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Relation entre composition salivaire, obésité et métabolisme lipidique postprandial chez l'Homme. 12. Journées Francophones de Nutrition (JFN)

International audience; OBJECTIVES: Klotho is an "aging-suppressor" gene and encodes a single-pass transmembrane protein predominantly expressed in renal tubules. Whether chronic kidney disease (CKD) affects serum Klotho is poorly documented. We aimed to measure the relationship of serum alpha-Klotho with renal function, acid-base status, bone biomarkers, and proteinuria in CKD patients. DESIGN SETTING, PARTICIPANTS, AND MEASUREMENTS: We measured serum alpha-Klotho, serum FGF23, and glomerular filtration rate by inulin clearance in 60 CKD patients between January and July 2011. We also measured serum creatinine, bicarbonate, calcium, phosphorus, parathyroid hormone, C-reactive protein, and 25-OH vitamin D. Proteinuria was obtained from a 24-h urine collection. RESULTS: The median serum alpha-Klotho was 478 (348-658) pg/mL. We found an inverse relationship between serum alpha-Klotho and serum creatinine (r = -0.36, P = .007), proteinuria (r = -0.36, P = .013), and a positive relationship with serum bicarbonate (r = 0.33, P = .011). There was no further significant relation between serum alpha-Klotho and inulin clearance or serum FGF23. Multiple regression analysis including serum bicarbonate, serum creatinine, and proteinuria indicated that only serum bicarbonate was associated with serum alpha-Klotho (P = .003). CONCLUSIONS: This study shows that in CKD, serum alpha-Klotho is related to serum bicarbonate and proteinuria and not to renal function. Further research is required to determine whether correcting these 2 amenable conditions would improve serum alpha-Klotho.

Background: Together with adiposity, plasma fatty acid (FA) composition can modulate the development of the metabolic syndrome (MS). Objective: Our aim was to investigate the relations of FA composition in plasma phospholipids and cholesterol esters (CEs) with weight status, MS, and inflammation in adolescents. Design: Plasma FA composition was measured by gas-liquid chromatography in 120 (60 normal-weight and 60 overweight) 12-y-old adolescents. We also measured the presence of MS, insulin resistance with the homeostasis model assessment, and interleukin 6 and C-reactive protein concentrations in the adolescents. Results: MS was present in 25% of the overweight adolescents but in none of the normal-weight adolescents. Compared with overweight adolescents, normal-weight adolescents had lower saturated FAs (SFAs) in both phospholipids (P < 0.001) and CEs (P < 0.01) and higher docosahexaenoic acid in phospholipids (P < 0.001). In overweight subjects, FA composition was associated with MS features independent of body fat. The odds ratios of MS for a 0.1 increase in the ratio of polyunsaturated FAs (PUFA) to SFAs (PUFA:SFA) were 0.91 in phospholipids (P = 0.03) and 0.90 in CEs (P = 0.06). In phospholipids, PUFA:SFA and linoleic acid were associated positively with HDL cholesterol (P < 0.01 for both). PUFA:SFA in phospholipids and CEs were associated inversely with interleukin 6 (P < 0.05 for both). Eicosapentaenoic acid in phospholipids (P = 0.06) and CEs (P < 0.05) and linolenic acid in CEs (P < 0.05) were inversely related to C-reactive protein. These relations remained significant after adjustment for the waist-to-hip ratio. No significant relation between FA composition and the homeostasis model assessment was observed. Conclusions: Plasma FA composition is associated with weight status in healthy adolescents. High intake of long-chain PUFAs, especially n-3 PUFAs, may protect obese subjects against MS and low-grade inflammation as early as adolescence.

While type 1 hyperlipidemia is associated with lipoprotein lipase or apoCII deficiencies, the etiology of type 5 hyperlipidemia remains largely unknown. We explored a new candidate gene, APOA5, for possible causative mutations in a pedigree of late-onset, vertically transmitted hyperchylomicronemia. A heterozygous Q139X mutation in APOA5 was present in both the proband and his affected son but was absent in 200 controls. It was subsequently found in 2 of 140 cases of hyperchylomicronemia. Haplotype analysis suggested the new Q139X as a founder mutation. Family studies showed that 5 of 9 total Q139X carriers had hyperchylomicronemia, 1 patient being homozygote. Severe hypertriglyceridemia in 8 heterozygotes was strictly associated with the presence on the second allele of 1 of 2 previously described triglyceride-raising minor APOA5 haplotypes. Furthermore, ultracentrifugation fraction analysis indicated in carriers an altered association of Apoa5 truncated and WT proteins to lipoproteins, whereas in normal plasma, Apoa5 associated with VLDL and HDL/LDL fractions. APOB100 kinetic studies in 3 severely dyslipidemic patients with Q139X revealed a major impairment of VLDL catabolism. Lipoprotein lipase activity and mass were dramatically reduced in dyslipidemic carriers, leading to severe lipolysis defect. Our observations strongly support in humans a role for APOA5 in lipolysis regulation and in familial hyperchylomicronemia.

Background In long-term parenteral nutrition (LTPN) patients, the use of a 50:50 mixture of medium- and long-chain triglyceride emulsion (MCT/LCT) has been suggested to prevent or correct fatty liver infiltration. However, the use of MCT/LCT lipid emulsion results in a 50% reduction of essential fatty acids and vitamin K1 supply and could induce essential fatty acid and vitamin K1 deficiencies. This study evaluated the effect of a long-term infusion of MCT/LCT lipid emulsion on plasma fatty acid (FA) and vitamin K1 levels on LTPN patients. Methods In a prospective nonrandomized crossover study, we measured plasma phospholipid FA composition by gas chromatography and vitamin K1 levels by high-performance liquid chromatography in 11 LTPN patients before and after a 4-month replacement of the usual 20% LCT lipid emulsion (20% Lipoven; Fresenius-Kabi France, Sevres, France) by a 20% MCT/LCT lipid emulsion (Medialipide B; Braun Medical, Boulogne, France). Results Patient received LTPN for 46 +/- 40 months; IV lipid emulsion was 827 +/- 336 mL/week. MCT/LCT lipid substitution did not change most of the essential plasma fatty acid concentrations and did not induce essential fatty acid deficiency. With both lipid emulsions, the triene/tetraene (20:3n-9/20:4n-6) ratio remained within the normal ranges. However, with MCT/LCT lipid emulsion, 22:4n-6 (LCT: 0.50 +/- 0.12; MCT/LCT: 0.63 +/- 0.11%) and 22:5n-6 (LCT: 0.32 +/- 0.11; MCT/LCT: 0.48 +/- 0.15%) increased significantly (p = .022 and 0.011, respectively). Plasma vitamin K1 levels decreased drastically with MCT/LCT lipid emulsion. Conclusions An amount of 2.85 +/- 1.55 g x kg(-1) week(-1) of MCT/LCT lipid emulsion neither induced essential fatty acid deficiency nor improved the fatty acid disturbances usually observed in LTPN patients but did induce a drop in plasma vitamin K1 levels.

In cystic fibrosis (CF), there is an imbalance in the oxidant/antioxidant system, leading to oxidative damage. The aim of this study was to assess antioxidant-scavenger deficiencies and lipid peroxide variations in three clinical situations (stable status, acute exacerbation, and after intravenous antibiotic treatment). The objective was also to correlate oxidative stress with age, nutritional status, and respiratory function. The study included prospectively 312 consecutive patients and 53 controls. Antioxidants (vitamin A, vitamin E, carotenoids, and glutathione) and oxidative markers (malondialdehyde and lipid peroxides) were measured in plasma. Regression analyses were performed. Antioxidant levels were lower in CF patients than in controls. These levels decreased during acute exacerbation and increased after antibiotic treatment. Carotenoid levels were not modified by infection or age. Only vitamin A and carotenoid levels were positively correlated to body mass index. Antioxidant levels were correlated to forced expiratory volume at 1 sec. Lipid peroxidation markers were lower in patients than in controls. Their levels decreased during infection, and increased after antibiotic treatment. Impaired lung function was correlated with elevated malondialdehyde levels. In conclusion, this study demonstrates antioxidant deficiency in a very large cohort of CF patients. Carotenoid and vitamin E deficiencies occur early in the course of the disease. Antioxidants decrease with bronchial infection. By contrast, nutritional disorders did not modify antioxidant levels during acute exacerbations. Thus, pulmonary disorders rather than nutritional disorders seem to be essential in the imbalance of the oxidant/antioxidant system. Results concerning glutathione and oxidative-marker levels highlighted the fact that their plasma values do not reflect oxidative stress in the respiratory tract.

