Impact of prolonged requirement for insulin on 90-day mortality in critically ill patients without previous diabetic treatments: a post hoc analysis of the CONTROLING randomized control trial.

BACKGROUND: Stress hyperglycemia can persist during an intensive care unit (ICU) stay and result in prolonged requirement for insulin (PRI). The impact of PRI on ICU patient outcomes is not known. We evaluated the relationship between PRI and Day 90 mortality in ICU patients without previous diabetic treatments. METHODS: This is a post hoc analysis of the CONTROLING trial, involving 12 French ICUs. Patients in the personalized glucose control arm with an ICU length of stay ≥ 5 days and who had never previously received diabetic treatments (oral drugs or insulin) were included. Personalized blood glucose targets were estimated on their preadmission usual glycemia as estimated by their glycated A1c hemoglobin (HbA1C). PRI was defined by insulin requirement. The relationship between PRI on Day 5 and 90-day mortality was assessed by Cox survival models with inverse probability of treatment weighting (IPTW). Glycemic control was defined as at least one blood glucose value below the blood glucose target value on Day 5. RESULTS: A total of 476 patients were included, of whom 62.4% were male, with a median age of 66 (54-76) years. Median values for SAPS II and HbA1C were 50 (37.5-64) and 5.7 (5.4-6.1)%, respectively. PRI was observed in 364/476 (72.5%) patients on Day 5. 90-day mortality was 23.1% in the whole cohort, 25.3% in the PRI group and 16.1% in the non-PRI group (p < 0.01). IPTW analysis showed that PRI on Day 5 was not associated with Day 90 mortality (IPTWHR = 1.22; CI 95% 0.84-1.75; p = 0.29), whereas PRI without glycemic control was associated with an increased risk of death at Day 90 (IPTWHR = 3.34; CI 95% 1.26-8.83; p < 0.01). CONCLUSION: In ICU patients without previous diabetic treatments, only PRI without glycemic control on Day 5 was associated with an increased risk of death. Additional studies are required to determine the factors contributing to these results.

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.

Bicarbonate Supplement Restores Urinary Klotho Excretion in Chronic Kidney Disease: A Pilot Study.

OBJECTIVE: We tested the hypothesis that correcting acidosis may improve urinary Klotho excretion and serum α-Klotho. DESIGN: This is a prospective, interventional, nonrandomized, open-label trial study. In this study setting, metabolic acidosis is commonly observed during chronic kidney disease (CKD). We reported a positive relationship between serum bicarbonate (Sbicar) and serum α-Klotho in these patients. SUBJECTS: The study involved 20 patients with a known kidney disease referred for renal checkup. Inclusion criteria were age ≥ 18 years, CKD stage 3-5 non dialysis, Sbicar < 22 mmol/L, and not receiving bicarbonate supplementation. INTERVENTION: Patients were then prescribed 1 g of oral sodium bicarbonate 3 times per day for 4 weeks. MAIN OUTCOME MEASURE: Patients were evaluated at two and 4 weeks by blood and urine measurements. RESULTS: Mean serum Klotho was 615 ± 287 pg/mL, and mean serum Sbicar was 19.3 ± 1.7 mmol/L at baseline. Sbicar increased from baseline at two (23.9 ± 2.9 mmol/L, P < .001) and 4 weeks (23.4 ± 1.9 mmol/L, P < .001). There was no change in serum Klotho at two (630 ± 333 mmol/L) and 4 weeks (632 ± 285 mmol/L). By contrast, urine Klotho/creatinine ratio, which was very low at baseline (34.6 ± 31.6 pg/mmoL), increased by 320% at two weeks (P < .005) and by 280% at 4 weeks (P < .01). CONCLUSIONS: Correcting acidosis by oral administration of sodium bicarbonate rapidly increases the urine excretion of soluble α-Klotho in CKD patients. However, a 4-week bicarbonate treatment was not able to increase serum α-Klotho. A longer study may confirm this pilot observation and increase serum Klotho, which has been shown to exert a protective cardiovascular effect during CKD.

Efficacy of two vitamin E formulations in patients with abetalipoproteinemia and chylomicron retention disease.

