Dietary inflammatory potential and arterial stiffness in a French cohort: Insights from the STANISLAS study.

BACKGROUND AND AIMS: Chronic inflammation plays a key role in arterial stiffness pathogenesis. Dietary components can display anti- or pro-inflammatory properties. Nonetheless, the association between the diet's overall inflammatory potential and arterial stiffness is unclear. This study aimed to assess the association between the diet's overall inflammatory potential and arterial stiffness assessed by carotid-femoral pulse wave velocity (cfPWV). METHODS AND RESULTS: This cross-sectional study included 1307 participants from the STANISLAS family cohort study. Dietary data were collected using a validated food frequency questionnaire. The adapted dietary inflammatory index (ADII) score was calculated to assess the inflammatory potential of the participants' diet. The association of ADII score quartile with cfPWV was assessed using IPW-weighted linear mixed models with random family effect. The median (Q1-Q3) ADII score was 0.45 (-1.57, 2.04). Participants exhibiting higher ADII scores demonstrated elevated energy intake, dietary saturated fat, and ultra-processed foods. Conversely, individuals with lower ADII scores exhibited higher vitamins and omega intakes, and a higher diet quality, as assessed by the DASH score. Despite these observations from the descriptive analyses, ADII score quartiles were not significantly associated with cfPWV (ß(95% CI) were 0.01 (-0.02,0.04) for Q2, 0.02 (-0.01,0.05) for Q3, and 0.02 (-0.01,0.05) for Q4 compared to Q1). CONCLUSION: In this cross-sectional study, participants had a relatively modest consumption of pro-inflammatory foods, no substantial associations were observed between the diet inflammatory potential and arterial stiffness. Further longitudinal studies in larger cohorts are needed to better understand the link between inflammatory diet and arterial stiffness.

Metabolic signature of 13C-labeled wheat bran consumption related to gut fermentation in humans: a pilot study.

PURPOSE: The aim of this pilot study was to analyze concomitantly the kinetics of production of 13C-labeled gut-derived metabolites from 13C-labeled wheat bran in three biological matrices (breath, plasma, stools), in order to assess differential fermentation profiles among subjects. METHODS: Six healthy women consumed a controlled breakfast containing 13C-labeled wheat bran biscuits. H2, CH4 and 13CO2, 13CH4 24 h-concentrations in breath were measured, respectively, by gas chromatography (GC) and GC-isotope ratio mass spectrometry (GC-IRMS). Plasma and fecal concentrations of 13C-short-chain fatty acids (linear SCFAs: acetate, propionate, butyrate, valerate; branched SCFAs: isobutyrate, isovalerate) were quantified using GC-combustion-IRMS. Gut microbiota composition was assessed by16S rRNA gene sequencing analysis. RESULTS: H2 and CH4 24 h-kinetics distinguished two groups in terms of fermentation-related gas excretion: high-CH4 producers vs low-CH4 producers (fasting concentrations: 45.3 ± 13.6 ppm vs 6.5 ± 3.6 ppm). Expired 13CH4 was enhanced and prolonged in high-CH4 producers compared to low-CH4 producers. The proportion of plasma and stool 13C-butyrate tended to be higher in low-CH4 producers, and inversely for 13C-acetate. Plasma branched SCFAs revealed different kinetics of apparition compared to linear SCFAs. CONCLUSION: This pilot study allowed to consider novel procedures for the development of biomarkers revealing dietary fiber-gut microbiota interactions. The non-invasive assessment of exhaled gas following 13C-labeled fibers ingestion enabled to decipher distinct fermentation profiles: high-CH4 producers vs low-CH4 producers. The isotope labeling permits a specific in vivo characterisation of the dietary fiber impact consumption on microbiota metabolite production. CLINICAL TRIAL REGISTRATION: The study has been registered under the number NCT03717311 at ClinicalTrials.gov on October 24, 2018.

Prebiotic dietary fibre intervention improves fecal markers related to inflammation in obese patients: results from the Food4Gut randomized placebo-controlled trial.