Introduction et but de l’etude En situation d’obesite, l’exposition par voie orale aux matieres grasses alimentaires peut moduler la digestion et l’absorption des lipides. Cependant, les mecanismes oraux sous-jacents n’ont pas ete clairement identifies. Nous avons teste l’hypothese que des composants de la salive impliques dans la sensibilite orale aux lipides alimentaires seraient differents selon l’indice de masse corporelle (IMC) et le metabolisme lipidique postprandial des individus. Materiel et methodes La salive a ete recueillie a jeun chez neuf sujets de poids normal (IMC = 22,3 ± 0,5 kg/m2) et neuf individus obeses (IMC = 31,7 ± 0,3 kg/m2) pour la mesure des parametres suivants : flux, teneur en proteines, lipolyse, amylase, proteolyse, pouvoir antioxydant, lysozyme, teneurs en lipocaline 1 et en anhydrase carbonique-VI (CAVI). Ce recueil a ete realise avant la consommation d’un repas contenant 40 g de matiere grasse, suivie d’un test d’exploration metabolique de 8 h, au cours duquel les sujets obeses ont revele un metabolisme lipidique postprandial retarde. Resultats et analyse statistique Nous avons montre que la lipolyse salivaire est plus faible chez les sujets obeses par rapport aux individus de poids normal alors que la proteolyse et la teneur en CAVI sont plus elevees ( Tableau 1 ). Par analyse multivariee et par test de Mann-Whitney, nous observons que ces differences de lipolyse et de proteolyse sont liees a des differences de metabolisme lipidique incluant l’absorption postprandiale des acides gras exogenes et leur beta oxydation. Conclusion Ces resultats suggerent un role de la salive sur le metabolisme lipidique postprandial. Ils amenent de nouvelles hypotheses causales sur les liens entre la composition de la salive, la sensibilite orale aux graisses alimentaires et le metabolisme lipidique postprandial en fonction de l’IMC.

It is now widely accepted that increased total plasma homocysteine (tHcy) is a risk factor for cardiovascular disease. Hyperhomocysteinemia can be caused by impaired enzyme function as a result of genetic mutation or vitamin B (B(2), B(6), B(9), B(12)) deficiency. A lot of methods are now available for tHcy determination. High-pressure liquid chromatography (HPLC) with fluorescence detection are at present the most widely used methods but immunoassays, easier to use, begin to supplant in-house laboratory methods. In order to help with the choice of a main relevant homocysteine analytical method, the characteristics, performances and limits of the main current methods are reviewed. One major drawback among all these available methods is the transferability which is not clearly established to date. The impact of both inter-method and inter-laboratory variations on the interpretation of the tHcy results are discussed.

Background : Our aim was to evaluate oxidative stress parameters on three groups of diabetic patients, insulin-dependent diabetes mellitus (IDDM), non-insulin-dependent diabetes mellitus (NIDDM), and insulin-treated type 2 diabetes mellitus (ITDM2), with similar HbA1c value and to determine if insulin's impact on these parameters was the same for IDDM and ITDM2. Methods : This study has been conducted on 18 IDDM, 55 NIDDM, 27 ITDM2, compared to 12 healthy subjects. Plasmatic concentrations of thiobarbituric acid reactive substances (TBARS), fatty acids, total antioxidant status (TAS), α-tocopherol, and erythrocyte reduced glutathione (GSH) were measured as well as enzymatic activities of superoxide dismutase (SOD), and glutathione peroxidase/reductase. Results : Diabetic patients have significant increase of SOD activity, of TBARS concentration (concomitant with low levels of unsaturated fatty acids) and significant decrease of GSH and α-tocopherol. NIDDM have significantly lower levels of GSH and higher levels of TBARS compared to IDDM. ITDM2 values are intermediate between IDDM and NIDDM but are far from reaching those of IDDM. Conclusion : Diabetic patients undergo an important oxidative stress that is nearly corrected for IDDM, but only partially improved for ITDM2, although length of insulin treatment and HbA1c values are similar, suggesting metabolic differences between the two types of diabetes.

The effects of frequent eating on health and particularly on appetite and metabolism are unclear. We have previously shown that frequent eating decreased appetite and energy intake at the subsequent meal in lean men. In the present study, we tested the same pattern in obese subjects. Seventeen obese men participated in: (i) two sessions consisting of a breakfast consumed in one eating episode at T0 (F1), or in four isocaloric eating episodes at T0, T60, T120, and T180 min (F4), followed by an ad libitum buffet (T240) in an experimental restaurant. Subjects rated their appetite throughout the sessions. (ii) two sessions consisting of the same breakfasts F1 and F4 in a Clinical Centre, followed by a standardized meal. Blood sampling was performed to study ghrelin, glucagon-like peptide-1 (GLP-1), and metabolic kinetics. Indirect calorimetry measurements were performed. After F4, at T240 min, ghrelin concentration (P = 0.03) and hunger ratings (P < 0.001) were lower while GLP-1 concentration (P = 0.006) and satiety ratings (P = 0.02) were higher. In F4, subjects consumed at the buffet, less food in grams (P = 0.04) and less energy from low energy dense foods (P = 0.01), but total energy intakes were not different between conditions. In F4, the area under the curve was lower for insulin (P = 0.02) and non-esterified fatty acids (NEFA) (P = 0.03). Diet induced thermogenesis was reduced in F4 (P = 0.03) between T0 and T240. Even if subjective and physiological data suggest a beneficial effect of frequent eating on appetite in obese men, no effect was demonstrated on energy intake. Moreover, the decrease in diet induced thermogenesis and lipolysis, reflected by NEFA profiles, could be deleterious on energy balance in the long run.

A new rapid and highly sensitive HPLC method with ortho-phthalaldehyde (OPA) pre-column derivatization has been developed for determination of reduced glutathione (GSH) and total glutathione (GSHt) in human red blood cells and cultured fibroblasts. OPA derivatives are separated on a reversed-phase HPLC column with an acetonitrile-sodium acetate gradient system and detected fluorimetrically. An internal standard (glutathione ethyl ester) is added to facilitate quantitation. Total glutathione is determined after reduction of disulfide groups with dithiothreitol; the oxidized glutathione (GSSG) concentration is calculated by subtraction of the GSH level from the GSHt level. The assay shows high sensitivity (50 fmol per injection, the lowest reported), good precision (C.V.5.0%), an analytical recovery of GSH and GSSG close to 100%, and linearity (r0.999). This HPLC technique is very simple and rapid. Its wide applicability and high sensitivity make it a convenient and reliable method for glutathione determination in various biological samples.

