. Individual faecal samples were collected and analysed to determine recoveries of rare earth elements and unabsorbed isotopic tracers. The mean values for recoveries were 94·1 (SD 4·5) % FOR THE FIVE RARE EARTH ELEMENTS, AND 103 (sd 3·0) % and 99·8 (sd 2·8) % for Sm and Yb respectively. For Fe consumed with the solution, excretion kinetics of the rare earth element marker and unabsorbed tracers with cumulative collections of the first two and three faecal samples were identical, but endogenous excretion of Fe was significant (P<0·05) in stools collected after the third. For Fe and Zn consumed with the meal, the excretion kinetics for the first two individual faecal samples and composites of sequential outputs were identical. Rare earth elements can be used as markers in studies of measurement of absorption. The dose of tracer required for the measurement of absorption would be reduced proportionally to the reduction of the period of faecal sampling, so that studies with stable isotopes would be more economical, thus enabling epidemiological investigations.

Data from clinical studies established that there was an inverse linear relationship between measures of postprandial blood glucose and insulin responses to an oral glucose load, consumed in a drink, and the logarithm of viscosity of the drink. These data have been re-analysed using concentration and molecular weight as the dependent variables. Molecular weight (M) of the β-glucans used was determined using high-performance size exclusion chromatography equipped with a triple detector system of right angle light scattering, viscometry and refractive index. A significant relationship between changes in peak blood glucose and a combination of logarithm of the concentration and logarithm of M was found.

We investigated whether short-term underfeeding could induce adaptative mechanisms in portal-drained viscera (PDV) that would allow nutrients to be spared for vital functions in adult ewes. Six ewes (three of them fitted with catheters in the mesenteric artery and portal and mesenteric veins) were fed, in a double 3×3 Latin square design (2 weeks per experimental period), a regrowth of natural grassland hay at 143 (high; H), 88 (medium; M) and 51 (low; L) % of their energy maintenance requirements. The digestibility of the diet was measured in all six ewes and the net portal fluxes of nutrients in the three catheterized ewes. The organic matter content and N digestibility of the diet were not affected by underfeeding. Urinary and faecal N losses and N balance were linearly related to feed intake. Arterial concentration of acetate was linearly related to feed intake. Arterial concentrations of the other volatile fatty acids, 3-hydroxybutyrate, lactate, glucose, NH3, urea and total amino acids were not affected by underfeeding. Arterial concentration of non-esterified fatty acids (NEFA) increased with underfeeding. The portal net release of all volatile fatty acids, 3-hydroxybutyrate and NH3 were linearly related to intake. The portal net flux of both essential and non-essential amino acids, and thus total amino acids, remained unchanged between levels H and M, and decreased between levels M and L. A significant net uptake for glycine and total non-essential amino acids occurred at level L. The portal net uptake of glucose, urea, glutamate and glutamine, and the portal net release of lactate and NEFA were not affected by underfeeding. Summation of portal energy fluxes indicated that 51 % of the metabolizable energy intake was recovered in the portal blood with the three levels of intake. In conclusion, no quantitative adaptation to spare energy, in terms of percentage of intake, occurred in PDV of short-term underfed ruminants, but the pattern of absorption of energetic nutrients was modified.

No sensitive functional index is currently available to assess Cu status in healthy human populations. This study evaluated the effect of Cu supplementation on putative indices of Cu status in twelve women and twelve men, aged between 22 and 45 years, who participated in a double-blind placebo controlled crossover study. The study consisted of three 6-week supplementation regimens of 3 mg CuSO4, 3 mg Cu-glycine chelate and 6 mg Cu-glycine chelate, each separated by placebo periods of equal length. Women had significantly higher caeruloplasmin oxidase activity (P < 0·001), caeruloplasmin protein concentration (P < 0·05), and serum diamine oxidase activity (P < 0·01) at baseline than men. Erythrocyte and leucocyte superoxide dismutase activity, leucocyte cytochrome c oxidase activity, and erythrocyte glutathione peroxidase activity did not respond to Cu supplementation. Platelet cytochrome c oxidase activity was significantly higher (P < 0·01), after supplementation with 6 mg Cu-glycine chelate in the total group and in women but did not change in men. Caeruloplasmin oxidase activity was significantly higher (P < 0·05), in men after supplementation with 3 mg Cu-glycine chelate, while caeruloplasmin protein concentration was significantly lower in men after supplementation with 6 mg Cu-glycine chelate (P < 0·05). Serum diamine oxidase activity was significantly higher after all supplementation regimens in the total group and in both men and women (P < 0·01). These results indicate that serum diamine oxidase activity is sensitive to changes in dietary Cu intakes and may also have the potential to evaluate changes in Cu status in healthy adult human subjects.

