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Sterol response element binding protein (SREBP) is a key transcription factor in insulin and glucose metabolism. We previously demonstrated that elevated levels of membrane sphingomyelin (SM) were related to peroxisome proliferator-activated receptor-γ (PPARγ), which is a known target gene of SREBP-1 in adipocytes. However, the role of SM in SREBP expression in adipocytes remains unknown. In human abdominal adipose tissue from obese women with various concentrations of fasting plasma insulin, SREBP-1 proteins decreased in parallel with increases in membrane SM levels. An inverse correlation was found between the membrane SM content and the levels of SREBP-1c/ERK/Ras/PPARγ/CREB proteins. For the first time, we demonstrate the effects of SM and its signaling pathway in 3T3-F442A adipocytes. These cells were enriched or unenriched with SM in a range of concentrations similar to those observed in obese subjects by adding exogenous natural SMs (having different acyl chain lengths) or by inhibiting neutral sphingomyelinase. SM accumulated in caveolae of the plasma membrane within 24 h and then in the intracellular space. SM enrichment decreased SREBP-1 through the inhibition of extracellular signal-regulated protein kinase (ERK) but not JNK or p38 mitogen-activated protein kinase (MAPK). Ras/Raf-1/MEK1/2 and KSR proteins, which are upstream mediators of ERK, were down-regulated, whereas SREBP-2/caveolin and cholesterol were up-regulated. In SM-unmodulated adipocytes treated with DL-1-Phenyl-2-Palmitoylamino-3-morpholino-1-propanol (PPMP), where the ceramide level increased, the expression levels of SREBPs and ERK were modulated in an opposite direction relative to the SM-enriched cells. SM inhibited the insulin-induced expression of SREBP-1. Rosiglitazone, which is an anti-diabetic agent and potent activator of PPARγ, reversed the effects of SM on SREBP-1, PPARγ and CREB. Taken together, these findings provide novel insights indicating that excess membrane SM might be critical for regulating SREBPs in adipocytes via a MAPK-dependent pathway.

Metabolic syndrome is a major risk factor for the development of diabetes mellitus and cardiovascular diseases. Pharmacological antagonism of the mineralocorticoid receptor (MR), a ligand-activated transcription factor, limits metabolic syndrome in preclinical models, but mechanistic studies are lacking to delineate the role of MR activation in adipose tissue. In this study, we report that MR expression is increased in visceral adipose tissue in a preclinical mouse model of metabolic syndrome and in obese patients. In vivo conditional upregulation of MR in mouse adipocytes led to increased weight and fat mass, insulin resistance, and metabolic syndrome features without affecting blood pressure. We identified prostaglandin D2 synthase as a novel MR target gene in adipocytes and AT56, a specific inhibitor of prostaglandin D2 synthase enzymatic activity, blunted adipogenic aldosterone effects. Moreover, translational studies showed that expression of MR and prostaglandin D2 synthase is strongly correlated in adipose tissues from obese patients., (© 2015 American Heart Association, Inc.)

Context: In spite of the existence of clinical guidelines and a legal framework in France, the withdrawal of artificial nutrition (AN) in palliative care remains a difficult situation for caregivers who are confronted with this reality., Objectives: To describe the perception of caregivers on the withdrawal of AN and to compare this perception between caregivers who have already been confronted with this situation and those who have not., Methods: Cross-sectional survey questionnaire of nurses and nurses' aides (n = 274) working in medicine, surgery, and palliative care departments of a regional hospital., Results: Of the caregivers, 59.5% declared having been confronted with the withdrawal of AN in their professional practice. This was associated with a better perception by these caregivers even if their knowledge on the criteria to be considered in the decision was not significantly modified., Conclusion: The coherence of the withdrawal of AN with the personal beliefs of the caregivers, already high in the absence of being confronted with this practice, is better among caregivers who have been confronted with this situation. The lack of information perceived by caregivers should prompt us to develop additional training on the withdrawal of AN, its objectives, and its clinical consequences., (© The Author(s) 2014.)

Background: Sleeve gastrectomy is a bariatric surgical procedure that may result in particular morbidity or mortality due to gastric fistula in the proximal part of the gastric tube. Two theories are currently proposed to explain this specific leak location. The vascular theory attributes the leaks to reduced perfusion in the gastric tube, and the mechanical theory suggests the etiology as gastric tube hyper-pressure due to pyloric conservation. The aim of this study was to map the arterial gastric vascular supply on fresh cadavers after performing sleeve gastrectomy to evaluate the effect of vascular changes on gastric leakage., Methods: We performed sleeve gastrectomies on 11 cadaveric trunks with a detailed anatomical study of the gastric vascular supply after latex injection in the three branches arising from the celiac trunk., Results: In 55 % of cases, the sleeve procedure changed the gastric vascular supply. In 9.1 %, it divided the three left gastric artery branches arising from the lesser curvature. Few changes were noted in the antrum or pylorus., Conclusions: This anatomical study demonstrates that the vascular supply of the proximal part of the gastric tube can be damaged by a sleeve procedure, which can sever one or more of the branches arising from the left gastric artery. Such weakness could be exacerbated by disparities in vascular supply. The uninterrupted vascular supply of the antrum and pylorus may explain the preferential localization of the fistula to the proximal part of the gastric tube.