PURPOSE: Inulin-type fructans (ITF) are prebiotic dietary fibre (DF) that may confer beneficial health effects, by interacting with the gut microbiota. We have tested the hypothesis that a dietary intervention promoting inulin intake versus placebo influences fecal microbial-derived metabolites and markers related to gut integrity and inflammation in obese patients. METHODS: Microbiota (16S rRNA sequencing), long- and short-chain fatty acids (LCFA, SCFA), bile acids, zonulin, and calprotectin were analyzed in fecal samples obtained from obese patients included in a randomized, placebo-controlled trial. Participants received either 16 g/d native inulin (prebiotic n = 12) versus maltodextrin (placebo n = 12), coupled to dietary advice to consume inulin-rich versus inulin-poor vegetables for 3 months, in addition to dietary caloric restriction. RESULTS: Both placebo and prebiotic interventions lowered energy and protein intake. A substantial increase in Bifidobacterium was detected after ITF treatment (q = 0.049) supporting our recent data obtained in a larger cohort. Interestingly, fecal calprotectin, a marker of gut inflammation, was reduced upon ITF treatment. Both prebiotic and placebo interventions increased the ratio of tauro-conjugated/free bile acids in feces. Prebiotic treatment did not significantly modify fecal SCFA content but it increased fecal rumenic acid, a conjugated linoleic acid (cis-9, trans-11 CLA) with immunomodulatory properties, that correlated notably to the expansion of Bifidobacterium (p = 0.031; r = 0.052). CONCLUSIONS: Our study demonstrates that ITF-prebiotic intake during 3 months decreases a fecal marker of intestinal inflammation in obese patients. Our data point to a potential contribution of microbial lipid-derived metabolites in gastro-intestinal dysfunction related to obesity. CLINICALTRIALS. GOV IDENTIFIER: NCT03852069 (February 22, 2019 retrospectively, registered).

Starch digestibility modulation significantly improves glycemic variability in type 2 diabetic subjects: A pilot study.

BACKGROUND AND AIMS: In type 2 diabetes (T2D) patients, the reduction of glycemic variability and postprandial glucose excursions is essential to limit diabetes complications, beyond HbA1c level. This study aimed at determining whether increasing the content of Slowly Digestible Starch (SDS) in T2D patients' diet could reduce postprandial hyperglycemia and glycemic variability compared with a conventional low-SDS diet. METHODS AND RESULTS: For this randomized cross-over pilot study, 8 subjects with T2D consumed a controlled diet for one week, containing starchy products high or low in SDS. Glycemic variability parameters were evaluated using a Continuous Glucose Monitoring System. Glycemic variability was significantly lower during High-SDS diet compared to Low-SDS diet for MAGE (Mean Amplitude of Glycemic Excursions, p < 0.01), SD (Standard Deviation, p < 0.05), and CV (Coefficient of Variation, p < 0.01). The TIR (Time In Range) [140-180 mg/dL[ was significantly higher during High-SDS diet (p < 0.0001) whereas TIRs ≥180 mg/dL were significantly lower during High-SDS diet. Post-meals tAUC (total Area Under the Curve) were significantly lower during High-SDS diet. CONCLUSION: One week of High-SDS Diet in T2D patients significantly improves glycemic variability and reduces postprandial glycemic excursions. Modulation of starch digestibility in the diet could be used as a simple nutritional tool in T2D patients to improve daily glycemic control. REGISTRATION NUMBER: in clinicaltrials.gov: NCT03289494.

Milk polar lipids reduce lipid cardiovascular risk factors in overweight postmenopausal women: towards a gut sphingomyelin-cholesterol interplay.

OBJECTIVE: To investigate whether milk polar lipids (PL) impact human intestinal lipid absorption, metabolism, microbiota and associated markers of cardiometabolic health. DESIGN: A double-blind, randomised controlled 4-week study involving 58 postmenopausal women was used to assess the chronic effects of milk PL consumption (0, 3 or 5 g-PL/day) on lipid metabolism and gut microbiota. The acute effects of milk PL on intestinal absorption and metabolism of cholesterol were assessed in a randomised controlled crossover study using tracers in ileostomy patients. RESULTS: Over 4 weeks, milk PL significantly reduced fasting and postprandial plasma concentrations of cholesterol and surrogate lipid markers of cardiovascular disease risk, including total/high-density lipoprotein-cholesterol and apolipoprotein (Apo)B/ApoA1 ratios. The highest PL dose preferentially induced a decreased number of intestine-derived chylomicron particles. Also, milk PL increased faecal loss of coprostanol, a gut-derived metabolite of cholesterol, but major bacterial populations and faecal short-chain fatty acids were not affected by milk PL, regardless of the dose. Acute ingestion of milk PL by ileostomy patients shows that milk PL decreased cholesterol absorption and increased cholesterol-ileal efflux, which can be explained by the observed co-excretion with milk sphingomyelin in the gut. CONCLUSION: The present data demonstrate for the first time in humans that milk PL can improve the cardiometabolic health by decreasing several lipid cardiovascular markers, notably through a reduced intestinal cholesterol absorption involving specific interactions in the gut, without disturbing the major bacterial phyla of gut microbiota. TRIAL REGISTRATION NUMBER: NCT02099032 and NCT02146339; Results.

Seven-day overfeeding enhances adipose tissue dietary fatty acid storage and decreases myocardial and skeletal muscle dietary fatty acid partitioning in healthy subjects.

