Oxytocin in metabolic homeostasis: implications for obesity and diabetes management.

Oxytocin was once understood solely as a neuropeptide with a central role in social bonding, reproduction, parturition, lactation and appetite regulation. Recent evidence indicates that oxytocin enhances glucose uptake and lipid utilization in adipose tissue and skeletal muscle, suggesting that dysfunction of the oxytocin system could underlie the pathogenesis of insulin resistance and dyslipidaemia. Murine studies revealed that deficiencies in oxytocin signalling and oxytocin receptor expression lead to obesity despite normal food intake, motor activity and increased leptin levels. In addition, plasma oxytocin concentration is notably lower in obese individuals with diabetes, which may suggest an involvement of the oxytocin system in the pathogenesis of cardiometabolic disease. More recently, small scale studies demonstrated that intranasal administration of oxytocin was associated with significant weight loss as well as improvements in insulin sensitivity and pancreatic ß-cell responsivity in human subjects. The multi-pronged effects of oxytocin signalling on improving peripheral insulin sensitivity, pancreatic function and lipid homeostasis strongly suggest a role for this system as a therapeutic target in obesity and diabetes management. The complexity of obesity aetiology and the pathogenesis of obesity-related metabolic complications underscore the need for a systems approach to better understand the role of oxytocin in metabolic function.

Reproducibility of glucose, fatty acid and VLDL kinetics and multi-organ insulin sensitivity in obese subjects with non-alcoholic fatty liver disease.

OBJECTIVE: Non-alcoholic fatty liver disease (NAFLD) is associated with abnormalities in basal glucose and free fatty acid (FFA) metabolism, multi-organ insulin resistance and alterations in lipoprotein kinetics. These metabolic outcomes can be evaluated in vivo by using stable isotopically labeled tracer methods. An understanding of the reproducibility of these measures is necessary to ensure adequate statistical power in studies designed to evaluate metabolic function in subjects with NAFLD. METHODS: We determined the degree of intra-individual variability of skeletal muscle, adipose tissue, and hepatic insulin sensitivity and basal plasma glucose, FFA, and very-low-density lipoprotein triglyceride and apolipoprotein B-100 (apoB-100) kinetics in eight obese subjects with NAFLD (age: 44 ± 3 years; body mass index: 38.2 ± 1.7 kg m(-2); intrahepatic triglyceride content: 24.5 ± 3.9%), by using the hyperinsulinemic-euglycemic clamp technique and stable isotope-labeled tracer methods and mathematical modeling on two separate occasions ∼2 months apart. RESULTS: The intra-individual variability (coefficient of variation) ranged from 6% for basal glucose production to 21% for insulin-stimulated glucose disposal (percentage increase from basal). We estimated that a 25% difference in any outcome measure can be detected with a sample size of ≤ 8 subjects for paired studies and ≤ 15 subjects per group for unpaired studies, assuming an α value of 0.05 and a ß value of 0.20 (that is, 80% power). CONCLUSION: These results demonstrate that only a small number of subjects are needed to detect clinically relevant effects in insulin sensitivity and hepatic lipoprotein metabolism in obese subjects with NAFLD, and will be useful to determine appropriate sample size for future metabolic studies.

Decrease in hepatic very-low-density lipoprotein-triglyceride secretion after weight loss is inversely associated with changes in circulating leptin.