Background: Enteral tube feeding can be a source of discomfort and reluctance from patients. We evaluated for the first time the tolerability of self-insertion of a nasogastric (NG) tube for home enteral nutrition (EN)., Materials and Methods: All patients requiring enteral tube feeding for chronic diseases were enrolled in a therapeutic patient education (TPE) program at Nancy University Hospital., Results: In our department, between November 2008 and August 2012, 66 patients received EN with an NG tube. Twenty-nine of 66 had self-insertion of the NG tube (median age, 44 years), 17 had an anatomical contraindication, and 20 were excluded because of cognitive disability or language barrier or refusal. Twenty-eight of 29 patients completed the TPE program. One patient died of pancreatic cancer in palliative care during the study. Median follow-up was 20 months (interquartile range [IQR], 4-31). Median gain weight was 3.1 kg (IQR, 1.8-6.0) (P = .0002). Median duration of self-insertion of the NG tube was 3 months (IQR, 2-5), and it was well tolerated by all 29 patients. Two patients described minor adverse events: abdominal pain and nausea for 1 patient and epistaxis leading to temporary discontinuation of EN for another patient. A group of 10 consecutive patients previously had a long-term NG tube for EN. If they had the choice between a self-inserted NG tube and a long-term NG tube, all 10 patients reported they would prefer to start again with the self-inserted NG tube., Conclusion: This pilot study suggests that self-insertion of an NG tube may be efficacious and well tolerated in patients receiving EN for chronic conditions., (© 2013 American Society for Parenteral and Enteral Nutrition.)

Background: Laparoscopic Roux-en-Y gastric bypass is one of the most commonly performed bariatric operation worldwide for the surgical management of obesity. Totally robotic Roux-en-Y gastric bypass (TR-RYGBP) has been considered to be a better approach by some groups especially early in a surgeon's experience. However, the learning curve associated with TR-RYGBP has been poorly evaluated yet. The aim of this study was to evaluate the learning curve of patients who underwent TR-RYGBP., Methods: This is a prospective study of 154 first consecutive patients undergoing TR-RYGBP to analyze the influence of surgeon experience, bedside first assistant, and patient factors on operative time and postoperative complications. To give a comprehensive view of success related to the learning process, a single hybrid variable was generated. Multivariate analysis predicted the risk factors for complications and operative time. A risk-adjusted cumulative sum analysis estimated the learning curve., Results: The learning curve for TR-RYGBP was 84 cases. Case rank and first assistant level were independent predictors of total operative time. Overall 30-day postoperative morbidity rate was 33.1 % and decreased over time. Surgeon experience (OR 2.6; CI 95 [1.290 to 5.479]; p = 0.0081) and first assistant level (OR 2.42; CI 95 [1.197 to 4.895]; p = 0.0139) remained independent predictors of composite event (operative time and complications)., Conclusions: This study identifed criteria that should be assessed in future studies about TR-RYGBP. Both surgeon experience and bedside first assistant level affected operative duration, but surgeon experience was the most significant factor in reducing complication rates.

Background: We investigated dietary beliefs and behavior in a large population of adult inflammatory bowel disease (IBD) patients and evaluated their impact on patients' social life., Methods: A questionnaire of 14 items was administered to all consecutive IBD patients followed at the Nancy University Hospital Department of Gastroenterology from February to July 2011., Results: A total of 244 patients participated in the survey; 15.6% (n = 38) of patients believed that diet could initiate the disease, while 57.8% (n = 141) believed that food can play a role in causing a relapse. Forty percent (107/244) of patients identified food as a risk factor for relapse. Seventy-three percent of respondents reported having already received nutritional advice. The majority of respondents (47.5%, n = 116) reported that the disease had changed the pleasure of eating. Only one-quarter of patients had a normal diet in case of relapse. Almost two out of three patients (66.8%, n = 163) reported not eating certain foods they usually like to eat in order to prevent a relapse. Dietary beliefs and behavior had an impact on their social life for one-fifth of patients. Excluding food was associated with refusing outdoor dining for fear of causing relapse (P = 0.006) and not sharing the same menu as the other members of the family living under the same roof (P = 0.002)., Conclusions: The majority of IBD patients are avoiding certain foods. Dietary beliefs and behavior have a strong impact on their social life.