Increased myocardial partitioning of dietary fatty acids (DFA) and decreased left ventricular (LV) function is associated with insulin resistance in prediabetes. We hypothesized that enhanced myocardial DFA partitioning and reduced LV function might be induced concomitantly with reduced insulin sensitivity upon a 7-day hypercaloric (+50% in caloric intake), high-saturated fat (~11%energy), and simple carbohydrates (~54%energy) diet (HIGHCAL) versus an isocaloric diet (ISOCAL) with a moderate amount of saturated fat (~8%energy) and carbohydrates (~50%energy). Thirteen healthy subjects (7 men/6 women) underwent HIGHCAL versus ISOCAL in a randomized crossover design, with organ-specific DFA partitioning and LV function measured using the oral 14(R,S)-[18F]fluoro-6-thia-heptadecanoic acid and [11C]acetate positron emission tomography methods at the end of both interventions. HIGHCAL induced a decrease in insulin sensitivity indexes with no significant change in body composition. HIGHCAL led to increased subcutaneous abdominal (+4.2 ± 1.6%, P < 0.04) and thigh (+2.4 ± 1.2%, P < 0.08) adipose tissue storage and reduced cardiac (-0.31 ± 0.11 mean standard uptake value [(SUV), P < 0.03] and skeletal muscle (-0.17 ± 0.08 SUV, P < 0.05) DFA partitioning without change in LV function. We conclude that early increase in adipose tissue DFA storage protects the heart and skeletal muscles from potential deleterious effects of DFA.

Attentional bias and response inhibition in severe obesity with food disinhibition: a study of P300 and N200 event-related potential.

BACKGROUND/OBJECTIVE: In obesity there is growing evidence for common mechanism between food intake regulation and substance use disorders, especially more attentional bias and less cognitive control. In the present study we investigated whether severely obese subjects with or without disordered eating exhibit electroencephalographic (EEG) event-related potential (ERP) modifications as observed in substance abusers. SUBJECTS/METHODS: A total of 90 women were included; 30 in the normal-weight (NW) group (18.5 < BMI < 24.5 kg/m2; no food disinhibition or restriction on the Three-Factor Eating Questionnaire) and 60 participants with BMI ≥ 35 kg/m2 were separated into two groups (n = 30): without food disinhibition (disinhibition score ≤8; ObFD- group) and with food disinhibition (score >8; ObFD+). Clinical and metabolic parameters as well as compartmental aspects (Eating Disorders Inventory-2, EDI-2) were assessed. Participants underwent an ERP recording with an auditory oddball paradigm. RESULTS: The mean ± SD P300 amplitudes in Pz were significantly (p < 0.05) lower in ObFD- (12.4 ± 4.6) and ObFD+ (12.5 ± 4.4) groups than in the NW group (15.8 ± 5.9). The mean ± SD N200 amplitude in Cz was significantly lower in the ObFD- group (-2.0 ± 5.4) than in the NW group (-5.2 ± 4.2 vs; p = 0.035). N200 Cz amplitude was correlated with EDI-2 Binge eating risk score (ρ = 0.331; p = 0.01), EDI-2 Body Dissatisfaction score (ρ = 0.351; p = 0.007), and Drive for Thinness score (ρ = 0.26; p = 0.05). CONCLUSIONS: The present study provides evidence for reduction of P300 and N200 amplitude in obese women and that N200 amplitude may be related to more disordered eating and eating disorder risk. This leads to consider attentional bias and response inhibition as core mechanisms in obesity and as possible targets for new therapeutic strategy.

3D Chemical Shift-Encoded MRI for Volume and Composition Quantification of Abdominal Adipose Tissue During an Overfeeding Protocol in Healthy Volunteers.