Patients receiving high-dose cyclophosphamide as a conditioning regimen for peripheral stem cell collection are subjected over a short period of time to significant exposure to reactive oxygen species (ROS). All these patients undergo profound leucopenia. Various other short-term toxicities are observed in a fraction of the patients, including febrile aplasia requiring hospitalization, thrombocytopenia and mucositis. Although stem cell collection is feasible in the majority of patients stimulated with haematopoietic growth factors, in some instances, graft collection cannot be performed because of insufficient concentrations of stem cells in peripheral blood. There is currently no predictive assay to determine which patients treated with high-dose cyclophosphamide have a high risk of febrile aplasia or will successfully undergo cytaphereses for stem cell collection. In order to identify such predictive factors, we analysed the level of expression before treatment of various ROS detoxification mechanisms in the peripheral blood of 37 patients receiving high-dose cyclophosphamide for lymphoproliferative diseases. Various parameters involved in the metabolism of ROS were measured in plasma and/or erythrocytes, including superoxide dismutase, glutathione, glutathione peroxidase, glutathione reductase and malondialdehyde. High levels of erythrocyte superoxide dismutase before cyclophosphamide therapy were correlated with an increased risk of hospitalization for febrile aplasia (65% vs. 29%, P = 0·013). High superoxide dismutase and low erythrocyte glutathione reductase were associated with lower CD34 yields. These data suggest that components of the ROS detoxification system modulate the degree of short-term toxicity of cyclophosphamide and could be used as predictive markers in individual patients.

Introduction et but de l’etude Le dosage des vitamines est indique chez l’homme afin d’apprecier son statut en micronutriments. Cependant la determination de ces concentrations est soumise i) a la variabilite analytique des techniques de dosage ainsi que ii) a la variabilite intra-individuelle et a la variabilite inter-individuelle. Pour une juste interpretation clinico-biologique des resultats et une evaluation de leur evolution dans le temps, il est indispensable de connaitre ces parametres. L’objectif de notre travail a ete de determiner les variabilites intra et inter-individuelle des concentrations en vitamines B1, B2, B6, B9, B12, C, A et E et de definir si ces concentrations etaient ou non impactees par les situations de jeun ou d’alimentation. Materiel et methodes 5 sujets sains ont ete preleves toutes les douze heures pendant 96 heures, a trois reprises, a 1 mois d’intervalle. Au cours de ces 3 periodes, il etait demande au sujet de conserver leurs habitudes alimentaires. La variabilite intraindividuelle a ete estimee comme etant equivalente a la moyenne des coefficients de variations (CV) des concentrations en vitamines obtenus lors des 18 mesures pour chaque individu et en soustrayant a ce CV la variabilite analytique estimee par le CV de reproductibilite du dosage. La variabilite interindividuelle a ete estimee comme etant egale a la moyenne des coefficients de variations des concentrations en vitamines obtenus lors des differentes mesures pour l’ensemble des individus et en soustrayant a ce CV la variabilite intra-individuelle et la variabilite analytique. Les concentrations obtenues en periode de jeun ont ensuite ete comparees aux concentrations postprandiales pour apprecier l’influence du moment de prelevement sur les concentrations en vitamines. Resultats et Analyse statistique La variabilite intra-individuelle des concentrations en vitamines etudiees oscille entre 3,9 et 21,1 % (Vitamine B1 : 8, 0 % ; B2 : 6, 3 % ; B6 : 20, 0 %, B9 : 18, 2 % ; B12 : 7, 8 % ; C : 26, 1 % ; A : 7,4 % et E : 14,7%). Comme attendu, la variabilite inter-individuelle des concentrations en vitamines depasse la variabilite intra-individuelle (Vitamine B1 : 10, 1 % ; B2 : 12, 3 % ; B6 : 25, 3 %, B9 : 25,1 % ; B12 : 30, 9 % ; C : 13,9 % ; A : 16,0 % et E : 31,1 %). Ces donnees sont en accord avec les resultats retrouves dans la litterature pour des matrices similaires. L’analyse des concentrations en vitamines a jeun par rapport a l’analyse des concentrations en vitamines en postprandial n’a pas revele de majoration des concentrations en vitamines en dehors des periodes de jeun a l’exception de la vitamine E qui voit sa concentration augmentee en postprandial, 8 heures apres l’absorption du repas (26,81 ± 0,96 vs 28,29 ± 0,38 μmol/L, p =0,05 : periode de jeun vs periode postprandiale). Conclusion Ces donnees nous ont permis d’evaluer la significativite des variations de concentrations obtenues en pratique pour chaque individu mais egalement d’etablir des specifications de qualite souhaitable pour nos techniques de mesures permettant de fixer les limites de justesse et d’exactitude de nos dosages. Ces donnees nous ont permis de savoir qu’a l’exception de la vitamine E, les prelevements de vitamines B1, B2, B6, B9, B12, C et A pouvaient etre realises a n’importe quelle periode de la journee et ne necessitait pas le respect d’un jeun pour suivre les variations en concentrations en vitamines.

Objective: CFRD is the most common comorbidity in CF. The recommended treatment of CFRD is Insulin, but other options are also in use. Only few data exist related to other treatment options. Therefore we analyzed the German CFregister for the documented therapy of CFRD. Methods: Data from the German CF-register were used from patients with CFRD in 2010 in a retrospective observational study. Delta FEV1% and delta BMI-Zscore from 2 year before diagnosis of CFRD to year of diagnosis and from year of diagnosis to 2 years after were calculated for each treatment group (Insulin, oral anti-diabetic drugs, no therapy with drugs) and compared using ANOVA-analysis. Results: 798 patients with CFRD were documented in 2010. 51.9%.were female; age (mean±SD) at diagnosis 23.8±9.3 years; CFRD duration 5.8±4.5 years. Treatment: 57.6% Insulin, 9.8% oral anti-diabetic drugs, 2.1% with both and 30.2% without any drug treatment. The mean (±SD) CFRD duration in the non-treated patients was 4.5±4.0 years. ANOVA tests showed no differences between treatment groups regarding changes in FEV1% and BMI-Z-score from 2 years before to the year of diagnosis and delta FEV1 and delta BMI-Z-score and from year of diagnosis to 2 years later. Conclusions: The percentage of patients treated with oral anti-diabetic drugs is in the international published range. We know the weakness of retrospective studies. Nevertheless the numbers are high and the observation time is long. Our data point to the question if insulin is the only successful initial treatment of CFRD in all CF patients. At least a part of patients with CFRD seems to be well treated with other regimes. Supported by German CF Foundation.

BACKGROUND Fecal biomarkers have emerged as an important tool for assessing and monitoring disease activity in patients with inflammatory bowel diseases (IBDs). We performed a prospective head-to-head comparison of the diagnostic accuracy of both fecal calprotectin (fCal) and neopterin (fNeo), and serum C-reactive protein in predicting endoscopic disease severity in patients with IBD. METHODS A total of 133 consecutive patients with IBD (78 Crohn's disease [CD] and 55 ulcerative colitis [UC]) undergoing a colonoscopy provided fecal samples for the measurement of fCal and fNeo concentrations and a blood sample for the serum C-reactive protein measurement. Endoscopic disease activities were scored independently according to the Simple Endoscopic Score for CD in patients with CD and to the Rachmilewitz Index in patients with UC. The respective performances of the fecal markers with respect to endoscopic disease severity were assessed by computing correlations, sensitivities, specificities, and overall accuracies at adjusted cutoffs and also test operating characteristics. RESULTS The fCal and fNeo concentrations differed significantly in clinically and endoscopically active IBD when compared with those in patients with inactive disease. Both fCal and fNeo concentrations correlated closer with endoscopic scores in UC (r = 0.75 and r = 0.72, respectively; P < 0.0001 for both) than in CD (r = 0.53 and r = 0.47, respectively; P < 0.0001 for both). Using cutoffs of 250 μg/g for fCal and 200 pmol/g for fNeo, both fecal markers had similar overall accuracies to predict endoscopic activity in patients with CD (74%) and also a higher and similar accuracies (88% and 90%, respectively) in patients with UC, whereas accuracies of C-reactive protein were slightly lower in patients with CD and UC. CONCLUSIONS The fNeo is a novel reliable surrogate biomarker with the potential to identify patients with IBD with active mucosal lesions and represents an alternative marker as accurate as fCal to predict and monitor the severity of mucosal damages in patients with IBD.