Autotaxin (ATX) is a lysophospholipase D involved in synthesis of a bioactive mediator: lysophosphatidic. ATX is abundantly produced by adipocytes and exerts a negative action on adipose tissue expansion. In both mice and humans, ATX expression increases with obesity in association with insulin resistance. In the present study, fat depot-specific regulation of ATX was explored in human. ATX mRNA expression was quantified in visceral and subcutaneous adipose tissue in obese (BMI > 40 kg/m(2); n = 27) and non-obese patients (BMI < 25 kg/m(2); n = 10). Whatever the weight status of the patients is, ATX expression was always higher (1.3- to 6-fold) in subcutaneous than in visceral fat. Nevertheless, visceral fat ATX was significantly higher (42 %) in obese than in non-obese patients, whereas subcutaneous fat ATX remained unchanged. In obese patients, visceral fat ATX expression was positively correlated with diastolic arterial blood pressure (r = 0.67; P = 0.001). This correlation was not observed with subcutaneous fat ATX. Visceral fat ATX was mainly correlated with leptin (r = 0.60; P = 0.001), inducible nitric oxide synthase (r = 0.58; P = 0,007), and apelin receptor (r = 0.50; P = 0.007). These correlations were not observed with subcutaneous fat ATX. These results reveal that obesity-associated upregulation of human adipose tissue ATX is specific to the visceral fat depot.

The aspartic protease cathepsin-D (cath-D) is overexpressed by human epithelial breast cancer cells and is closely correlated with poor prognosis in breast cancer. The adipocyte is one of the most prominent cell types in the tumor-microenvironment of breast cancer, and clinical studies have shown that obesity increases the incidence of breast cancer. Here, we provide the first evidence that cath-D expression is up-regulated in adipose tissue from obese human beings, as well as in adipocytes from the obese C57BI6/J mouse. Cath-D expression is also increased during human and mouse adipocyte differentiation. We show that cath-D silencing in 3T3-F442A murine preadipocytes leads to lipid-depleted cells after adipogenesis induction, and inhibits of the expression of PPARγ, HSL and aP2 adipocyte differentiation markers. Altogether, our findings demonstrate the key role of cath-D in the control of adipogenesis, and suggest that cath-D may be a novel target in obesity.

General practitioners are placed in an ideal position to manage obesity. First, they have to consider the motivation of the obese patient to change his habits. When the patient is not motivated to loss weight, their role is to identify and treat co-morbidities, to evaluate the risk related to the obesity and to establish a therapeutic diagnosis to evaluate motivation and ability to change. If the patient is motivated, the therapeutic choices have to be adapted individually to each patient. An inadequate management may not only result in a failure but may increase obesity. The objectives in obesity treatment are to achieve weight loss in order to reduce health risk as far as possible, to maintain that weight loss, to restore quality of life. Goals and methods must be realistic. Even a modest weight loss (5-10 % of initial weight) will improve health indices in an obese patient. Dietary treatment and physical activity are fundamental to the management of obesity. Compliance with the diet is the major problem, especially during the phase of weight maintenance after the excess weight loss has been lost. Initial weight reduction depends on the level of energy deficit and weight maintenance on compliance to a low fat diet and a physical activity programme. Cognitive behavioural approaches should be an integral part of the management of a chronic disease. This treatment is very useful to improve body image, self-esteem, management of stress and control of disordered eating patterns. A psychotherapeutic approach is often necessary, especially when the obesity is psycho-determined. Obesity drugs should be used for carefully selected patients, as an adjunct to diet therapy and lifestyle modifications, under medical supervision., (Copyright © 2010 Elsevier Masson SAS. All rights reserved.)

The cell surface low-density lipoprotein receptor-related protein 1, LRP1, plays a major role in lipid metabolism. The question that remains open concerns the function of LRP1 in adipogenesis. Here, we show that LRP1 is highly expressed in murine preadipocytes as well as in primary culture of human adipocytes. Moreover, LRP1 remains abundantly synthesised during mouse and human adipocyte differentiation. We demonstrate that LRP1 silencing in 3T3F442A murine preadipocytes significantly inhibits the expression of PPARgamma, HSL and aP2 adipocyte differentiation markers after adipogenesis induction, and leads to lipid-depleted cells. We further show that the absence of lipids in LRP1-silenced preadipocytes is not caused by lipolysis induction. In addition, we provide the first evidences that LRP1 is significantly up-regulated in obese C57BI6/J mouse adipocytes and obese human adipose tissues. Interestingly, silencing of LRP1 in fully-differentiated adipocytes also reduces cellular lipid level and is associated with an increase of basal lipolysis. However, the ability of mature adipocytes to induce lipolysis is independent of LRP1 expression. Altogether, our findings highlight the dual role of LRP1 in the control of adipogenesis and lipid homeostasis, and suggest that LRP1 may be an important therapeutic target in obesity.