AIM: Although weight loss usually decreases very-low-density lipoprotein-triglyceride (VLDL-TG) secretion rate, the change in VLDL-TG kinetics is not directly related to the change in body weight. Circulating leptin also declines with weight loss and can affect hepatic lipid metabolism. The aim of this study was to determine whether circulating leptin is associated with weight loss-induced changes in VLDL-TG secretion. METHODS: Ten extremely obese subjects were studied. VLDL-TG secretion rate and the contribution of systemic (derived from lipolysis of subcutaneous adipose tissue TG) and non-systemic fatty acids (derived primarily from lipolysis of intrahepatic and intraperitoneal TG, and de novo lipogenesis) to VLDL-TG production were determined by using stable isotopically labelled tracer methods before and 1 year after gastric bypass surgery. RESULTS: Subjects lost 33 +/- 12% of body weight, and VLDL-TG secretion rate decreased by 46 +/- 23% (p = 0.001), primarily because of a decrease in the secretion of VLDL-TG from non-systemic fatty acids (p = 0.002). Changes in VLDL-TG secretion rates were not significantly related to reductions in body weight, body mass index, plasma palmitate flux, free fatty acid or insulin concentrations. The change in VLDL-TG secretion was inversely correlated with the change in plasma leptin concentration (r = -0.72, p = 0.013), because of a negative association between changes in leptin and VLDL-TG secretion from non-systemic fatty acids (r = -0.95, p < 0.001). CONCLUSIONS: Weight loss-induced changes in plasma leptin concentration are inversely associated with changes in VLDL-TG secretion rate. Additional studies are needed to determine whether the correlation between circulating leptin and VLDL-TG secretion represents a cause-and-effect relationship.

Estimated liver weight is directly related to hepatic very low-density lipoprotein-triglyceride secretion rate in men.

BACKGROUND: Animal studies suggest that liver weight is directly related to hepatic very low-density lipoprotein-triglyceride (VLDL-TG) secretion, independently of body size. This relationship has never been examined in humans. MATERIALS AND METHODS: We measured VLDL-TG secretion rate by using stable isotope-labelled tracers in 21 healthy, non-obese men (age: 25 +/- 3 years; body mass index: 24.8 +/- 1.6 kg m(-2)), and evaluated the relationship between VLDL-TG secretion and indices of total and regional adiposity (body mass index, total body fat, trunk fat), metabolic parameters (free fatty acid, glucose, and insulin concentrations, homeostasis model assessment index of insulin resistance, resting energy expenditure), and estimated liver weight. RESULTS: Correlation analysis showed that estimated liver weight was positively associated with total VLDL-TG secretion rate (r = 0.722, P < 0.001), VLDL-TG secretion rate per liter of plasma (r = 0.562, P = 0.008), VLDL-TG secretion rate per kilogram of body weight (r = 0.555, P = 0.009), and VLDL-TG secretion rate per kilogram of liver weight (r = 0.620, P = 0.003). In multiple regression analysis, estimated liver weight was the only significant predictor of VLDL-TG secretion rate regardless of units of expression, explaining 31-52% of total variance; none of the metabolic parameters and indices of body fatness entered the regression models. CONCLUSIONS: We conclude that estimated liver weight is directly related to hepatic VLDL-TG secretion rate in healthy non-obese men; this relationship is likely not mediated by interindividual variation in body size.

Effect of obesity on the plasma lipoprotein subclass profile in normoglycemic and normolipidemic men and women.

OBJECTIVE: To determine the effect of obesity without the confounding effect of metabolic complications on the lipoprotein subclass profile in men and women. DESIGN: Cross-sectional study. SUBJECTS: A total of 40 lean (body mass index (BMI): 18.5-25 kg/m(2)) and 40 obese (BMI: 30-45 kg/m(2)) subjects, with blood pressure <140/90 mm Hg, fasting plasma glucose concentration <100 mg per 100 ml and total triglyceride concentration <150 mg per 100 ml; all obese subjects had normal oral glucose tolerance. MEASUREMENTS: Fasting concentrations of very low-, intermediate-, low- and high-density lipoproteins (VLDL, IDL, LDL, and HDL, respectively) and average VLDL, LDL and HDL particle sizes were evaluated by using proton nuclear magnetic resonance spectroscopy. RESULTS: Obese compared with lean individuals of both sexes had increased plasma concentrations of VLDL (by approximately 50%), IDL (by approximately 100%), LDL (by approximately 50%), and to some extent HDL (by approximately 10%) particles (P<0.05). The contribution of large VLDL to total VLDL concentration, small LDL to total LDL concentration, and small HDL to total HDL concentration was greater in obese than lean subjects (P<0.05), resulting in larger average VLDL size but smaller average LDL and HDL sizes (P<0.05). Women, compared with men, had reduced concentrations of total VLDL particles (by approximately 10%) due to lower concentrations of large and medium VLDL and a shift toward large at the expense of small HDL particles (P<0.05), with no difference in total HDL particle concentration. IDL and total LDL concentrations and LDL subclass distribution were not different between men and women. CONCLUSION: Obesity is associated with pro-atherogenic alterations in the lipoprotein subclass profile, which may increase cardiovascular disease risk even in the absence of classical metabolic risk factors. On the other hand, the female cardiovascular disease risk advantage is probably largely related to differences in traditional lipid risk factors (plasma triglyceride and HDL-cholesterol concentrations) because sex differences in the plasma lipoprotein subclass profile are minimal.