BACKGROUND: Overweight and obesity are major worldwide health concerns characterized by an abnormal accumulation of fat in adipose tissue (AT) and liver. PURPOSE: To evaluate the volume and the fatty acid (FA) composition of the subcutaneous adipose tissue (SAT) and the visceral adipose tissue (VAT) and the fat content in the liver from 3D chemical-shift-encoded (CSE)-MRI acquisition, before and after a 31-day overfeeding protocol. STUDY TYPE: Prospective and longitudinal study. SUBJECTS: Twenty-one nonobese healthy male volunteers. FIELD STRENGTH/SEQUENCE: A 3D spoiled-gradient multiple echo sequence and STEAM sequence were performed at 3T. ASSESSMENT: AT volume was automatically segmented on CSE-MRI between L2 to L4 lumbar vertebrae and compared to the dual-energy X-ray absorptiometry (DEXA) measurement. CSE-MRI and MR spectroscopy (MRS) data were analyzed to assess the proton density fat fraction (PDFF) in the liver and the FA composition in SAT and VAT. Gas chromatography-mass spectrometry (GC-MS) analyses were performed on 13 SAT samples as a FA composition countermeasure. STATISTICAL TESTS: Paired t-test, Pearson's correlation coefficient, and Bland-Altman plots were used to compare measurements. RESULTS: SAT and VAT volumes significantly increased (P < 0.001). CSE-MRI and DEXA measurements were strongly correlated (r = 0.98, P < 0.001). PDFF significantly increased in the liver (+1.35, P = 0.002 for CSE-MRI, + 1.74, P = 0.002 for MRS). FA composition of SAT and VAT appeared to be consistent between localized-MRS and CSE-MRI (on whole segmented volume) measurements. A significant difference between SAT and VAT FA composition was found (P < 0.001 for CSE-MRI, P = 0.001 for MRS). MRS and CSE-MRI measurements of the FA composition were correlated with the GC-MS results (for ndb: rMRS/GC-MS = 0.83 P < 0.001, rCSE-MRI/GC-MS = 0.84, P = 0.001; for nmidb: rMRS/GC-MS = 0.74, P = 0.006, rCSE-MRI/GC-MS = 0.66, P = 0.020) DATA CONCLUSION: The follow-up of liver PDFF, volume, and FA composition of AT during an overfeeding diet was demonstrated through different methods. The CSE-MRI sequence associated with a dedicated postprocessing was found reliable for such quantification. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2019;49:1587-1599.

Comparison of MRI-derived vs. traditional estimations of fatty acid composition from MR spectroscopy signals.

INTRODUCTION: The composition of fatty acids in the body is gaining increasing interest, and can be followed up noninvasively by quantitative magnetic resonance spectroscopy (MRS). However, current MRS quantification methods have been shown to provide different quantitative results in terms of lipid signals, with possible varying outcomes for a given biological examination. Quantitative magnetic resonance imaging using multigradient echo sequence (MGE-MRI) has recently been added to MRS approaches. In contrast, these methods fit the undersampled magnetic resonance temporal signal with a simplified model function (expressing the triglyceride [TG] spectrum with only three TG parameters), specific implementations and prior knowledge. In this study, an adaptation of an MGE-MRI method to MRS lipid quantification is proposed. METHODS: Several versions of the method - with time data fully or undersampled, including or excluding the spectral peak T2 knowledge in the fitting - were compared theoretically and on Monte Carlo studies with a time-domain, peak-fitting approach. Robustness, repeatability and accuracy were also inspected on in vitro oil acquisitions and test-retest in vivo subcutaneous adipose tissue acquisitions, adding results from the reference LCModel method. RESULTS: On simulations, the proposed method provided TG parameter estimates with the smallest variability, but with a possible bias, which was mitigated by fitting on undersampled data and considering peak T2 values. For in vitro measurements, estimates for all approaches were correlated with theoretical values and the best concordance was found for the usual MRS method (LCModel and peak fitting). Limited in vivo test-retest variability was found (4.1% for PUFAindx, 0.6% for MUFAindx and 3.6% for SFAindx), as for LCModel (7.6% for PUFAindx, 7.8% for MUFAindx and 3.0% for SFAindx). CONCLUSION: This study shows that fitting the three TG parameters directly on MRS data is one valuable solution to circumvent the poor conditioning of the MRS quantification problem.

Physical activity, energy expenditure and sedentary parameters in overfeeding studies - a systematic review.

BACKGROUND: It has been proposed that compensations in physical activity, energy expenditure and sedentary parameters can occur as a result of overfeeding studies in order to maintain body weight; however, the evidence has not yet been systematically reviewed. METHODS: The current study systematically reviewed the literature on this subject to determine the common tools used in overfeeding studies and to explore whether overfeeding produces changes in physical activity, energy expenditure and sedentary parameters. Eight electronic databases were searched to identify experimental studies using keywords pertaining to overfeeding, exercise, physical activity and sedentariness. Articles included healthy adults (aged 18-64 years) participating in an overfeeding study that examined at least one parameter of sedentary, energy expenditure or physical activity. Of 123 full-text articles reviewed, 15 met the inclusion criteria. RESULTS: The common tools used in overfeeding studies were doubly labeled water (n = 6), room calorimeter (n = 4), accelerometer (n = 7), pedometer (n = 3), radar sensor (n = 4) and survey (n = 1). Parameters partaining to energy expenditure increased between 7 to 50% with different overfeeding duration. Physical activity parameters, such as number of steps and spontaneous activity, increased or decreased significantly in three studies, while five studies showed no significant change. Sedentary parameters were examined by only one study and its results were not significant after 3 days of overfeeding. Methodological issues existed concerning the small number of studies, disparities in sedentary and physical activity parameters and various definitions of free-living experimental conditions and physical activity limits. CONCLUSIONS: There is actually a use of many tools and a large variation of parameters for physical activity in overfeeding studies. Contradictory findings showed changes in physical activity parameters following overfeeding and limited findings support the absence of changes in sedentariness. While energy expenditure parameters are more numerous and all show an increase after an overfeeding period, further studies are required to confirm changes in physical activity and sedentary parameters.