Obese patients have high plasma leptin concentrations that do not induce the expected responses on weight regulation, suggesting a leptin resistance in obesity. Elevated leptin levels are also thought to be related to a high sympathetic nervous system (SNS) activity. This effect could be preserved, lowered, or even abolished in obesity. We planned to investigate the possible association in a longitudinal study. Ninety-five normotensive healthy women, aged 40.4 +/- 11.4 years and body mass index of 33.2 +/- 2.3 kg/m(2), were studied. Baseline leptin, fat mass, and heart rate variability were measured and included in a 6-month longitudinal study. Body composition was measured by dual-energy x-ray absorption. Time domain heart rate variability, QT dynamicity, and spectral components on ambulatory electrocardiographs were analyzed. Dietary advice was given by a dietitian to the patient (maximum caloric reduction of 30%), and subjects were randomized in 3 treatment groups: sibutramine 10 mg, sibutramine 20 mg, or placebo. At baseline, low frequencies (LF) and the LF-high frequencies (HF) ratio, mainly related to the SNS, were negatively correlated to leptin concentration (r = -0.30, P = .002 and r = -0.36, P < .001) and to the leptin-fat mass ratio (r = -0.28, P = .004 and r = - 0.33, P = .0007), thus explaining 38% of the LF variance and 33% of the LF/HF variance. Diastolic blood pressure was also negatively correlated to leptin concentrations (-0.20, P = .04) and to the leptin-fat mass ratio (-0.22, P = .022). In contrast, no consistent correlations between leptin and the time domain components related to vagal activity were observed. At 6 months, after completion of the weight loss program, LF significantly decreased (-7.7% +/- 7.9%, P < .001), whereas HF was higher than the initial value (+20% +/- 5.2%). The leptin-fat mass ratio remained negatively correlated to the LF (r = -0.34, P = .030) and to LF/HF (r = -0.35, P = .021) values, explaining 21% of the LF variation. None of the pairwise comparisons between the 2 sibutramine groups and the placebo group were statistically significant for heart rate variability. High leptin concentration is associated with low indexes of cardiac SNS activity and with a lower diastolic blood pressure in normotensive obese women. Our results imply therefore that the relationship between leptin and the autonomic nervous system is disturbed in normotensive obese subjects.

We have recently identified apelin as a novel adipokine up-regulated by insulin and obesity. Since obesity and insulin resistance are associated with chronically elevated levels of both insulin and TNFalpha, the present study was performed to investigate a putative regulation of apelin expression in adipocytes by TNFalpha. Herein, we report a tight correlation between apelin and TNFalpha expression in adipose tissue of lean and obese humans. Apelin regulation by TNFalpha was further studied in cultured explants of human adipose tissue. The endogenous expression of TNFalpha in adipocytes isolated from the explants was accompanied by a 6-9 h subsequent increase of apelin expression in adipocytes. This increase was reversed by inhibiting TNFalpha expression with 100 microM isobutylmethylxanthine. In different mouse models of obesity, expression of both TNFalpha and apelin was also significantly increased in adipocytes of obese mice. Furthermore, short-term exposure to an i.p. injection of TNFalpha in C57Bl6/J mice induced an increase of apelin expression in adipose tissue as well as apelin plasma levels. Finally, a direct positive effect of TNFalpha has been shown in differentiated 3T3F442A adipocytes on apelin expression and secretion. The signaling pathways of TNFalpha for the induction of apelin were dependent of PI3-kinase, c-Jun NH2-terminal kinase (JNK), and MAPK but not PKC activation. All together, these findings suggest that apelin might be a candidate to better understand potential links between obesity and associated disorders such as inflammation and insulin resistance.

Objective: This study was undertaken to further analyze the response of the cardiovascular autonomic nervous system (ANS) to changes in plasma insulin concentration induced by an oral glucose load. We hypothesized that, as a consequence of insulin resistance, an inability of insulin to increase the sympathetic modulation of heart rate (HR) and blood pressure (BP) would be observed in normotensive obese patients., Methods: We used spectral analysis to measure simultaneously the short-term variability of HR and BP in 23 never-obese subjects and in 70 normotensive overweight or obese patients subdivided into 3 subgroups: (1) overweight group (body mass index [BMI], 25-29.9 kg/m 2 ), n = 23; (2) class I-II obese group (BMI, 30-39.9 kg/m 2 ), n = 23; (3) class III obese group (BMI, > or =40 kg/m 2 ), n = 23., Results: Oral glucose ingestion and the related increased insulinemia caused significant changes in the indices of sympathetic modulation (low-frequency [LF] power and LF/high-frequency ratio) of both HR and BP in normal weight, overweight, and obese subjects. However, the LF increments gradually decreased with the BMI classes, suggesting that sympathetic nervous system modulation in these subjects may be insulin-resistant., Conclusion: Obesity could develop resistance to the sympatho-excitatory effects of insulin that might play a role in the etiology of obesity. Spectral analysis of BP and HR can be used in research to evaluate the reactivity of the sympathetic nervous system in a manner that represents another feature of the obesity/insulin-resistance syndrome.