Physical activity counteracts increased whole-body protein breakdown in chronic obstructive pulmonary disease patients.

Chronic obstructive pulmonary disease (COPD) is associated with increased whole body protein breakdown and low-grade systemic inflammation. We aimed to determine if physical training of patients with COPD induces anti-inflammatory effects and decreases whole-body protein breakdown. Nineteen subjects with severe (FEV(1)=31+/-1) COPD were randomized into a training group (n=9) and a control group (n=10). Twenty healthy subjects were studied for baseline comparison. The "COPD training" group participated in an outpatient rehabilitation program consisting of endurance training (walking at 85% of VO(2max)) twice weekly for 7 weeks plus daily home-based training. Maximum walking distance increased by almost 70% in the training group after 7 weeks of training. At baseline, the concentrations of C-reactive protein (CRP) and IL-18 in plasma were increased in subjects with COPD compared with healthy subjects (P<0.05) and leucine rate of appearance (R(a)) was approximately 15% greater (P<0.05) in subjects with COPD. Training had no effect on the plasma concentration of inflammatory markers but decreased leucine R(a) in subjects with COPD by approximately 10% (P<0.05). In conclusion, 7 weeks of physical training markedly improved endurance in patients with COPD and accelerated whole-body protein breakdown in patients with COPD was attenuated by physical training independent of changes in inflammatory markers.

The type and intensity of exercise have independent and additive effects on bone mineral density.

Previous research on the effects of running and swimming on areal bone mineral density (aBMD) is inconclusive. This study examined the putative roles of the type and intensity of exercise in this respect, by measuring aBMD (adjusted for age, weight, and height) of the total body and of various subregions in 52 males aged 17 - 30 yr (21 runners, 16 swimmers, 15 controls). The athletes were competing at either long-distance ("endurance", n = 17) or short-distance ("sprint", n = 20) events. Compared with controls, runners had significantly higher leg aBMD (+ 6.7 %, p < 0.05), while swimmers had significantly lower leg and total body aBMD (- 9.8 % and - 7.0 %, respectively, p < 0.05). Endurance athletes had significantly lower total body aBMD than controls (- 4.9 %, p < 0.05). Sprint athletes did not differ significantly from controls at any site, but they had significantly higher aBMD than endurance athletes throughout the skeleton (p < 0.05). Compared with controls, endurance swimmers had significantly lower aBMD at the legs and total body (- 14.8 % and - 10.4 %, respectively, p < 0.05), while sprint runners had significantly higher values for the legs, trunk, and total body (+ 8.0 %, + 10.0 %, and + 6.3 %, respectively, p < 0.05). Sprint swimmers and endurance runners did not differ from controls at any site or the total body. These results suggest that the type and intensity of exercise have independent and additive effects on bone density.

Dietary supplementation with flaxseed oil lowers blood pressure in dyslipidaemic patients.