The main purpose of treating diabetes is to prevent chronic complications. Strict glycemic control is known to suppress the occurrence and progression of these complications. The test for plasma glucose is essential to identify diabetic patients, as mild hyperglycemia without symptoms can be a risk factor for complications. The new classification and diagnostic criteria for diabetes were proposed by the American Diabetes Association (ADA), WHO and Japan Diabetes Society (JDS) between 1997 and 1999. Diabetes is classified into four etiological categories; type 1, type 2, diabetes due to other specific mechanisms or conditions, and gestational diabetes. Another classification system according to the degree of metabolic abnormality has also been adopted. For diagnosis of diabetes, the JDS Committee classified the glycemic state into three categories based on fasting plasma glucose (FPG) and 2-h plasma glucose in the 75 g oral glucose tolerance test (2hPG); normal type (FPG <110 and 2hPG <140 mg/dl), diabetic type (FPG <126 and/or 2hPG <200 mg/dl), and borderline type (neither normal nor diabetic type). The borderline type corresponds to the sum of impaired fasting glycemia (IFG) and impaired glucose tolerance (IGT) based on ADA and WHO. Using the JDS criteria, diabetes is diagnosed when hyperglycemia of ‘diabetic type’ is confirmed on two or more occasions. ADA recommends the use of FPG alone for the diagnosis of diabetes, but findings from both Japan and Europe indicate that many diabetic subjects would be classified as non-diabetic solely on the FPG test. JDS recommends the use of the glucose tolerance test when the elevation of FPG is mild. Keeping glycemia near-normal by periodic monitoring of glycemic parameters and by appropriate treatment would prevent or reduce the diabetic complications in patients to a minimum.

To study the intestinal metabolism of lignans, the concentrations of plant and mammalian lignans in intestinal digesta sampled along the intestinal tract of pigs were determined by isotope dilution GC–MS. The pigs were fed rye-bread diets made from either whole rye-grains or rye-grain milling fractions enriched in pericarp–testa, aleurone or endosperm cells. The content and characteristics of dietary fibre varied between diets and had been shown to induce different colon fermentation patterns. As the metabolism of lignans depends on the action of the intestinal flora, we tested whether the rye-bread diets influence the metabolism of lignans. In the ileum, the lignans were mainly present as conjugated plant lignans, which were determined only when the analytical procedure included a hydrolysis step. High recovery of dietary lignans in the ileum may indicate that the lignans enter the enterohepatic circulation. In addition, two to three times the intake of lignans were recovered in the faeces when the diets had a high content of dietary fibre suggesting underestimation of plant lignans in the diet. Most of the plant lignans disappeared from the intestinal tract between the terminal ileum and the caecum. The intestinal concentrations and the disappearance of lignans correlated with the content of lignans in the diet, being highest on the pericarp–testa diet and lowest on the endosperm diet. No effect of fermentation pattern on the intestinal metabolism of lignans was observed. The lignans were liberated from the pericarp–testa diet although the plant cell walls remained largely undegraded.