Background: Patients with chronic pancreatitis (CP) are at high risk of antioxidant deficiencies. Furthermore, this disease can lead to diabetes mellitus (DM) that could exacerbate the severity of oxidative stress. Oxidative stress and the resulting LDL oxidation are a major cause of atherosclerosis., Objective: The objective of the study was to ascertain whether diabetes significantly modifies oxidative status in patients with CP., Design: CP patients with or without DM were compared with type 1 DM patients and healthy control subjects., Results: Two-way factorial analyses showed that a decrease in the plasma concentrations of vitamin A, vitamin E, and carotenoids accompanied both CP and DM, and CP was also associated with lower plasma concentrations of selenium and zinc, lower catalase activity, and higher plasma concentrations of copper. The lag phase of LDL oxidation was lower in CP patients with or without DM than in the control subjects, whereas there was no significant difference between type 1 DM patients and control subjects. Multivariate analysis showed that LDL vitamin E (R2 = 0.24, P < 0.0001) and fasting plasma glucose (R2 = 0.32, P < 0.0001) concentrations were the main determinants of the lag phase of LDL oxidation., Conclusions: Antioxidant status is altered in CP patients, particularly in those who also have DM. In these patients, a vitamin E deficiency and an elevated plasma glucose concentration were associated with significantly higher LDL oxidizability.

Obesity is known to predispose to obstructive sleep apnea (OSA), a condition characterized by repeated episodes of apnea or hypopnea during sleep, due to the interruption of airflow through the nose and mouth. These episodes lead to the fragmentation of sleep and to decrease in oxyhaemoglobin saturation. Patients with massive obesity, with or without daytime hypersomnolence should be systematically screened for OSA, because many of them appear to be asymptomatic and unaware of their breathing abnormalities during sleep. Polysomnography (PSG) in an attended hospital laboratory setting is the gold standard for the diagnosis of OSA. However portable recording devices can be used for screening with good sensibility and specificity, and even for diagnosis when the apnea-hypopnea index is high. However the final diagnosis can only be carried out in a sleep laboratory using PSG by highly-qualified personnel, because of the limitations of the portable recording device. There is a strong association between OSA and the risk of traffic accidents. It has been established that OSA affects quality of life. There is also increasing evidence that OSA is an independent risk factor for cardio-vascular diseases. This has been successfully demonstrated for hypertension by prospective studies. But the evidence remains weak for myocardial infarction, stroke or mortality. Treating OSA with continuous positive airway pressure (CPAP) is the treatment of choice. CPAP improves quality of life, driving simulator performance, blood pressure and sleepiness, as demonstrated by randomised placebo controlled trials. The majority of obese OSA patients are currently not being offered diagnosis testing and treatment. It's a real challenge due to the epidemic increase of obesity prevalence. Portable recording devices could be available outside the sleep laboratory in nutrition department, where morbid obesity is treated. This emphasizes the need for a real collaboration between these departments and sleep experts.