International audience; There is evidence that high-density lipoproteins (HDLs) may regulate platelet function, but disparate results exist regarding the effects of oxidized HDLs on platelets. The objective of our study was to determine the role of in vivo oxidized HDLs on platelet aggregation. Platelet aggregation and redox status were investigated in 5 patients with abetalipoproteinemia (ABLP) or homozygous hypobetalipoproteinemia, two rare metabolic diseases characterized by the absence of apolipoprotein B-containing lipoproteins, compared to 5 control subjects. Platelets isolated from plasma of patients with ABLP aggregated 4 to 10 times more than control platelets, depending on the agonist. By contrast, no differences in the extent of platelet aggregation were observed between ABLP platelet-rich plasma (PRP) and control PRP, suggesting the presence of a protective factor in ABLP plasma. ABLP HDLs inhibited agonist-induced platelet aggregation by binding to SR-BI, while control HDLs had no effect. On the other hand, lipoprotein-deficient plasma from patients with ABLP did not inhibit platelet aggregation. Severe oxidative stress was evidenced in patients with ABLP. Compared to control HDLs, ABLP HDLs showed a 40% decrease of α-tocopherol and an 11-fold increased malondialdehyde concentration. These results demonstrate that in vivo oxidized HDLs do not lose their antiaggregatory properties despite oxidation.-Calzada, C., Véricel, E., Colas, R., Guillot, N., El Khoury, G., Drai, J., Sassolas, A., Peretti, N., Ponsin, G., Lagarde, M., Moulin, P. Inhibitory effects of in vivo oxidized high-density lipoproteins on platelet aggregation: evidence from patients with abetalipoproteinemia.

The effects of increasing eating frequency on human health are unclear. This study used an integrated approach to assess the short-term consequences on appetite and metabolism. Twenty normal-weight men participated in: (i) two sessions consisting of a breakfast consumed in one eating episode at T0 (F1), or in four isocaloric eating episodes at T0, T60, T120, and T180 min (F4), and followed by an ecological ad libitum buffet meal (T240) designed in an experimental restaurant. Intakes were assessed for the whole buffet meal and for each temporal quarter of the meal. (ii) two sessions consisting of the same two breakfasts F1 and F4 in a Clinical Investigation Centre. Blood sampling was performed to study the kinetics of ghrelin, glucagon-like peptide-1 (GLP-1), glucose, insulin, triglycerides and non-esterified fatty acids (NEFA). Substrate oxidation was measured by indirect calorimetry. During each of the 4 sessions, participants rated their appetite throughout the experiment. After F4, at T240 min, GLP-1 concentration was higher (P = 0.006) while ghrelin concentration and hunger ratings were lower (P < 0.001). We showed a trend for subjects to consume less energy (− 88 ± 61 kcal, P = 0.08) at the buffet after F4, explained by a decrease in lipid intake (P = 0.04). Marked differences in consumption were observed during the last temporal quarter of the meal for total energy and lipid intake (P = 0.03). Mixed models highlighted differences between F1 and F4 for the kinetics of glucose, insulin and NEFA (P < 0.001). The area under the curve was lower for insulin (P < 0.001) and NEFA in F4 (P = 0.03). Diet induced thermogenesis was reduced in F4 (P < 0.05). This study demonstrated the beneficial short-term effect of increasing eating frequency on appetite in lean men considering subjective, physiological and behavioral data. However, the loss of the inter-prandial fast was associated with an inhibition of lipolysis, reflected by NEFA profiles, and a decrease in energy expenditure.

International audience; BACKGROUND: Prolonged postprandial hypertriglyceridemia is a potential risk factor for cardiovascular diseases. In the context of obesity, this is associated with a chronic imbalance of lipid partitioning oriented toward storage and not toward β-oxidation. OBJECTIVE: We tested the hypothesis that the physical structure of fat in a meal can modify the absorption, chylomicron transport, and further metabolic handling of dietary fatty acids. DESIGN: Nine normal-weight and 9 obese subjects were fed 40 g milk fat (+[(13)C]triacylglycerols), either emulsified or nonemulsified, in breakfasts of identical composition. We measured the postprandial triacylglycerol content and size of the chylomicron-rich fraction, plasma kinetics of [(13)C]fatty acids, exogenous lipid oxidation with breath-test/indirect calorimetry, and fecal excretion. RESULTS: The emulsified fat resulted in earlier (>1 h) and sharper chylomicron and [(13)C]fatty acid peaks in plasma than in spread fat in both groups (P < 0.0001). After 2 h, the emulsified fat resulted in greater apolipoprotein B-48 concentrations (9.7 ± 0.7 compared with 7.1 ± 0.9 mg/L; P < 0.05) in the normal-weight subjects than did the spread fat. In the obese subjects, emulsified fat resulted in a 3-fold greater chylomicron size (218 ± 24 nm) compared with the spread fat (P < 0.05). The emulsified fat induced higher dietary fatty acid spillover in plasma and a sharper (13)CO(2) appearance, which provoked increased exogenous lipid oxidation in each group: from 45% to 52% in normal-weight subjects (P < 0.05) and from 40% to 57% in obese subjects (P < 0.01). CONCLUSION: This study supports a new concept of "slow vs fast fat," whereby intestinal absorption can be modulated by structuring dietary fat to modulate postprandial lipemia and lipid β-oxidation in humans with different BMIs. This trial was registered at clinicaltrials.gov as NCT01249378.

Introduction et but de l’etude Les techniques et les automates permettant le dosage de l’albumine ont evolue. Une nouvelle standardisation a ete proposee aux fournisseurs en 2010, mais la dispersion des resultats des controles de qualite montre qu’elle n’est pas optimale. Le but de l’etude a ete de rechercher si les valeurs d’albuminemie sont technique- et/ou automate-dependants aux seuils diagnostiques recommandes, selon l’âge des patients, dans un cadre nutritionnel : 20, 25, 30, 35 g/L. Materiel et methodes Dans le cadre d’une etude multicentrique (six sites), des pools de plasma ( n = 30) correspondant a cinq niveaux d’albuminemie (15 a 50 g/L) ont ete realises. Le dosage d’albumine a ete effectue sur chaque pool par des techniques : immunoturbidimetriques (IT) ( n = 3), immunonephelemetriques (IN) ( n = 4), colorimetriques (C) pourpre (PBC) ( n = 1) et vert de bromocresol (VBC) ( n = 3), sur les automates : Architect (Abbott) ( n = 3) ; AU2700 et Immage (Beckman Coulter Olympus) ( n = 3) ; Modular et Cobas (Roche) ( n = 2) ; BN et Vista (Siemens) ( n = 3). La comparaison entre les techniques et les automates a ete realisee par un test de Bland–Altman. Resultats Les valeurs d’albuminemie (g/L) des pools plasmatiques obtenues sont presentees dans le Tableau 1 par niveau de concentration : moyenne ± ecart-type (valeurs extremes). Il est observe une dispersion des resultats selon les techniques, particulierement importante pour les valeurs p Conclusion Notre etude confirme que les resultats d’albumine sont lies au tandem technique–automate. Le biais entre les resultats d’un meme pool peut atteindre 4 g/L au niveau des seuils diagnostiques de denutrition. Cette notion de variabilite de resultats n’est generalement pas prise en compte dans leur interpretation et tout changement de technique au sein d’un laboratoire doit etre anticipe. De plus, l’utilisation simultanee de plusieurs techniques au sein d’un meme laboratoire est un facteur de risque critique qui doit etre maitrise. Il apparait necessaire de verifier les seuils d’albumine retenus par les referentiels Anaes-HAS et de definir, s’il y a lieu, de nouveaux seuils en fonction de la technique utilisee. L’impact sur le codage des diagnostics dans le recueil PMSI devra aussi etre envisage.