Rainbow trout (Oncorhynchus mykiss) hepatocytes were cultured under simulated conditions of varying nutritional status to explore the short-term modulation by dietary substrates of the main lipogenic enzymes: glucose-6-phosphate dehydrogenase (G6PD), malic enzyme (ME), ATP-citrate lyase (ACL), acetyl-CoA carboxylase (ACoAC) and fatty acid synthetase (FAS). Primary cultures were individually exposed to varying amounts of glucose, hydrolysed casein and long-chain polyunsaturated fatty acids (PUFA) for 12 h. A second set of experiments was designed to evaluate the effects of mixing different relative amounts of these macronutrients in the culture medium. Glucose concentrations of up to 20–25 mM SHOWED A STIMULATORY EFFECT ON G6PD, ME, ACL AND ACOAC ACTIVITY (P<0·05) WHILE AN EARLIER INHIBITORY EFFECT ON FAS WAS OBSERVED AT 10–20 Mm glucose (P<0·05). The use of hydrolysed casein as a nutritional source of amino acids inhibited the activity of FAS and ME (P<0·05), and stimulated G6PD, ACoAC and ACL activity (P<0·05). Low levels of linolenic acid exerted a stimulatory effect on all the lipogenic enzymes assayed (P<0·05) with the exception of FAS, and increased amounts showed some inhibition of lipogenic activities (P<0·05). Eicosapentaenoic acid and docosahexaenoic acid showed a similar effect, although the former strongly inhibited FAS activity while the latter showed greater potential to inhibit ACoAC and G6PD. A complete change in the relative levels of glucose, hydrolysed casein and PUFA in turn led to changes in the enzyme activity patterns observed. The present study shows the feasibility of exploring the direct regulation of lipogenesis in isolated fish cells by varying the relative amounts of main macronutrients, mimicking in vivo dietary conditions. It is felt that such an approach may serve to investigate the macronutrient regulation of other metabolic pathways.

Vitamin E is the main biological lipid-soluble antioxidant and plays a crucial role in the maintenance of the immune system. In the present work, twenty-one guinea-pigs (3-weeks-old) were distributed into three groups, which during 5 weeks ingested different amounts of vitamin E (/kg diet): 15 mg (low vitamin E diet), 150 mg (medium vitamin E diet; control) or 1500 mg (high vitamin E diet). The function of lymphocytes and macrophages were then studied. In macrophages obtained from the peritoneum several steps of the phagocytic process (chemotaxis, ingestion and superoxide anion production) were assayed, as well as chemotaxis and proliferation of peritoneal and spleen lymphocytes. The results indicate that with respect to the medium vitamin E diet, low ingestion of vitamin E causes a decrease in chemotaxis and production of superoxide anion by macrophages and an increase in the phagocytic capacity. With the high vitamin E diet an increase in macrophage and lymphocyte chemotaxis, superoxide anion production and lymphoproliferative capacity, as well as a decrease in phagocytosis, were observed. Therefore, diet supplementation with higher than usual levels of vitamin E appears to be beneficial for the immune system.

The purpose of this study was to determine the effect of altering substrate availability on metabolism and performance during intense cycling. Seven highly trained men ingested a random order of three isoenergetic meals 90 min before cycling at 80 % maximal oxygen uptake (VO2max) for 20 min (about 310 W), followed by a 600 kJ time trial lasting about 30 min. Meals consisted of either 1·2 g saturated fat/kg body mass (BM) with 3500 U heparin intravenously (HIFAT) to elevate circulating plasma free fatty acid (FA) concentration, 2·5 g carbohydrate/kg BM (CHO) to elevate plasma glucose and insulin concentrations or 2·5 g carbohydrate+20 mg nicotinic acid/kg BM (NA) to suppress lipolysis and reduce free FA concentration. HIFAT elevated free FA concentration (HIFAT 1·3 (SEM 0·2), CHO 0·2 (sem 0·1), NA 0·1 (sem 0·1) mm; P<0·001), lowered the RER (HIFAT 0·94 (sem 0·01), CHO 0·97 (sem 0·01), NA 0·98 (sem 0·01); P<0·01) and increased the rate of fat oxidation (HIFAT 24 (sem 3), CHO 12 (sem 2), NA 8 (sem 3) μmol/kg per min; P<0·01) during the 20 min ride. Marked differences in fat availability and fuel utilisation, however, had little effect on performance in the subsequent time trial (HIFAT 320 (sem 16), CHO 324 (sem 15), NA 315 (sem 13) W). We conclude: (1) increased fat availability during intense cycling increases the rate of fat oxidation; but (2) the reduction in the rate of carbohydrate oxidation in the presence of high circulating plasma free FA is unlikely to enhance intense exercise performance lasting about 1 h; (3) substrate selection during intense (about 80 % VO2max) exercise is dominated by carbohydrate oxidation.