The complex mechanisms by which obesity predisposes to insulin resistance are not clearly understood. According to a cell membrane hypothesis of insulin resistance, the defects in insulin action could be related to changes in membrane properties. The purpose of this work was to examine the relationship between 2 markers of insulin resistance (fasting plasma insulin [FPI] and homeostasis model assessment [HOMA IR]) and erythrocyte membrane lipid composition. In the first cross-sectional study, 24 premenopausal nondiabetic overweight women (body mass index [BMI], 32.5 +/- 0.9 kg/m(2); age, 35.7 +/- 2.2 years) were compared to 21 lean healthy women (BMI, 21 +/- 0.4 kg/m(2); age, 35.4 +/- 2.2 years). The second study examined whether a 3-month diet-induced weight loss, which usually improves insulin resistance, could also affect the membrane phospholipid (PL) composition and fluidity in the overweight group. Overweight women had significantly higher FPI levels (P <.0001), HOMA IR (P <.0001), membrane sphingomyelin (SM) (P <.05), and cholesterol (P <.05) contents than lean women. Baseline FPI and HOMA IR were positively correlated with membrane SM (P <.005), phosphatidylethanolamine (PE) (P <.005), and phosphatidylcholine (PC) (P <.05) contents, and negatively with phosphatidylinositol (PI) (P <.05) contents in the whole population. Multivariate regression analyses showed that 2 membrane parameters, PE and SM, were among the independent predictors of FPI or HOMA IR in the whole population, but also in the lean and the obese groups separately. Intervention induced a significant reduction in body weight (-5.7% +/- 0.7%), fat mass (-11.3% +/- 1.4%), and FPI (-10.2% +/- 5.4%). An improvement in membrane lipid composition was only observed in the insulin resistant subgroup (FPI > 9.55 mU/L). The reduction in FPI or HOMA IR was directly associated with reduction in SM and PE contents, a finding independent of the reduction in fat mass. A stepwise multiple regression analysis indicated that the changes in SM accounted for 26.6% of the variance in the changes in FPI as an independent predictor, with the changes in fat mass and PE as other determinants (27.8% and 20%, respectively, adjusted r(2) =.704, P <.0001). These results suggest that the abnormalities in the membrane PL composition could be included in the unfavorable lipid constellation of obesity which correlated with impaired insulin sensitivity., (Copyright 2002, Elsevier Science (USA). All rights reserved.)

The metabolism of apolipoprotein (apo) A-IV in diabetes mellitus (DM) is poorly understood. Several factors, such as dietary fat intake, fat malabsorption, acute inflammation, and hormonal dysregulation can disturb the plasma apo A-IV concentration. We have compared the plasma apo A-IV concentrations in patients with type 1 DM and DM secondary to chronic pancreatitis to determine the effects of combinations of these factors. We examined 4 groups of male patients with chronic pancreatitis without diabetes (ND-CP) (n = 12), diabetes secondary to chronic pancreatitis and insulin-treated (CP-DM) (n = 32), type 1 diabetes (n = 25), and controls (n = 20). Plasma apo A-IV was significantly lower in the chronic pancreatitis patients (ND-CP and CP-DM) than in the other patients. Inflammatory proteins (fibrinogen, ceruloplasmin, and haptoglobin) were significantly elevated in the 2 chronic pancreatitis groups. The apo A-IV concentration was positively correlated with hemoglobin A(1c) (HbA(1c)) percentage in each group of diabetic patients (CP-DM, r =.35; P =.046; type 1 DM, r =.53; P =.010), in both groups of diabetic patients (r =.472; P <.0001) and negatively correlated with ceruloplasmin concentration in each group of diabetic patients (CP-DM, r = -.48; P =.0052; type 1 DM, r = -.66; P =.003), in both groups of diabetic patients (r = -.561; P <.0001), and in the whole population (r = -.463; P <.0001). Apo A-IV was also negatively correlated with haptoglobin in type 1 DM patients (r = -.434; P =.0435), in the both groups of diabetic patients (r = -.349; P =.0154), and in the whole population (r = -.351; P =.0019). Multiple linear regression analysis revealed that only HbA(1c) and ceruloplasmin were independent explanatory variables. Plasma apo A-IV is positively correlated with HbA(1c) suggesting that hyperglycemia per se selectively affects apo A-IV metabolism. The correlation between the concentrations of inflammatory protein and apo A-IV suggest a link between chronic inflammation and apo A-IV synthesis or catabolism. As apo A-IV is involved in reverse cholesterol transport, its low level in CP-DM may contribute to the accelerated development of atherosclerosis in these patients., (Copyright 2001 by W.B. Saunders Company)

The effects of physiological dietary phytosterol supplements on intestinal microflora activity and faecal sterols and their capacity to protect rats fed a normal or high saturated fatty-acid diet against tumour development were studied. A group of 80 female Wistar rats were fed an 8% lipid diet for 4 weeks (adaptation period) and then randomly assigned in a factorial experimental design study to diets containing 8% or 24% hydrogenated coconut oil, with or without a 24-mg/day/rat phytosterol supplement. They were instilled intrarectally with saline or methyl-nitroso-urea (MNU). Faecal sterol output was analysed for one week each month. Pathological analysis was done at the end of the 30-week experiment. Animals treated with MNU and given phytosterol supplements had tumour frequencies (8/20) similar to those not fed phytosterols (11/20). The fat-supplemented diet had no significant influence. Colonic glands were found in area of lymphoid follicles in all the groups, but were more frequent in rats on high-fat diets (P < 0.01). The coprostanol and the cholesterol excretion of the phytosterol-supplemented rats was significantly enhanced. Therefore phytosterols have an unfavourable effect on bacterial activity. These data confirm the capacity of phytosterols to decrease cholesterol absorption, but indicate that a large excess of phytosterol must be avoided until further research on its effects on carcinogenesis has been done.