EASL-EASD-EASO clinical practice guidelines for the management of non-alcoholic fatty liver disease in severely obese people: do they lead to over-referral?

AIMS/HYPOTHESIS: We aimed to assess the application of the recent European Association for the Study of the Liver (EASL)-European Association for the Study of Diabetes (EASD)-European Association for the Study of Obesity (EASO) clinical practice guidelines for the management of non-alcoholic fatty liver disease (NAFLD) in severely obese individuals in routine clinical practice. METHODS: We performed a single-centre retrospective observational study of 385 patients referred for severe obesity (BMI ≥ 35 kg/m2) to our Endocrinology, Diabetes and Nutrition department, between 1 November 2014 and 31 December 2015. The recent EASL-EASD-EASO clinical practice guidelines for the management of NAFLD were retrospectively applied to the cohort using, successively, the NAFLD fibrosis score (NFS) and a combination of the NFS and transient elastography (TE) measurement in a subgroup of individuals. RESULTS: We identified 313 (81.3%) individuals with NAFLD in the cohort. The application of the EASL-EASD-EASO guidelines using NFS would lead to referral to a specialist for up to 289 individuals (75.1%) in the cohort. The combination of NFS and TE measurement reclassified 28 (25%) individuals from the medium/high risk group to low risk and would lead to the referral of 261 (67.7%) individuals to a specialist. These proportions appear to be excessive given the expected prevalence of advanced fibrosis and non-alcoholic steatohepatitis (NASH) of around 10% and 30%, respectively, in the severely obese population. CONCLUSIONS/INTERPRETATION: This is the first study to assess the strategy proposed by the EASL-EASD-EASO clinical practice guidelines for the management of NAFLD in severely obese individuals. The retrospective application of the guidelines in a cohort representing the routine clinical practice in our department would lead to an excessive number of specialist referrals and would also lead to an unjustified increase in health costs. Biomarkers and specific strategy for the screening of NASH and advanced fibrosis in morbidly obese individuals are thus crucially needed and would help to improve the actual guidelines.

Emulsifying dietary fat modulates postprandial endotoxemia associated with chylomicronemia in obese men: a pilot randomized crossover study.

BACKGROUND: Postprandial hyperlipemia is recognized as a major cardio-metabolic risk factor, recently linked to the co-absorption of pro-inflammatory lipopolysaccharides with dietary lipids. This causes endotoxemia that is involved in the pathophysiology of obesity and insulin resistance, but to date the impact of food formulation is unknown. We tested a novel concept that endotoxin absorption can be modulated by fat emulsified structure in the meal, and potentially differently in obese vs. lean men. METHODS: In a randomized controlled crossover study, eight normal-weight and eight obese age-matched healthy men ingested two isocaloric, isolipidic breakfasts of identical composition including 40 g of milk fat that was emulsified or unemulsified. Plasma- and chylomicron-endotoxemia and chylomicron-triglycerides were measured during 8 h after breakfast ingestion. RESULTS: After emulsion consumption, parallel to an enhanced chylomicronemia, obese subjects presented an early and sharp increase in chylomicron-endotoxemia at 60 min (P time = 0.02), which was higher than (i) after spread fat in obese subjects (P < 0.05) and (ii) after both spread and emulsified fat in normal-weight subjects (P < 0.05). However in obese subjects, the iAUC of plasma endotoxemia over 8 h was lower after emulsion than after spread fat (P < 0.05) whereas in NW subjects such reduction of plasma LPS-iAUC was not observed (P = 0.67). CONCLUSION: This study provides initial evidence that optimizing fat structure in the meal can be part of a dietary strategy to lower the metabolic impact of postprandial endotoxemia in obese men. TRIAL REGISTRATION: Registered at ClinicalTrials.gov # NCT01249378 on July 13, 2010.

PIK3R1 mutations cause syndromic insulin resistance with lipoatrophy.