Introduction Ventricular myocardial remodeling is a cause of heart failure in ARVD patients. Angiotensin-converting enzyme (ACE) inhibitors inhibit the TGF-B pathway and have an anti-apoptotic action. ACE inhibitors are currently prescribed to reduce hypertension, to treat heart failure or to protect the heart following ischemic insult. Expression patterns of matrix metalloproteinase-9 (MMP-9) and its specific inhibitors, tissue inhibitor of metalloproteinases (TIMP) 1 and 2, are closely correlated with physiological and pathological processes characterized by the degradation and accumulation of the extracellular matrix. We aimed to study the turnover of tissue collagen in patients. Methods Dosages ofmmP9 and its inhibitors, TIMP1 and TIMP2, were performed in 26 patients treated with beta blockers (BB) and ACEs and in 20 patients treated with BB without ACEs. Each patient had blood samples taken one year apart. Tissue collagen turnover was identified by the evolution of themmP9/TIMP1 ratio and themmP9/TIMP2 ratio between the 2 time samples (Student’s t-test for paired samples). Results A stabilization of themmP9/TIMP1 andmmP9/TIMP2 ratio was present in patients treated with angiotensin-converting enzyme inhibitors (3.04±1.88 vs 3.36±2.86 formmP9/TIMP1; 8.79±8.18 vs 8.31±6.70 formmP9/ TIMP2). In contrast, there was a significant increase of themmP9/TIMP1 ratio in patients treated without ACE inhibitors (2.74±2.36 vs 4.53±3.62, p=0.03). No significant increase ofmmP9/TIMP2 was observed (7.39±5.17 vs 9.00±6.64) in these patients. The increasedmmP9/TIMP1 ratio for BB patients was triggered by an increase inmmP9 concentration (554.8±368.5 vs. 876.0±619.7, p=0.04) and a decrease in TIMP1 concentration (223.2±72.8 vs 205.1±71.6, p=0.01). Conclusion This study suggests that ACE inhibitors decrease myocardial damage in ARVD patients and strengthens the need for a prospective clinical evaluation of antifibrotic drugs in this disease.

Objective The beneficial effects of ω-3 polyunsaturated fatty acids (PUFAs) in cardiovascular disease are partly attributed to their anti-inflammatory properties. Their potential effect on the adipose tissue of chronic kidney disease (CKD) patients has never been explored. Methods To determine the metabolic effect of supplementation with two different doses of fish oil (FO), 12 non-dialyzed patients with stage IV/V CKD were randomly allocated to receive 1.8 g or 3.6 g/d of ω-3 PUFA for 10 wk. Metabolic parameters, adipose tissue function, and gene expression were evaluated at baseline and 10 wk. Results Body weight, fat mass, energy intake, fasting glucose, and insulin were unchanged. The daily intake of 3.6 g of ω-3 PUFA resulted in decreased serum triacylglycerol and increased high-density lipoprotein cholesterol, whereas low-density lipoprotein cholesterol increased with 1.8 g of ω-3 PUFA. Serum adiponectin, leptin, C-reactive protein, and tumor necrosis factor-α were not modified in either group. Interleukin-6 levels tended to decrease with 1.8 g of ω-3 PUFA. Additionally, a subset of inflammation-related genes ( CD68 and MMP9 ) was reduced in subcutaneous adipose tissue in this group. Adiponectin, leptin, and adipoR2 gene expression were upregulated with 3.6 g of ω-3 PUFA. Conclusions A moderate dose of FO alters the gene expression profile of adipose tissue to a more antiinflammatory status. Higher doses of FO have a favorable effect on lipid profile and lead to the upregulation of adipokines gene expression suggesting a different dose response to ω-3 PUFA administration in patients with CKD.

Objectives Osteocalcin, a small peptide secreted by osteoblasts, has been recently described as a circulating hormone involved in the regulation of energy metabolism. In addition, experimental data suggest a regulation of adipocytes by bone, with a stimulation of adiponectin synthesis by osteocalcin and an inverse relationship between serum adiponectin level and bone mineral density (BMD). However, this relationship has not been explored during chronic kidney disease (CKD). Methods Osteocalcin, adiponectin and leptin were prospectively measured in a cohort of 61 CKD patients. A new non-invasive 3D bone imaging technique was performed (high-resolution peripheral quantitative computed tomography, HR-pQCT), measuring volumetric BMD (vBMD) and microarchitecture parameters at the distal tibia. Results Patients' mean age was 67.2 +/- 13.9 years and mean GFR 33 +/- 12 mL/min/1.73 m(2). We found a positive association between serum osteocalcin and adiponectin (r = 0.29, P = 0.021). Univariate analysis showed inverse correlations between serum adiponectin and total vBMD (r = -0.33, P = 0.01), cortical thickness (r = -0.34, P = 0.008) and trabecular vBMD (r = -0.27, P = 0.04). These associations remained significant in multivariate analysis between serum adiponectin and total vBMD, cortical vBMD and cortical thickness. Conclusion We report for the first time an inverse relationship between bone density and adiponectin, as well as a positive association between osteocalcin and adiponectin in CKD II-IV patients.

Compounds involved in the regulation of appetite and body composition appear to be of interest in chronic kidney disease. The purpose of this study was to analyze plasma obestatin and acyl and des-acyl ghrelin in patients on hemodialysis (HD).Fifty patients on HD (56.0% women, mean age 62.2 ± 15.2 y) were studied. Blood samples were collected during fasting, before a regular HD session. Serum acyl and des-acyl ghrelin levels, leptin, and obestatin were measured using enzyme immunometric assay methods. Anthropometric parameters, appetite score, and food intake were recorded.Patients showed elevated serum leptin (34.1 ± 30 ng/mL), normal acyl ghrelin (137 ± 116.5 pg/mL), high des-acyl ghrelin (670 ± 479 pg/mL), and low obestatin (2.0 ± 1.4 ng/mL) levels compared with healthy volunteers. According to body mass index (BMI), patients with a BMI23 kg/m(2) had significantly lower plasma obestatin. In contrast, leptin levels were increased and acyl ghrelin tended to be higher in these patients. There was a strong positive correlation between obestatin and des-acyl ghrelin (r = 0.56, P = 0.0001) and inverse correlations between obestatin and BMI (r = -0.40, P = 0.007), waist circumference (r = -0.38, P = 0.024), and C-reactive protein (r = -0.29, P = 0.048). By multivariate analysis, obestatin was independently and positively correlated with des-acyl ghrelin (P = 0.01), but not with C-reactive protein, BMI, or waist circumference.In summary, patients on HD exhibited increased plasma levels of des-acyl ghrelin, normal acyl ghrelin levels, and low obestatin levels. In lean patients, the obestatin and des-acyl ghrelin levels were increased, suggesting that these hormones may influence appetite and body composition in patients on HD.

The present authors investigated whether cystic fibrosis is linked to a defect in fatty acids and assessed the impact of the main patients' characteristics on the levels of several fatty acids, mostly during respiratory exacerbation and after antibiotic therapy. Fatty acid phospholipid and cholesteryl ester levels were measured in stable-state patients and controls. No differences were found concerning either the fractions of palmitic and oleic acids or the cholesteryl esters of alpha-linolenic and arachidonic acids. However, phospholipids of alpha-linolenic and arachidonic acids, as well as cholesteryl esters and phospholipids of stearic and linoleic acids, were lower in patients than in controls, but fractions of dihomo-gamma-linolenic, docosatetraenoic, docosapentaenoic, palmitoleic and eicosatrienoic acids were higher. Fatty acid levels, oxidative stress markers, nutrients, body mass index and forced expiratory volume in one second (FEV(1)) were measured in patients before and after antibiotic courses for bronchial exacerbation. After adjustments, palmitic, stearic, alpha-linolenic, linoleic, arachidonic, palmitoleic and oleic acids generally decreased during exacerbation but almost all increased after antibiotic courses. Nearly all fractions increased along with FEV(1) and a positive relationship linked fatty acids to lipid hydroperoxides. There was no general drop in fatty acids. Patients' fatty acid profiles depended on the pulmonary function and the inflammation state.