OBJECTIVE: Alpha-linolenic acid (ALA) is the natural precursor of the cardioprotective long-chain n-3 fatty acids. Available data indicate a possible beneficial effect of ALA on cardiovascular disease (CVD), but the response of various CVD risk factors to increased ALA intake is not well characterized. The purpose of the present study was to examine the effect of increased ALA intake on blood pressure in man. DESIGN, SETTING, SUBJECTS AND INTERVENTIONS: We used a prospective, two-group, parallel-arm design to examine the effect of a 12-week dietary supplementation with flaxseed oil, rich in ALA (8 g/day), on blood pressure in middle-aged dyslipidaemic men (n=59). The diet of the control group was supplemented with safflower oil, containing the equivalent n-6 fatty acid (11 g/day linoleic acid (LA); n=28). Arterial blood pressure was measured at the beginning and at the end of the dietary intervention period. RESULTS: Supplementation with ALA resulted in significantly lower systolic and diastolic blood pressure levels compared with LA (P=0.016 and P=0.011, respectively, from analysis of variance (ANOVA) for repeated measures). CONCLUSIONS: We observed a hypotensive effect of ALA, which may constitute another mechanism accounting in part for the apparent cardioprotective effect of this n-3 fatty acid.

Differences in the quantitative and qualitative performance of a calcium-specific food frequency questionnaire across age and sex.

OBJECTIVE: To examine putative differences in the quantitative and qualitative performance of a food frequency questionnaire (FFQ) for assessing dietary calcium intake across age and sex in the Greek population. MATERIALS AND METHODS: A total of 351 children (189 girls and 162 boys, aged 11.9 +/- 1.2 years), 260 adults (192 women and 68 men, aged 29.6 +/- 2.7 years) and 390 elderly individuals (317 women and 73 men, aged 68.6 +/- 4.6 years) were recruited. Estimates of calcium intake from the 30-item FFQ were compared with those from a multi-pass 24-h recall. RESULTS: The FFQ significantly underestimated mean calcium intake in all age groups and both sexes (P < 0.05). The magnitude of underestimation, however, was greater in adults (-207 +/- 344 mg day(-1)), less in the elderly (-137 +/- 310 mg day(-1)) and even less in children (-74 +/- 340 mg day(-1); P < 0.025), with no differences between sexes. Calcium intakes by the two methods were positively and significantly correlated in all study groups (r = 0.536-0.739, P < 0.001). Cohen's weighted kappa statistic ranged from 0.39 to 0.57, indicating moderate agreement between the two methods. The 95% limits of agreement were comparably wide across age and sex (boys: -762, 585 mg day(-1); girls: -747, 624 mg day(-1); adult men: -972, 505 mg day(-1); adult women: -867, 412 mg day(-1); elderly men: -858, 486 mg day(-1); elderly women: -732, 480 mg day(-1)). A significant association between age, sex and the classification of individuals as true/false positive/negative was detected (P < 0.001), implying that sensitivity, specificity, positive and negative predictive values of the FFQ were not independent of the age and sex of the participants. Gross misclassification by the FFQ ranged from 0% to 4.2%, whereas 75.3-87.3% of the subjects were correctly classified. In this respect, the FFQ performed similarly across the study groups (P = 0.065). Without controlling for age, however, gross misclassification appeared to be higher in females than in males (3.2% versus 0.7%, respectively, P = 0.048). CONCLUSIONS: There may be several significant differences in the quantitative and qualitative performance of a calcium-specific FFQ across age and sex. This should be taken into account when attempting to evaluate dietary calcium intake in men and women or in different age groups, as some of the differences between study groups may actually be due to the different response of these groups to the FFQ.

Diet, blood lipid profile and physical activity patterns in primary school children from a semi-rural area of Greece.

BACKGROUND: Risk factors for heart disease are becoming increasingly prevalent among young populations. The aim of this study was to assess the cardiovascular risk profile of young adolescents living in a semi-rural area of mainland Greece, Volos. MATERIALS AND METHODS: A total of 198 children (106 females and 92 males) aged 11.6 +/- 0.4 years were randomly recruited. RESULTS: Mean body mass index was 20.4 +/- 3.5 kg m(-2), while 30.3% of children were overweight and 6.7% were obese; no differences were observed between boys and girls. Mean plasma cholesterol (4.93 +/- 0.75 mmol L(-1)), low-density lipoprotein-cholesterol (3.29 +/- 0.64 mmol L(-1)) and triglyceride (0.97 +/- 0.31 mmol L(-1)) concentrations were above age-specific recommended values. On the other hand, mean high-density lipoprotein-cholesterol was acceptable for 92.3% of the children. Self-reported daily energy intake (8.37 +/- 3.06 MJ) was adequate for age, but intake of fat was high (42.0 +/- 9.2% of energy) and that of carbohydrate was relatively low (44.5 +/- 10.0% of energy). Saturated fat consumption was elevated (15.6 +/- 4.3% of energy), while polyunsaturated fat intake fell short (4.8 +/- 1.6% of energy). The study participants spent 9.60 +/- 6.44 h week(-1) on moderate to vigorous physical activities, while they devoted 16.60 +/- 8.81 h week(-1) to sedentary activities. Boys spent significantly more time than girls on both physical (P < 0.001) and sedentary (P = 0.001) activities. No major gender differences were observed in anthropometric, dietary and plasma lipid parameters. CONCLUSION: The findings from the present study support the worrisome trends that have been documented in Greek youngsters elsewhere, and predict an unfavourable cardiovascular risk profile for the Greek population in the foreseeable future.