Short stature, hyperextensibility of joints and/or inguinal hernia, ocular depression, Rieger anomaly, and teething delay (SHORT) syndrome is a developmental disorder with an unknown genetic cause and hallmarks that include insulin resistance and lack of subcutaneous fat. We ascertained two unrelated individuals with SHORT syndrome, hypothesized that the observed phenotype was most likely due to de novo mutations in the same gene, and performed whole-exome sequencing in the two probands and their unaffected parents. We then confirmed our initial observations in four other subjects with SHORT syndrome from three families, as well as 14 unrelated subjects presenting with syndromic insulin resistance and/or generalized lipoatrophy associated with dysmorphic features and growth retardation. Overall, we identified in nine affected individuals from eight families de novo or inherited PIK3R1 mutations, including a mutational hotspot (c.1945C>T [p.Arg649Trp]) present in four families. PIK3R1 encodes the p85α, p55α, and p50α regulatory subunits of class IA phosphatidylinositol 3 kinases (PI3Ks), which are known to play a key role in insulin signaling. Functional data from fibroblasts derived from individuals with PIK3R1 mutations showed severe insulin resistance for both proximal and distal PI3K-dependent signaling. Our findings extend the genetic causes of severe insulin-resistance syndromes and provide important information with respect to the function of PIK3R1 in normal development and its role in human diseases, including growth delay, Rieger anomaly and other ocular affections, insulin resistance, diabetes, paucity of fat, and ovarian cysts.

Barriers to metabolic surgery and how to address them.

After bariatric surgery, patients with obesity achieve sustainable weight loss, gain in mobility, quality of life and life expectancy. Bariatric surgery can lead to remission of type 2 diabetes or to long term glycaemic control for patients with type 2 diabetes, while medical treatment has a preventive efficacy on micro and macrovascular complications. This has led to the concept of metabolic surgery to treat type 2 diabetes. Despite the benefits, only a small proportion of eligible patients undergo bariatric/metabolic surgery. Powerful antidiabetic medications, self-estimated lack of knowledge by medical professionals and fear of surgical complications are some of the arguments to prefer medical treatment of type 2 diabetes obesity versus metabolic surgery. We have reviewed in this paper the barriers which explain the low referral rate to metabolic surgery. With the point of view of the diabetologist, the general practitioner and the patient, we have addressed them to help clinicians and patients model an evidenced-based patient-oriented medical plan.

Parental history of type 2 diabetes, TCF7L2 variant and lower insulin secretion are associated with incident hypertension. Data from the DESIR and RISC cohorts.

AIMS/HYPOTHESIS: The relationship between insulin secretion and the incidence of hypertension has not been well characterised. We hypothesised that both a parental history of diabetes and TCF7L2 rs7903146 polymorphism, which increases susceptibility to diabetes because of impaired beta cell function, are associated with incident hypertension. In a separate cohort, we assessed whether low insulin secretion is related to incident hypertension. METHODS: Nine year incident hypertension was studied in 2,391 normotensive participants from the Data from an Epidemiological Study on the Insulin Resistance Syndrome (DESIR) cohort. The relationship between insulin secretion and 3 year incident hypertension was investigated in 1,047 non-diabetic, normotensive individuals from the Relationship between Insulin Sensitivity and Cardiovascular Disease (RISC) cohort. Insulin secretion during OGTT was expressed in relation to the degree of insulin resistance, as assessed by a hyperinsulinaemic-euglycaemic clamp. RESULTS: In the DESIR cohort, a parental history of diabetes and the TCF7L2 at-risk variant were both associated with hypertension incidence at year 9, independently of waist circumference, BP, fasting glucose, insulin levels and HOMA-IR at inclusion (p = 0.02 for parental history, p = 0.006 for TCF7L2). In the RISC cohort, a lower insulin secretion rate during the OGTT at baseline was associated with both higher BP and a greater risk of hypertension at year 3. This inverse correlation between the insulin secretion rate and incident hypertension persisted after controlling for baseline insulin resistance, glycaemia and BP (p = 0.007). CONCLUSIONS/INTERPRETATION: Parental history of diabetes, TCF7L2 rs7903146 polymorphism and a reduced insulin secretion rate were consistently associated with incident hypertension. A low insulin secretion rate might be a new risk factor for incident hypertension, beyond insulin resistance.

A role for adipocyte-derived lipopolysaccharide-binding protein in inflammation- and obesity-associated adipose tissue dysfunction.