Opioid agonistic and antagonistic peptides which are inactive within the sequence of the precursor milk proteins can be released and thus activated by enzymatic proteolysis, for example during gastrointestinal digestion or during food processing. Activated opioid peptides are potential modulators of various regulatory processes in the body. Opioid peptides can interact with subepithelial opioid receptors or specific luminal binding sites in the intestinal tract. Furthermore, they may be absorbed and then reach endogenous opioid receptors.

Diabetes mellitus is one of the most prevalent diseases among adult population in Japan. The persistent hyperglycemia is responsible for the appearance of various organ and tissue damage in diabetic subjects. Eyes, kidneys and peripheral nerves are frequently damaged due to diabetes-specific alteration in microvessels. Furthermore, large vessels are also damaged causing severe diseases such as myocardial infarction, cerebral infarction and gangrene. The pathogenesis of these alterations in small and large vessels has been extensively studied and various metabolic abnormalities induced by hyperglycemia are proposed to play a major role in the development of these diabetic vascular complications. Among those metabolic abnormalities, the activation of the diacyl glycerol-protein kinase C pathway has been proposed to play a pivotal role in the pathogenesis of not only microvascular complications but also macrovascular complications. The beneficial effect of a protein kinase C inhibitor on renal, retinal and atherosclerotic lesions in diabetic animal models may support this notion. The results of several large-scale clinical trials have confirmed the efficacy of glycemic control as well as blood pressure control in the management of diabetic complications. It is a prerequisite, therefore, to obtain near-normal glycemic and blood pressure control in order to prevent the appearance of diabetic complications and also suppress their progression. In this aspect nutritional consideration may be an important way to improve the quality of these managements.

The effect of abomasal infusion of glucose (120 kJ/d per kg body weight (BW)0·75, 758 mmol/d) on urea production, plasma alanine-N flux rate and the conversion of alanine-N to urea was studied in sheep offered a low-N diet at limited energy intake (500 kJ/d per kg BW0·75), based on hay and grass pellets. Glucose provision reduced urinary N (P = 0·040) and urea (P = 0·009) elimination but this was offset by poorer N digestibility. Urea-N production was significantly reduced (822 v. 619 mmol/d, P = 0·024) by glucose while plasma alanine-N flux rate was elevated (295 v. 342 mmol/d, P = 0·011). The quantity of urea-N derived from alanine tended to be decreased by glucose (127 v. 95 mmol/d) but the fraction of urea production from alanine was unaltered (15 %). Plasma urea and alanine concentrations (plus those of the branched chain amino acids) decreased in response to exogenous glucose, an effect probably related to enhanced anabolic usage of amino acids and lowered urea production.

Adult offspring of severely diabetic pregnant rats are insulin resistant and display cardiovascular dysfunction. When pregnant they develop mild hyperglycaemia. Diets high in saturated fat have been implicated in the development of cardiovascular disease and vascular dysfunction. In the present study we have determined vascular function in small mesenteric arteries from offspring of normal (OC) and diabetic (OD) rats fed standard chow and offspring of diabetic rats fed a diet high in saturated fats (OD-HF) from weaning to adulthood, and throughout their subsequent pregnancies. OD rats displayed an increased sensitivity to noradrenaline (P < 0·05) and impaired sensitivity to the endothelium-dependent vasodilator, acetylcholine. The component of acetylcholine-induced relaxation attributable to endothelium-derived hyperpolarizing factor was reduced in OD-HF rats. Pregnant OD rats also demonstrated impaired maximum relaxation to acetylcholine (pregnant OD rats v. pregnant OC rats P < 0·05). In pregnant OD-HF rats noradrenaline sensitivity was enhanced and endothelium-dependent relaxation further reduced (pregnant OD-HF rats v. pregnant OC rats P < 0·001). The isoprostane, 8-epi-prostaglandin F2α, a marker of oxidative stress, was increased in pregnant OD rats (pregnant OD rats v. pregnant OC rats P < 0·001) and further increased in pregnant OD-HF rats (pregnant OD-HF rats v. pregnant OD rats P < 0·05). We conclude that a high-saturated-fat diet leads to deterioration in specific components of vascular function in OD rats. When pregnant, vascular function of OD-HF rats is further compromised. Pregnancy in the OD rats is associated with a striking increase in a marker of oxidative stress, which increases further if the saturated fat intake is raised.