The effect of MTHFR(C677T) genotype on plasma homocysteine concentrations in healthy children is influenced by gender.

OBJECTIVE: To explore the influence of gender, together with folate status, on the relation between the common methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and plasma total homocysteine (tHcy) concentrations in healthy children. DESIGN: Cross-sectional study by face-to-face interview. SETTING AND SUBJECTS: A total of 186 sixth-grade students participated from twelve randomly selected primary schools in Volos, Greece. METHODS: Fasting tHcy, folate, and vitamin B(12) were measured in plasma. The MTHFR genotypes were determined. Anthropometric and dietary intake data by 24-h recall were collected. RESULTS: Geometric means for plasma tHcy, plasma folate and energy-adjusted dietary folate did not differ between females and males. The homozygous mutant TT genotype was associated with higher tHcy only in children with lower plasma folate concentrations (<19.9 nmol/l, P = 0.012). As a significant gender interaction was observed (P = 0.050), we stratified the lower plasma folate group by gender and found that the association between the genotype and tHcy was restricted to males (P = 0.026). Similar results were obtained when folate status was based on estimated dietary folate. Specifically, only TT males that reported lower dietary folate consumption (<37 microg/MJ/day) had tHcy that was significantly higher than tHcy levels of C-allele carriers (P = 0.001). CONCLUSIONS: Under conditions of lower folate status (as estimated by either plasma concentration or reported dietary consumption), gender modifies the association of the MTHFR(C677T) polymorphism with tHcy concentrations in healthy children. SPONSORSHIP: Kellog Europe.

Secular trends in cardiovascular risk factors among school-aged boys from Crete, Greece, 1982-2002.

OBJECTIVE: The aim of the present study was to examine secular trends in major cardiovascular disease (CVD) risk factors, that is, obesity and dyslipidaemia, among Cretan children during 1982-2002. DESIGN: Epidemiological survey. SETTING AND SUBJECTS: A total of 528 boys in 1982 and 620 boys in 2002, aged 12.1+/-0.1 y, were randomly selected from urban and rural regions throughout the county of Iraklio, Crete, Greece. Care was taken so that all procedures in 2002 closely matched those in 1982. RESULTS: Mean height, weight, and body mass index (BMI) were 1.1, 9.6, and 8.4% higher, respectively, in 2002 vs 1982 (P<0.001). The prevalence of overweight and obesity has risen by 63 and 202%, respectively (P<0.001). Contemporary children were found to have 3.6% higher total cholesterol (TC), 24.9% lower high-density lipoprotein-cholesterol (HDL-C), 25.3% higher low-density lipoprotein-cholesterol (LDL-C), 19.4% higher triacylglycerol, 36.6% higher TC/HDL-C ratio, and 60.3% higher LDL-C/HDL-C ratio compared with their peers in 1982 (P<0.003). These differences persisted even when adjusting for BMI (P<0.02). The proportion of children having abnormal lipid values was much greater nowadays than in the 1980s, yielding odds ratios of 1.4-8.8 (P<0.005). CONCLUSIONS: Results are indicative of a largely deteriorated CVD risk profile in Cretan children since 1982, and predict an unfavourable CVD morbidity and mortality for this population in the foreseeable future.