AIMS/HYPOTHESIS: Circulating lipopolysaccharide-binding protein (LBP) is an acute-phase reactant known to be increased in obesity. We hypothesised that LBP is produced by adipose tissue (AT) in association with obesity. METHODS: LBP mRNA and LBP protein levels were analysed in AT from three cross-sectional (n = 210, n = 144 and n = 28) and three longitudinal (n = 8, n = 25, n = 20) human cohorts; in AT from genetically manipulated mice; in isolated adipocytes; and in human and murine cell lines. The effects of a high-fat diet and exposure to lipopolysaccharide (LPS) and peroxisome proliferator-activated receptor (PPAR)γ agonist were explored. Functional in vitro and ex vivo experiments were also performed. RESULTS: LBP synthesis and release was demonstrated to increase with adipocyte differentiation in human and mouse AT, isolated adipocytes and human and mouse cell lines (Simpson-Golabi-Behmel syndrome [SGBS], human multipotent adipose-derived stem [hMAD] and 3T3-L1 cells). AT LBP expression was robustly associated with inflammatory markers and increased with metabolic deterioration and insulin resistance in two independent cross-sectional human cohorts. AT LBP also increased longitudinally with weight gain and excessive fat accretion in both humans and mice, and decreased with weight loss (in two other independent cohorts), in humans with acquired lipodystrophy, and after ex vivo exposure to PPARγ agonist. Inflammatory agents such as LPS and TNF-α led to increased AT LBP expression in vivo in mice and in vitro, while this effect was prevented in Cd14-knockout mice. Functionally, LBP knockdown using short hairpin (sh)RNA or anti-LBP antibody led to increases in markers of adipogenesis and decreased adipocyte inflammation in human adipocytes. CONCLUSIONS/INTERPRETATION: Collectively, these findings suggest that LBP might have an essential role in inflammation- and obesity-associated AT dysfunction.

Cereal processing influences postprandial glucose metabolism as well as the GI effect.

OBJECTIVE: Technological processes may influence the release of glucose in starch. The aim of this study was to compare the metabolic response and the kinetics of appearance of exogenous glucose from 2 cereal products consumed at breakfast. METHODS: Twenty-five healthy men were submitted to a randomized, open, crossover study that was divided into 2 parts: 12 of the 25 subjects were included in the "isotope part," and the 13 other subjects were included in the "glycemic part." On test days, subjects received biscuits (low glycemic index [GI], high slowly available glucose [SAG]) or extruded cereals (medium GI, low SAG) as part of a breakfast similar in terms of caloric and macronutrient content. The postprandial phase lasted 270 minutes. RESULTS: The rate of appearance (RaE) of exogenous glucose was significantly lower after consumption of biscuits in the first part of the morning (90-150 minutes) than after consumption of extruded cereals (p ≤ 0.05). Conversely, at 210 minutes, it was significantly higher with biscuits (p ≤ 0.01). For the first 2 hours, plasma glucose and insulin were significantly lower after biscuits during the glycemic part. C-peptide plasma concentrations were significantly lower at 90, 120, and 150 minutes after ingestion of the biscuits (p ≤ 0.05). CONCLUSION: The consumption of biscuits with a high content of slowly digestible starch reduces the appearance rate of glucose in the first part of the morning and prolongs this release in the late phase of the morning (210 minutes). Our results also emphasize that modulation of glucose availability at breakfast is an important factor for metabolic control throughout the morning in healthy subjects due to the lowering of blood glucose and insulin excursions.

[Importance of the postprandial phase in human health]. / Intérêt de la phase postprandiale pour la santé de l'homme.

Humans spend more than three-quarters of their lives in the postprandial state. Although the link between metabolic and cardiovascular diseases and fasting lipid and carbohydrate metabolism has been extensively studied and illustrated on the basis of conventional parameters (cholesterol, triglycerides, glucose, insulin, etc), it is equally legitimate and important to examine the role of these metabolic parameters in lipotoxicity and glucotoxicity occurring during the postprandial phase. However, studies of postprandial excursions, peaks and 2-hour post-meal follow-up are not sufficient to characterize integrative metabolic responses during the postprandial phase. Studies of the modulation of postprandial hyperlipidemia and hyperglycemia, using integrated kinetic monitoring and stable isotope tracers, are of prime importance to highlight the metabolic phenomena underlying lipemic and glycemic responses and to better characterize their long-term metabolic consequences.

Early humoral response to COVID-19 vaccination in patients living with obesity and diabetes in France. The COVPOP OBEDIAB study with results from the ANRS0001S COV-POPART cohort.