Abetalipoproteinemia (ABL) and chylomicron retention disease (CMRD) are extremely rare recessive forms of hypobetalipoproteinemia characterized by intestinal lipid malabsorption and severe vitamin E deficiency. Vitamin E is often supplemented in the form of fat-soluble vitamin E acetate, but fat malabsorption considerably limits correction of the deficiency. In this crossover study, we administered two different forms of vitamin E, tocofersolan (a water-soluble derivative of RRR-α-tocopherol) and α-tocopherol acetate, to three patients with ABL and four patients with CMRD. The aims of this study were to evaluate the intestinal absorption characteristics of tocofersolan versus α-tocopherol acetate by measuring the plasma concentrations of α-tocopherol over time after a single oral load and to compare efficacy by evaluating the ability of each formulation to restore vitamin E storage after 4 months of treatment. In patients with ABL, tocofersolan and α-tocopherol acetate bioavailabilities were extremely low (2.8% and 3.1%, respectively). In contrast, bioavailabilities were higher in patients with CMRD (tocofersolan, 24.7%; α-tocopherol acetate, 11.4%). Plasma concentrations of α-tocopherol at 4 months were not significantly different by formulation type in ABL or CMRD. This study provides new insights about vitamin E status in ABL and CMRD and suggests the potential of different formulations as treatment options.

Vascular endothelial function masks increased sympathetic vasopressor activity in rats with metabolic syndrome.

Sympathetic hyperactivation, a common feature of obesity and metabolic syndrome, is a key trigger of hypertension. However, some obese subjects with autonomic imbalance present a dissociation between sympathetic activity-mediated vasoconstriction and increased blood pressure. Here, we aimed to determine in a rat model of metabolic syndrome whether the endothelium endothelial nitric oxide (NO) synthase (eNOS)-NO pathway contributes to counteract the vasopressor effect of the sympathetic system. Rats were fed a high-fat and high-sucrose (HFS) diet for 15 wk. Sympathovagal balance was evaluated by spectral analysis of heart rate variability and plasmatic catecholamine measurements. Blood pressure was measured in the presence or absence of N-nitro-l-arginine methyl ester (l-NAME) to inhibit the contribution of eNOS. Vascular reactivity was assessed on isolated aortic rings in response to α1-adrenergic agonist. The HFS diet increased sympathetic tone, which is characterized by a higher low on the high-frequency spectral power ratio and a higher plasmatic concentration of epinephrine. Despite this, no change in blood pressure was observed. Interestingly, HFS rats exhibited vascular hyporeactivity (-23.6%) to α1-adrenergic receptor stimulation that was abolished by endothelial removal or eNOS inhibition (l-NAME). In addition, eNOS phosphorylation (Ser1177) was increased in response to phenylephrine in HFS rats only. Accordingly, eNOS inhibition in vivo revealed higher blood pressure in HFS rats compared with control rats (147 vs. 126 mmHg for mean blood pressure, respectively). Restrain of adrenergic vasopressor action by endothelium eNOS is increased in HFS rats and contributes to maintained blood pressure in the physiological range. NEW & NOTEWORTHY Despite the fact that prohypertensive sympathetic nervous system activity is markedly increased in rats with early metabolic syndrome, they present with normal blood pressure. These observations appear to be explained by increased endothelial nitric oxide synthase response to adrenergic stimulation, which results in vascular hyporeactivity to α-adrenergic stimulation, and therefore blood pressure is preserved in the physiological range. Listen to this article's corresponding podcast at http://www.physiology.org/doi/10.1152/ajpheart.00217.2017 .

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.

Probiotic yogurt and acidified milk similarly reduce postprandial inflammation and both alter the gut microbiota of healthy, young men.

Probiotic yogurt and milk supplemented with probiotics have been investigated for their role in 'low-grade' inflammation but evidence for their efficacy is inconclusive. This study explores the impact of probiotic yogurt on metabolic and inflammatory biomarkers, with a parallel study of gut microbiota dynamics. The randomised cross-over study was conducted in fourteen healthy, young men to test probiotic yogurt compared with milk acidified with 2 % d-(+)-glucono-δ-lactone during a 2-week intervention (400 g/d). Fasting assessments, a high-fat meal test (HFM) and microbiota analyses were used to assess the intervention effects. Baseline assessments for the HFM were carried out after a run-in during which normal milk was provided. No significant differences in the inflammatory response to the HFM were observed after probiotic yogurt compared with acidified milk intake; however, both products were associated with significant reductions in the inflammatory response to the HFM compared with the baseline tests (assessed by IL6, TNFα and chemokine ligand 5) (P<0·001). These observations were accompanied by significant changes in microbiota taxa, including decreased abundance of Bilophila wadsworthia after acidified milk (log 2-fold-change (FC)=-1·5, P adj=0·05) and probiotic yogurt intake (FC=-1·3, P adj=0·03), increased abundance of Bifidobacterium species after acidified milk intake (FC=1·4, P adj=0·04) and detection of Lactobacillus delbrueckii spp. bulgaricus (FC=7·0, P adj<0·01) and Streptococcus salivarius spp. thermophilus (FC=6·0, P adj<0·01) after probiotic yogurt intake. Probiotic yogurt and acidified milk similarly reduce postprandial inflammation that is associated with a HFM while inducing distinct changes in the gut microbiota of healthy men. These observations could be relevant for dietary treatments that target 'low-grade' inflammation.