Objectives The aim of DIAMUCO study is to describe the natural history of the glucose tolerance (GT) and to identify predictive factors of the changes in GT in cystic fibrosis (CF) patients for a three-year period. Methods We used a cross-sectional study design and included a total of 228 patients, 111 children (between 10 and 18 years) and 117 adults between 2009 and 2011. All patients had an annual screening. Patients were classified as having normal glucose tolerance (NGT), impaired glucose tolerance (IGT), or CF-related diabetes mellitus (CFRD) using the 2-h oral glucose tolerance test (OGTT). Results At baseline, 67.1% (n = 153) patients were classified as NGT, 25.4% (n = 58) as IGT and 7.4% (n = 17) as CFRD. Over half of patients changed at least once of glucose tolerance status during follow-up. The mean decline of FEV1 was 1.54 per year without difference between female and male. A decrease in FEV1 (p TableClinical characteristicsTotalCFRDIGTNTpAge20.1±8.124.3±9.319.3±7.420.0±8.20.1FEV172.4±24.165.0±22.173.8±23.972.6±24.50.4Weight z-score0.5±1.5−0.70±1.24−0.79±1.18−0.37±1.50.1 Conclusion We confirm the variability of glucose tolerance status over time. The impact of glucose tolerance status on respiratory deterioration seems to concern only patients with permanently CFRD status. The early treatment decision must therefore be careful.

CS+IS therapy (21.5% vs. 12.5%; p

Objectif Une elevation de TSH a ete rapportee dans la population obese. Cette etude a pour objectif de determiner les liens statistiques potentiels entre la masse grasse, la leptine et le niveau de TSH. Patients et methodes Huit cents sujets consecutifs hospitalises pour un bilan d’obesite (incluant une mesure de la TSH) ont ete inclus. L’IMC et la leptinemie ont ete utilises comme reflet de l’exces d’adiposite. Une analyse statistique univariee puis multivariee a ete realisee pour identifier les parametres influencant le niveau de TSH. Resultats Nous confirmons la correlation lineaire positive entre IMC et TSH (rho = 0,085). Cette correlation est encore plus marquee entre leptine et TSH (rho = 0,146). Apres ajustement sur les facteurs de confusion dont l’IMC, la leptine reste positivement correlee a la TSH. Dans le quartile de patients avec la TSH la plus haute, l’IMC moyen est plus eleve de meme que le taux de leptine en comparaison au quartile de patients avec la TSH la plus basse. Discussion Nous rapportons chez le sujet obese un lien statistique entre le taux plasmatique de TSH et de leptine independamment de l’IMC. La litterature existante apporte des arguments en faveur d’une regulation fonctionnelle reciproque entre le tissu adipeux et l’axe thyreotrope. Le niveau de leptine qui depend a la fois de la masse de tissu adipeux et de l’etat de la balance energetique pourrait moduler la fonction thyroidienne du sujet obese pour augmenter la depense energetique et limiter la prise de poids. Declaration d’interet Les auteurs declarent ne pas avoir d’interet direct ou indirect (financier ou en nature) avec un organisme prive, industriel ou commercial en relation avec le sujet presente.

Despite its high efficacy on CML, long-term exposure to nilotinib, a second generation tyrosine kinase inhibitor (TKI2), has been reported to increase the onset of arterial cardiovascular events (CVE) in chronic phase (CP) CML patients (pts), especially in pts with cardiovascular risk factors. However, some pts without any cardiovascular risk factors may experience arterial thrombotic events and the pathogenesis of this phenomenon remains obscure. Homocystein (HC) is a key sulphured amino-acid derived from methionin, independently associated with increased frequencies of thrombo-embolic events, early arteriosclerosis and increased cardiovascular mortality (Nygard NEJM 1997). In addition, in vitro, this amino-acid induces the proliferation of smooth muscle cells, endothelial cell dysfunction, increased collagen synthesis and exerts pro-inflammatory rearrangements within the arterial wall. In the present study, we wanted to determine if hyperhomocysteinemia might influence the onset of cardio-vascular events in a series of 114 CP CML pts on nilotinib. We have prospectively analysed in a multicentric study, on-nilotinib cohorts of CP CML pts between September 2011 and July 2014 with standard clinical assessments [height, weight, body mass index (BMI)], onset of any CV events, and basic routine blood metabolic laboratory assessments (fasting glucose, total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides, glycosylated haemoglobin, homocysteinemia (Biorad kit on HLPC on Summit Dionex system, Thermo Fischer scientific, France), vitamines B9 and B12. All the 114 pts were in CP-CML on nilotinib [43 as first-line, 71 as second-line or more, since a median of 51.5 (3-164) months], 49 were males, with a median age of 51.7 (18-81) at CML diagnosis and 58 (82-20) at nilotinib initiation. Twenty-eight (24.5%) pts presented some CV risk factors prior to nilotinib initiation, and 24 (21%) had an active tobacco abuse at assessment (4 patients unknown). Median weight was 69 (44-149) kg and median BMI was 24.5 (16.5-46) kg/m2 (8 patients >30). Overall, 21 (18.5) pts presented new or worsened pre-existing CVE on nilotinib after a median follow-up of 51.5 months since TKI2 initiation. These CVE occurred after a median of 47 (7.5-82.3) months with a regular increase along the years (Cumulative incidence (CI) 3% at 1 year, 4.12% at 2, 5.15% at 3, 9.30 at 5 and 20.62% at 8.3 years). In total, 3 pts died, 2 from brain stroke, 1 from sudden death in a pt with a history of myocardial infarction. In an univariate analysis we compared our cohort of nilotinib pts to a similar cohort of 17 pts on imatinib as control [median age 56 years since CML diagnosis (p=ns), median duration of imatinib 39 months (p=ns), median weight 70.5 kg (p=ns), BMI 25.9 kg/m2 (p=ns)]. None of these imatinib pts had shown any CVE during follow-up. HC was significantly lower in imatinib-treated pts (p=0.029), in female pts (p=0.018) and increased with age (p Figure 1 Cumulative incidence of CVE on nilotinib according to the level of HC. Figure 1. Cumulative incidence of CVE on nilotinib according to the level of HC. The CI of CVE was significantly higher in pts on nilotinib 800 mg daily (38% at latest follow-up) versus pts on ≤600 mg daily, (10%, p=0.005, Gray test). Finally multivariate analysis identified age [p In conclusion, nilotinib seems to favour CVE in the long-term in CP CML pts, especially in patients with CV risk factors, and these CVE are specifically linked to higher doses of nilotinib and high levels of homocysteinemia. This marker could represent a useful tool to detect pts at risk of arterial CVE on nilotinib. Whether hyperhomocysteinemia is one of the causes of CVE of a consequence of nilotinib treatment remains to be determined. Disclosures Michallet: Genzyme: Consultancy; Oseus: Consultancy; BMS: lectures, lectures Other; Novartis: lectures, lectures Other; MSD: lectures Other. Etienne:Novartis: Consultancy; BMS: lectures, lectures Other. Nicolini:Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria.

Introduction et but de l’etude Il a ete precedemment rapporte une elevation moderee de la TSH dans la population obese1. L’objectif de cette etude etait de determiner le lien entre l’elevation de la TSH et l’augmentation de la masse grasse chez les sujets obeses. Materiel et methodes 800 sujets consecutifs hospitalises pour un bilan d’obesite ont ete inclus. L’IMC, la leptinemie et l’insuline-mie ont ete utilises comme reflet de l’exces d’adiposite. D’autres parametres incluant notamment le taux de cholesterol et de tricgly-cerides, l’HbA1c et la CRP ont egalement ete etudies. Une analyse statistique univariee puis multivariee a ete realisee pour identifier les parametres influencant le niveau de TSH. Resultats et Analyse statistique Nous confirmons la correlation lineaire positive entre l’IMC et le taux de TSH (rho =0,085). Cette correlation est encore plus marquee entre les taux de leptine et de TSH (rho =0,146). Nous ne notons par contre pas de correlation entre le taux de TSH et le taux de triglycerides, de cholesterol, d’insuline, d’HbA1c et de CRP. Apres ajustement sur les facteurs de confusion dont l’IMC, la leptine reste positivement correlee a la TSH. Dans le quartile de patients avec la TSH la plus haute, l’IMC moyen est plus eleve de meme que le taux de leptine en comparaison au quartile de patients avec la TSH la plus basse. Conclusion Nous rapportons chez le sujet obese un lien statistique entre le taux plasmatique de TSH et de leptine independamment de l’IMC. La litterature existante apporte des arguments en faveur d’une regulation fonctionnelle reciproque entre le tissu adipeux et l’axe thyreotrope. Le niveau de leptine qui depend a la fois de la masse de tissu adipeux et de l’etat de la balance energetique pourrait moduler la fonction thyroidienne du sujet obese pour augmenter la depense energetique et limiter la prise de poids.