BACKGROUND: Patients with diabetes and obesity are populations at high-risk for severe COVID-19 outcomes and have shown blunted immune responses when administered different vaccines. Here we used the 'ANRS0001S COV-POPART' French nationwide multicenter prospective cohort to investigate early humoral response to COVID-19 vaccination in the sub-cohort ('COVPOP OBEDIAB') of patients with obesity and diabetes. METHODS: Patients with diabetes (n = 390, type 1 or 2) or obesity (n = 357) who had received two vaccine doses and had no history of previous COVID-19 infection and negative anti-nucleocapsid (NCP) antibodies were included and compared against healthy subjects (n = 573). Humoral response was assessed at baseline, at one month post-first dose (M0) and one-month post-second dose (M1), through percentage of responders (positive anti-spike SARS-CoV-2 IgG antibodies (Sabs), geometric means of Sabs; BAU/mL), proportion of individuals with anti-RBD antibodies, and proportion of individuals with anti-SARS-CoV-2-specific neutralizing antibodies (Nabs). Potential clinical and biological factors associated with weak response (defined as Sabs < 264 BAU/mL) and presence of non-reactive anti-RBD antibodies at M1 were evaluated. Univariate and multivariate regressions were performed to estimate crude and adjusted coefficients with 95 % confidence intervals. Poor glycemic control was defined as HbA1c ≥ 7.5 % at inclusion. RESULTS: Patients with diabetes, particularly type 2 diabetes, and patients with obesity were less likely to have positive Sabs and anti-RBD antibodies after the first and second dose compared to controls (p < 0.001). At M1, we found Sabs seroconversion in 94.1 % of patients with diabetes versus 99.7 % in controls, anti-RBD seroconversion in 93.8 % of patients with diabetes versus 99.1 % in controls, and Nabs seroconversion in 95.7 % of patients with diabetes versus 99.6 % in controls (all p < 0.0001). Sabs and anti-RBD seroconversion at M0 and M1 were also significantly lower in obese patients than controls, at respectively 82.1 % versus 89.9 % (p = 0.001; M0 Sabs), 94.4 % versus 99.7 % (p 0.001; M1 Sabs), 79.0 % vs 86.2 % (p = 0.004 M0 anti-RBD), and 96.99 % vs 99.1 % (p = 0.012 M1 anti-RBD). The factors associated with low vaccine response (BAU < 264/mL) in patients with diabetes were chronic kidney disease (adjusted OR = 6.88 [1.77;26.77], p = 0.005) and poor glycemic control (adjusted OR = 3.92 [1.26;12.14], p = 0.018). In addition, BMI ≥ 40 kg/m2 was found to be associated with a higher vaccine response (adjusted OR = 0.10 [0.01;0.91], p = 0.040) than patients with BMI < 40 kg/m2. CONCLUSION: COVID-19 vaccine humoral response was lower in patients with obesity and diabetes one month after second dose compared to controls, especially in diabetic patients with CKD or inadequate glycemic control. These findings point to the need for post-vaccination serological checks in these high-risk populations.

Association between eating behaviour and 13-year cardiovascular damages in the initially healthy STANISLAS cohort.

AIMS: Several dimensions of eating behaviour (EB), such as restrained eating (RE), appear to be cross-sectionally associated with certain cardiovascular (CV) diseases and metabolic risk factors although little is known regarding longitudinal associations. This study aimed to assess the associations between EB and CV damage or metabolic syndrome after 13 years, in initially healthy individuals. METHODS AND RESULTS: This study included 1109 participants from the familial STANISLAS (Suivi Temporaire Annuel Non-Invasif de la Santé des Lorrains Assurés Sociaux) cohort study. Emotional eating (EmE), RE, and external eating were assessed using the Dutch Eating Behaviour Questionnaire. Metabolic syndrome and CV damages such as carotid-femoral pulse-wave velocity (cfPWV), left ventricular mass, carotid intima-media thickness, and diastolic dysfunction (DD) were measured after a period of 13 years. Mixed model analysis with a family random effect and adjustment for age, sex, education, temporal gap, physical activity, metabolic factors at baseline, and the onset of CV disease during follow-up, and mediation analysis were performed in adults and adolescents separately. Among adults, EmE was associated with a 38% increased risk of DD 13 years later [odds ratio = 1.38 (1.05; 1.83)]. Stress level mediated 31.9% of this association (P = 0.01). Emotional eating was positively associated with cfPWV (ß=0.02 [0.01; 0.04]). External eating was slightly associated with lower cfPWV (ß=-0.03 [-0.05; -0.01]). No associations were observed between EB dimensions and metabolic syndrome. Energy intake was not found to be a mediator of any associations. CONCLUSION: Our results suggest that CV prevention should also take into account EB and include emotion regulation skills teaching.

The association of three dimensions of eating behaviour [emotional eating, restrained eating, and external eating] with 13 years later cardiovascular damages have been investigated in the initially healthy STANISLAS (Suivi Temporaire Annuel Non-Invasif de la Santé des Lorrains Assurés Sociaux) cohort. Emotional eating was associated with higher pulse-wave velocity and an increased risk of diastolic dysfunction. External eating was associated with lower pulse-wave velocity. Stress level was found to be a mediator of the association found between emotional eating and diastolic dysfunction.