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.

Mitochondrial oxidative phosphorylation efficiency is upregulated during fasting in two major oxidative tissues of ducklings.

Fasted endothermic vertebrates must develop physiological responses to maximize energy conservation and survival. The aim of this study was to determine the effect of 1-wk. fasting in 5-wk. old ducklings (Cairina moschata) from whole-body resting metabolic rate and body temperature to metabolic phenotype of tissues and mitochondrial coupling efficiency. At the level of whole organism, the mass-specific metabolic rate of ducklings was decreased by 40% after 1-wk. of fasting, which was associated with nocturnal Tb declines and shallow diurnal hypothermia during fasting. At the cellular level, fasting induced a large reduction in liver, gastrocnemius (oxidative) and pectoralis (glycolytic) muscle masses together with a fuel selection towards lipid oxidation and ketone body production in liver and a lower glycolytic phenotype in skeletal muscles. At the level of mitochondria, fasting induced a reduction of oxidative phosphorylation activities and an up-regulation of coupling efficiency (+30% on average) in liver and skeletal muscles. The present integrative study shows that energy conservation in fasted ducklings is mainly achieved by an overall reduction in mitochondrial activity and an increase in mitochondrial coupling efficiency, which would, in association with shallow hypothermia, increase the conservation of endogenous fuel stores during fasting.

Effects of training and detraining on adiponectin plasma concentration and muscle sensitivity in lean and overweight men.

PURPOSE: To delineate the direct effect of physical activity on adiponectin metabolism, we investigated the impact of contrasted physical activity changes, independent of body mass changes, on adiponectin plasma concentration and muscle sensitivity in lean and overweight adult males. METHODS: Eleven physically active lean men (70.6 ± 2.1 kg) were subjected to 1-month detraining; 9 sedentary lean men (73.1 ± 3.3 kg); and 11 sedentary overweight men (97.5 ± 3.0 kg) participated in a 2-month aerobic-exercise training program. Diet was controlled to maintain stable energy balance. Body composition, VO2peak, circulating adiponectin, adipose and muscle tissue adiponectin, muscle adiponectin receptors, and APPL1 mRNAs were measured before and after the interventions. RESULTS: At baseline, plasma high-molecular-weight adiponectin concentration was lower in both active lean (5.44 ± 0.58 µg/mL) and sedentary overweight (5.30 ± 1.06 µg/mL) than in sedentary lean participants (7.44 ± 1.06 µg/mL; both p < 0.05). Training reduced total and high-molecular-weight adiponectin concentrations by, respectively, -32 and -42 % in sedentary lean, and -26 and -35 % in sedentary overweight, while detraining increased them by +25 and +27 % in active lean participants. Total and high-molecular-weight adiponectin changes were inversely correlated with VO2peak changes (respectively, R 2 = 0.45, R 2 = 0.59; both p < 0.001) and positively with changes in fasting plasma insulin (both p < 0.05). Muscle and adipose tissue adiponectin mRNA did not differ between groups and with interventions. Muscle AdipoR2 and APPL1 mRNAs were lower in sedentary groups compared with the active group; and were positively associated with VO2peak and inversely with fasting plasma insulin concentration. CONCLUSION: Plasma adiponectin concentration is inversely correlated with aerobic capacity. Future investigations will need to confirm the contribution of changes in muscle adiponectin sensitivity.

Levels of Fecal Calprotectin Are Associated With the Severity of Postoperative Endoscopic Recurrence in Asymptomatic Patients With Crohn's Disease.