Obesity and visceral or upper body fat distribution, have a major impact on insulin sensitivity. There is strong evidence to suggest that free fatty acids (FFA) contribute to the pathogenesis of insulin resistance and the metabolic syndrome. Increased FFA release from adipose tissue or failure of FFA using tissues to remove them normally, lead to increased triglycerides (TG) and FFA fluxes. Increased delivery of FFA to muscle reduces muscle glucose uptake and utilisation by substrate competition or direct inhibition of glucose transport. Insulin resistance has been correlated with the size of intramuscular TG store. Intracellular TG have been involved in beta cell failure the so called lipotoxicity phenomena. The rate of FFA to the liver is a major determinant of hepatic TG secretion. So the regulation of FFA distribution between FFA using tissues and the partition of FFA between storage and oxidation could be involved in the developpment of insulin resistance. The dietary macronutrients could play a role in nutrient partitioning but their role in the etiology of insulin resistance is poorly understood due to a paucity of credible intervention studies in humans. However deleterious effects of saturated fatty acids on insulin action and the beneficial effects of polyunsaturated fatty acids (PUFAs) could be suspected from animal studies, and from epidemiological or clinical studies in humans. A very high intake of sucrose or fructose could be deleterious but low glycemic index foods, and fibers could have protective effects. Weight loss can induce marked improvement in insulin resistance, but weight maintenance is also required to keep long term good metabolic results.

The objectives of this study were to investigate cardiac and peripheral autonomic nervous system changes in normotensive overweight or obese subjects and the possible relation between these changes and insulin resistance independent of age. The authors used spectral analysis to measure simultaneously the short-term variability of heart rate (HR) and blood pressure (BP) using a Finapres device, in 67 normotensive overweight or obese patients (age 37 +/- 12 y, body mass index [BMI] = 37 +/- 9 kg/m2) and 45 never-obese subjects (controls; age 41 +/- 13 y, BMI 22 +/- 2 kg/m2). The spectral density was determined in three situations: subjects in the supine position, spontaneously breathing; subjects in the supine with controlled breathing; and subjects standing. The insulin sensitivity of overweight and obese subjects was determined from homeostatic model assessment (HOMA). The variability of normalized low-frequency (LF) spectral analysis of both HR and BP was lower in overweight or obese subjects than in controls, in the supine and standing positions (p <0.01). Normalized LF spectral analysis was negatively correlated to BMI independent of age, whatever the position. Homeostatic model assessment values were negatively correlated to the normalized LF spectral of HR, systolic BP and diastolic BP, in the standing position independent of BMI and age (p <0.05). Normalized high frequency (HF) of HR during controlled breathing decreased with age but not with BMI. In normotensive overweight or obese subjects, changes in sympathetic nervous system modulation are strongly correlated to insulin resistance. Decreased HR and BP variability could partly account for the higher cardiovascular risk and incidence of sudden death in obese persons.

The importance of accurate methods for homocysteine measurement has been emphasized. We compared the results obtained with the most commonly used high-performance liquid chromatography (HPLC) assay, and two recently commercially available methods: another HPLC and a fluorescence polarization immunoassay, in plasmas from normo- or hyperhomocysteinemic patients. A significant agreement between the different methods in classifying the results as hyper or normal-homocysteinemia was observed. However, a significant difference between the results was found. Standardization is urgently necessary to improve the concordance of homocysteine determination.

Energy balance and macronutrient balance are the cornerstones upon which any theories of obesity must be built. Obesity can only occur when energy intake remains higher than energy expenditure for an extended period of time. However the macronutrient composition of the diet can also affect energy balance. Fat is a key nutrient because it is poorly regulated at both the level of consumption and oxidation. Psychological and behavioural profiles of obese subjects are clearly important because they can affect food choice and eating patterns. The role of eating frequency and circadian distribution of food is still debated. Eating disorders could be implicated in the development of obesity, but it is uncertain whether obesity is a direct result or a cause of the eating disorder. There are strong evidence to suggest that dietary restraint is associated with loss of dietary control and excessive eating. Early stages of fat storage involve expansion of existing adipocytes (hypertrophy) and later stages involve the recruitment of new adipocytes (hyperplasia). The mechanisms controlling the transformation of preadipocyte could also involve specific dietary components such as polyunsaturated fatty acids or proteins. The age of adiposity rebound, that is a risk factor for later obesity has been found significantly younger in children consuming a high protein diet. These factors could be involved during early infancy or even in utero, according to the hypothesis of fetal programming of adult diseases. There is a need for more longitudinal studies on the role of macronutrient composition, food choice or eating disorders, especially among children, teenagers and young adults.