Serum lacticodehydrogenase (LDH) is commonly increased in patients with haematopoietic malignancies and has been shown to be a prognostic factor in patients with non-Hodgkin's lymphoma (NHL) and myeloma. We have examined the LDH isoenzyme content in serum of 326 patients, including 252 patients with NHL (202 at diagnosis and 50 at relapse), 28 patients with Hodgkin's disease, 17 patients with CLL, 16 patients with myeloproliferative syndromes and 13 patients with multiple myeloma. Among these, 160 pts (49%) had increased serum LDH. The analysis of LDH isoenzyme profiles in all patients showed increased percentages of isoenzyme 2 in patients with NHL, CLL and myeloproliferative syndromes, but not in samples from patients with myeloma or Hodgkin's disease. Isoenzyme alterations were then analyzed for their prognostic value in patients with NHL. In univariate analyses, increased isoenzyme 2 percentages, increased isoenzyme 3 values, total serum LDH, performance status, stage and tumour aggressiveness were prognostic variables for survival. In a multivariate analysis increased LDH isoenzyme 3 values, high isoenzyme 2 percentages and the performance status, but not total serum LDH, were independent prognostic factor for survival. High isoenzyme 3 values were predictive of early death in NHL patients. In patients with relapsing NHL, the overall survival was 12 months in patients with normal isoenzyme 3 but only 2 months in patients with increased isoenzyme 3 values. We conclude that there are characteristic alterations in serum LDH profiles in patients with haematopoietic malignancies and that some of these may be more interesting in terms of prognostic value than total serum LDH.

FREE RADICALS AND THE THEORY OF AGING: Severe oxidative stress progressively leads to cell dysfunction and ultimately cell death. Oxidative stress is defined as an imbalance between pro-oxidants and/or free radicals on the one hand, and anti-oxidizing systems on the other. The oxygen required for living may indirectly be responsible for negative effects; these deleterious effects are due to the production of free radicals, which are toxic for the cells (superoxide anions, hydroxyl radicals, peroxyl radicals, hydrogen peroxide, hydroperoxides and peroxinitrite anions). Free radical attacks are responsible for cell damage and the targeted cells are represented by the cell membranes, which are particularly rich in unsaturated fatty acids, sensitive to oxidation reactions; DNA is also the target of severe attacks by these reactive oxygen species (ROS).These are represented by the enzymes and free radical captors. The latter are readily oxidizable composites. The free radical captor or neutralization systems of these ROS use a collection of mechanisms, vitamins (E and C), enzymes [superoxide dismutase (SOD), glutathion peroxidase (GPx) and others], and glutathion reductase (GSH), capable of neutralizing peroxinitrite. The efficacy of this system is dependent on the genome for the enzymatic defence systems, and on nutrition for the vitamins. Some strategies aimed at reducing oxidative stress-related alterations have been performed in animals. However, only a few can be used and are efficient in humans, such as avoidance of unfavourable environmental conditions (radiation, dietary carcinogens, smoking...) and antioxidant dietary supplementation.Epidemiological data suggest that antioxidants may have a beneficial effect on many age-related diseases: atherosclerosis, cancer, some neurodegenerative and ocular diseases. However, the widespread use of supplements is hampered by several factors: the lack of prospective and controlled studies; insufficient knowledge on the pro-oxidant, oxidant and ant-oxidant properties of the various supplements; growing evidence that free radicals are not only by-products, but also play an important role in cell signal transduction, apoptosis and infection control.Although current data indicate that antioxidants cannot prolong maximal life span, the beneficial impact of antioxidants on various age-related degenerative diseases may forecast an improvement in life span and enhance quality of life. The current lack of sufficient data does not permit the systematic recommendation of anti-oxidants. Nevertheless, antioxidant-rich diets with fruit and vegetables should be recommended.

Objectif Suite aux recommandations du groupe international IADPSG, le diabete gestationnel se depiste desormais par une glycemie anormale a jeun et/ou une ou deux heures apres une charge orale de 75 g de glucose entre 24 et 32 SA. Nous avons cherche a determiner l’heterogeneite des femmes depistees par cette methode. Patients et methodes Dans le cadre d’une etude prospective regionale en cours, 140 femmes avec un diabete gestationnel suivant les normes IADPSG ont ete recrutees sur 12 mois pour l’elaboration d’un index predictif de diabete 2 (etude IMAGE), dont 71 avec une anomalie de la glycemie a jeun (IFG) parfois isolee (n = 16), et 69 avec une intolerance au glucose mais avec une glycemie a jeun normale (IGT). Toutes ont beneficie d’une etude des adipocytokines et des marqueurs du stress oxydant. Resultats Lors d’une analyse preliminaire chez 50 % de l’effectif, les femmes du groupe IFG avaient une augmentation significative de l’IMC initial (28,6[20,7–43,4] vs 25.3 [17,4–39,8], p Conclusion Le diabete gestationnel est une entite frequente, mais dont le depistage actuel aboutit a des profils heterogenes, avec des femmes presentant un syndrome metabolique avec insulinoresistance et d’autres femmes avec plutot une carence en insuline. Les resultats preliminaires de l’etude IMAGE identifie la glycemie a jeun en fin de gestation comme un element pejoratif associe avec l’insulinoresistance, le stress oxydatif et l’inflammation. Des analyses prospectives permettront de determiner les meilleurs facteurs predictifs de diabete de type 2.

Introduction Il est actuellement decrit de nombreux roles extra-osseux de la vitamine D. Elle pourrait notamment etre impliquee dans la physiopathologie du diabete de type 2. L’obesite, facteur de risque majeur d’insulinoresistance, est egalement associee a des deficits en vitamine D parfois tres severes. Cette etude a pour but d’etudier les liens entre statut vitaminique D et insulinoresistance chez le sujet obese. Patients et methodes Il s’agit d’une etude observationnelle retrospective portant sur 943 patients avec un IMC median de 38,9 kg/m2. L’insulinoresistance est evaluee par le HOMA-IR. L’exposition de la population aux UVB est egalement prise en compte. Les liens entre 25 (OH) D, IMC, exposition theorique aux UVB et insulinoresistance ont ete etudies en analyses categorielles et lineaires. Resultats L’IMC (r = − 0,38, p Le niveau d’insulinoresistance est inversement correle a l’exposition theorique aux UVB de la population. Il existe une relation lineaire inverse entre 25 (OH) D et insulinoresistance et cette relation est independante des parametres anthropometriques (IMC, leptine) et du niveau d’exposition aux UVB. Discussion Ces resultats, mis en perspectives avec les donnees physiopathologiques de la litterature retrouvant une action moleculaire de la vitamine D sur les voies de signalisation insulinique, nous permettent d’evoquer un role direct du deficit en vitamine D dans l’insulinoresistance des sujets obeses faisant de cette vitamine l’un des mediateurs potentiels des variations saisonnieres de l’insulinoresistance. Ainsi, le deficit en vitamine D est en theorie une cause reversible d’insulinoresistance chez le sujet obese. Une etude prospective d’intervention visant a evaluer l’efficacite d’une supplementation vitaminique D dans le traitement de l’insulinoresistance du sujet obese est en preparation.