We have studied the effect of common mutations (677C-->T and 1298A-->C) of the methylenetetrahydrofolate reductase (MTHFR) gene in sixty-six healthy French subjects, aged 27-47 years. Serum folate, vitamin B12, and plasma total homocysteine were measured as well as the specific activity of MTHFR in lymphocytes. The frequency of subjects homozygous for the 677TT genotype was 18%, and that of those homozygous for the 1298CC genotype was 12.5%. The frequency of individuals heterozygous for both mutations was 23.5%. The 1298A-->C mutation was associated with decreased MTHFR specific activity in subjects with both 677CC and 677CT genotypes. This activity was 60% for the 677CC/1298AC genotype and 52% for the 677CC/1298CC genotype when compared with the MTHFR specific activity of the 677CC/1298AA genotype. Heterozygotes for both mutations (677CT/1298AC genotype) had 36% of the reference specific activity. Although homocysteine levels in 677TT and 1298CC genotype subjects were higher than for other genotypes, no significant differences were observed among different genotypes. This may be due to high serum folate level in our samples, and suggests that folate therapy may be useful to prevent hyperhomocysteinaemia in homozygous mutant subjects.

Drug therapy of obesity (DTO) has not been extensively used in diabetic patients so far, although excessive adipose mass largely contributes to insulin resistance which characterizes this disease together with insulin secretion failure. Orlistat is the sole currently available treatment, but several other new treatments are under investigation, such as sibutramine already marketed in other countries. Both drugs were found to be efficient in long term studies (1 year). However it is puzzling to note that weight loss induced by the drug as well as during placebo treatment is less pronounced in diabetic patients as compared with non diabetic subjects. Short term studies had already documented a lower response to DTO in diabetic patients by 2-fold. The reasons for this weight loss resistance in diabetics under DTO remain unclear and could be linked with metabolism. A weight loss > or = 5% initial body weight is required to obtain a significant lowering of HbA1c. Weight variations (weight delta > or = 5-10% initial weight) and results on glucose control (HbA1c delta > or = 0.5% after 3 to 6 months, or fasting blood glucose delta > or = 1 mmol/l within a few weeks) allow to define good DTO responders which should preferentially be eligible for this treatment. A decisional diagram is suggested.

Objective: This study was done to evaluate a new test for fat malabsorption caused by chronic pancreatitis. Postprandial plasma apolipoprotein B-48 was measured as an indicator of the intestinal assimilation of exogenous lipid., Methods: Twenty-three patients with chronic pancreatitis, including 19 insulin-treated diabetic patients, were compared with 14 healthy subjects and seven type-1 diabetic patients. Each was given a test meal containing 40 g lipid; the triglyceride apolipoprotein B-48 concentrations in chylomicrons were determined 240 min later., Results: The postprandial chylomicron apolipoprotein B-48 concentrations in the three groups were statistically different at 240 min: pancreatitis versus controls, p < 0.01, and pancreatitis versus type-1 diabetes subjects, p < 0.01. The delta plasma apo B-48, the change in apolipoprotein B-48 between 0 and 240 min, was significantly smaller in chronic pancreatitis patients than in controls (p < 0.001) and type-1 diabetes subjects (p < 0.001). The sensitivity of the test was better than 89% for a delta apo B-48 threshold value of 0.42 mg/dl., Conclusions: This new indirect test is relatively simple to use and could be practical for evaluating exogenous lipid malabsorption due to chronic pancreatitis.

This study was done to determine whether a high dietary calcium carbonate concentration could protect against colon tumors in rats. Female Wistar rats were randomly assigned to one of four groups and maintained on an 8% lipid diet for an adaptation period of four weeks. All groups were then fed a 24% lipid diet (sunflower oil), with (Groups 2 and 4) or without (Groups 1 and 3) a 1.5% calcium carbonate supplement. They were intrarectally instilled with saline (Groups 1 and 2) or nitrosomethylurea (NMU) (Groups 3 and 4). Fecal sterol output and pH were analyzed for one week each month. Histological analysis was done at the end of the 32-week experiment. No tumors were found in the non-NMU-treated animals. The NMU-treated rats had tumors: 31% in Group 3 and 30% in Group 4. The calcium carbonate supplement had no effect on this incidence. The lipid and cholesterol excretions of the calcium carbonate-supplemented rats were significantly enhanced. The coprostanol output was not altered, although its fecal concentration of the calcium-supplemented rats was decreased. Although neither lipid overload nor NMU treatment altered the fecal pH, it was significantly increased in both calcium carbonate-supplemented groups. These findings suggest that additional calcium as carbonate has no effect on colon tumor incidence, although the fecal composition is altered. The increased pH of the feces due to the carbonate could have the opposite effect to calcium.