Rationnel L’inflammation a bas bruit est aujourd’hui reconnue comme une caracteristique metabolique majeure en situation d’obesite qui augmente les risques d’insulinoresistance et de maladies cardiovasculaires. Parmi les facteurs possibles declenchant et entretenant cette inflammation, la litterature recente et nos travaux ont revele le role de l’absorption des lipopolysaccharides (LPS, aussi appeles endotoxines) du microbiote intestinal durant la digestion des lipides alimentaires. Nous avons recemment montre chez l’animal que la resultante inflammatoire d’un regime hyperlipidique est aussi etroitement associee aux types de transporteurs et recepteurs plasmatiques des LPS : LBP, sCD14. Patients et methodes Dans nos recentes etudes chez l’homme, des volontaires sains de poids normal (20 Resultats En aigu, l’augmentation des apports en lipides est associee a une augmentation de l’endotoxemie circulante aussi bien chez les sujets de poids normal que chez les obeses. Le profil associe en LBP et sCD14 differe entre normoponderes et obeses. Suite a une augmentation chronique des apports en lipides, l’augmentation d’inflammation metabolique est associee aux modifications d’endotoxemie a jeun et en periode postprandiale. Conclusion Nos resultats montrent ainsi que l’augmentation des apports en lipides contribue a l’inflammation metabolique par des voies impliquant les endotoxines et leurs recepteurs.

Introduction Les deficiences en micronutriments ont ete associees au surpoids et aux caracteristiques du syndrome metabolique (Smet). Notre objectif est d’etudier 1) si ces associations sont expliquees par un effet du statut vitaminique sur les concentrations plasmatiques de leptine et d’adiponectine, independamment du poids et 2) les interactions potentielles avec l’activite physique (AP) a l’adolescence. Materiels et methodes L’indice de masse corporelle (IMC), le tour de taille (T), la masse grasse mesuree par impedancemetrie (MG), l’AP de loisir, les concentrations plasmatiques de vitamines anti-oxydantes (C, E et beta-carotene), les cytokines (leptine, adiponectine) et les caracteristiques du Smet (indice HOMA, insulinemie, lipides, CRP-US et IL6) ont ete obtenus chez 246 adolescents (âge : 15 ± 0,5 ans) de l’etude ICAPS (Intervention Centree sur l’Activite Physique et la Sedentarite). Des modeles lineaires mixtes ont ete utilises. Resultats Apres ajustements multiples y compris sur l’AP, des taux faibles de vitamine C, mais pas de vitamine E, sont associes a un IMC plus eleve. Independamment de l’IMC et de la MG, les vitamines C et E sont inversement associees a l’indice HOMA (p Conclusion Ces resultats suggerent que, conjointement avec l’AP, une deficience en vitamine anti-oxydante est susceptible d’affecter le metabolisme de la leptine et contribuer aux caracteristiques du Smet liees au surpoids. Ces resultats viennent a l’appui des recommandations en faveur de la consommation d’aliments riches en anti-oxydants et de la pratique d’une activite physique reguliere, des l’adolescence.

International audience; BACKGROUND: Chylomicron retention disease (CMRD), a rare genetic hypocholesterolemia, results in neuro-ophtalmologic damages, which can be prevented by high doses of vitamin E during infancy. In these patients, plasma vitamin E concentration is significantly reduced due to defects of chylomicron secretion. Vitamin E in adipose tissue (AT) and red blood cells (RBC) have been proposed as potential relevant biomarkers of vitamin E status but no reference values in children are available. The objectives were (i) to establish age-reference intervals in healthy children for alpha-tocopherol in plasma, red blood cells (RBC) and adipose tissue (AT) and (ii) to determine the variations of alpha-tocopherol in patients with CMRD after oral treatment with vitamin E. METHODS: This prospective study included 166 healthy children (1 month - 18 years) and 4 patients with CMRD. Blood and AT were collected in healthy children during a scheduled surgery and in patients before and after a 4-month treatment with alpha-tocopherol acetate. RESULTS: The reference ranges for alpha-tocopherol were 11.9 - 30 mumol/L in plasma, 2.0 - 7.8 mumol/L packed cells in RBC and 60 - 573 nmol/g in AT. alpha-tocopherol levels in plasma correlated with those of RBC (r = 0.31; p \textless 0.01). In patients with CMRD after 4 months treatment, alpha-tocopherol concentrations remained less than 70 % of the control values in plasma, increased by 180 % to reach normal values in RBC, and remained stable in the normal range in AT. CONCLUSION: This study establishes pediatric reference intervals for alpha-tocopherol in plasma, RBC and AT. These values will be beneficial in assessing accurate alpha-tocopherol status in children and to optimize the monitoring of rare diseases such as CMRD. Our data suggest that RBC alpha-tocopherol, appears as a relevant biomarker to appreciate the effectiveness of treatment with alpha-tocopherol in patients with a rare primary hypocholesterolemia. The biopsy of AT could be used at diagnosis to assess the severity of the vitamin E deficiency and periodically after a long duration of vitamin E therapy to assess whether the treatment is effective, based on reference intervals defined in this study.

International audience; Background Postprandial hyperlipemia and altered dietary lipid beta-oxidation are now recognized as metabolic risk factors in obesity that are directly associated with dietary fat intake. The amount and size of chylomicrons are known to impact their clearance and thus possibly modulate the final partitioning of dietary fatty acids (FA) between β-oxidation and storage, which is altered in obesity. However, the detailed impact of ingested fat amount on postprandial lipemia and dietary FA fate in obese subjects remains to be elucidated. Methods In a randomized crossover study, eighteen healthy normal-weight (NW) and obese men ingested meals containing 10g or 40g of fat (typical breakfast fat contents) labeled with a mix of 13C-triglyceride tracers. Chylomicron triglyceride content and size were measured during 8h of digestion. Plasma concentrations of 13C-palmitate and 13C-oleate were also measured during 8h in parallel with their fecal loss (72h-stool collection). 13CO2 breath-test coupled to indirect calorimetry measures during 8h allowed to calculate exogenous lipid fate. Results Chylomicron triglycerides increased in all subjects according to ingested fat amount (P

International audience; Purpose: Hyperglycaemia is an adaptive response to stress commonly observed in critical illness. Its management remains debated in the intensive care unit (ICU). Individualising hyperglycaemia management, by targeting the patient's pre-admission usual glycaemia, could improve outcome.Methods: In a multicentre, randomized, double-blind, parallel-group study, critically-ill adults were considered for inclusion. Patients underwent until ICU discharge either individualised glucose control by targeting the pre-admission usual glycaemia using the glycated haemoglobin A1c level at ICU admission (IC group), or conventional glucose control by maintaining glycaemia below 180 mg/dL (CC group). A non-commercial web application of a dynamic sliding-scale insulin protocol gave to nurses all instructions for glucose control in both groups. The primary outcome was death within 90 days.Results: Owing to a low likelihood of benefit and evidence of the possibility of harm related to hypoglycaemia, the study was stopped early. 2075 patients were randomized; 1917 received the intervention, 942 in the IC group and 975 in the CC group. Although both groups showed significant differences in terms of glycaemic control, survival probability at 90-day was not significantly different (IC group: 67.2%, 95% CI [64.2%; 70.3%]; CC group: 69.6%, 95% CI [66.7%; 72.5%]). Severe hypoglycaemia (below 40 mg/dL) occurred in 3.9% of patients in the IC group and in 2.5% of patients in the CC group (p = 0.09). A post hoc analysis showed for non-diabetic patients a higher risk of 90-day mortality in the IC group compared to the CC group (HR 1.3, 95% CI [1.05; 1.59], p = 0.018).Conclusion: Targeting an ICU patient's pre-admission usual glycaemia using a dynamic sliding-scale insulin protocol did not demonstrate a survival benefit compared to maintaining glycaemia below 180 mg/dL.