OBJECTIVES: Fecal calprotectin (fCal) is widely used as marker of gut inflammation and is strongly associated with the severity of endoscopic lesions in Crohn's disease (CD). We analyzed the relationships between levels of fCal and high-sensitivity C-reactive protein (hsCRP) and the presence and severity of postoperative endoscopic recurrence in asymptomatic CD patients (Harvey-Bradshaw index≤3). METHODS: Blood and fecal samples were collected in consecutive asymptomatic CD patients (Harvey-Bradshaw index 0.85 ± 0.19, mean ± s.e.m.) who had undergone an ileocolonic resection. hsCRP and fCal were measured and a routine ileocolonoscopy was performed within 18 months (median 7 months) from resection, to detect endoscopic recurrence according to the Rutgeerts score. RESULTS: Eighty-six patients were included in this prospective multicenter observational cohort. fCal concentrations differed significantly in patients with endoscopic recurrence when compared with those in endoscopic remission (mean ± s.e.m.: 473 ± 78 µg/g vs. 115 ± 18 µg/g; P<0.0001). The area under the receiver operating characteristic (ROC) curve to discriminate between patients in endoscopic remission and recurrence was 0.86 for fCal and lower for hsCRP (0.70). The best cutoff point for fCal to distinguish between endoscopic remission and recurrence was 100 µg/g as determined by the ROC curve, and its sensitivity, specificity, positive and negative predictive values (NPVs), as well as overall accuracy were 95%, 54%, 69%, 93%, and 77%, respectively. CONCLUSION: Measurement of fCal concentrations is a promising and useful tool for monitoring asymptomatic CD patients after ileocolonic resection. Taking into account the high NPV of fCal, a threshold below 100 µg/g could avoid systematic ileocolonoscopies in 30% of patients from this population.

Skeletal muscle phenotype affects fasting-induced mitochondrial oxidative phosphorylation flexibility in cold-acclimated ducklings.

Starvation is particularly challenging for endotherms that remain active in cold environments or during winter. The aim of this study was to determine whether fasting-induced mitochondrial coupling flexibility depends upon the phenotype of skeletal muscles. The rates of oxidative phosphorylation and mitochondrial efficiency were measured in pectoralis (glycolytic) and gastrocnemius (oxidative) muscles from cold-acclimated ducklings (Cairina moschata). Pyruvate and palmitoyl-l-carnitine were used in the presence of malate as respiratory substrates. Plasma metabolites, skeletal muscle concentrations of triglycerides, glycogen and total protein and mitochondrial levels of oxidative phosphorylation complexes were also quantified. Results from ad libitum fed ducklings were compared with those from ducklings that were fasted for 4 days. During the 4 days of nutritional treatment, birds remained in the cold, at 4°C. The 4 days of starvation preferentially affected the pectoralis muscles, inducing an up-regulation of mitochondrial efficiency, which was associated with a reduction of both total muscle and mitochondrial oxidative phosphorylation protein, and with an increase of intramuscular lipid concentration. By contrast, fasting decreased the activity of oxidative phosphorylation but did not alter the coupling efficiency and protein expression of mitochondria isolated from the gastrocnemius muscles. Hence, the adjustment of mitochondrial efficiency to fasting depends upon the muscle phenotype of cold-acclimated birds. Furthermore, these results suggest that the reduced cost of mitochondrial ATP production in pectoralis muscles may trigger lipid storage within this tissue and help to sustain an important metabolic homeostatic function of skeletal muscles, which is to maintain levels of amino acids in the circulation during the fast.

Inhibitory effects of in vivo oxidized high-density lipoproteins on platelet aggregation: evidence from patients with abetalipoproteinemia.

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.

In chronic kidney disease, serum α-Klotho is related to serum bicarbonate and proteinuria.

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 α-Klotho with renal function, acid-base status, bone biomarkers, and proteinuria in CKD patients. DESIGN SETTING, PARTICIPANTS, AND MEASUREMENTS: We measured serum α-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 α-Klotho was 478 (348-658) pg/mL. We found an inverse relationship between serum α-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 α-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 α-Klotho (P = .003). CONCLUSIONS: This study shows that in CKD, serum α-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 α-Klotho.

13C tracer recovery in human stools after digestion of a fat-rich meal labelled with [1,1,1-13C3]tripalmitin and [1,1,1-13C3]triolein.

Lipid metabolism studies focus mainly on oxidation and storage but rarely on faecal elimination, which is needed to assess total lipid distribution during the postprandial period. The purpose of the present work was to set up and validate the analysis of lipid tracers in stools, with an aim of later using this methodology in studies of postprandial lipid tracer metabolism. Eight subjects received a mixture of [1,1,1-(13)C3]tripalmitin and [1,1,1-(13)C3]triolein with a fat-rich meal. The nature and amounts of (13)C lipids excreted in stools during 3 days post-dose were determined by gas chromatography/mass spectrometry (GC/MS) and gas chromatography/combustion/isotope ratio mass spectrometry (GC/C/IRMS) analysis of fatty acid methyl esters (FAMEs) from total fatty acid (TFA), free fatty acid (FFA) and triacylglycerol (TAG) fractions. The results were expressed as the Cumulative Tracer Recovery of the administered dose (CTR%). The quantities and labelling of FAMEs were higher in FFA than in TAG, indicating that label loss was not due to a lack of digestive lipase activity. The labelling was higher for C16:0 than for C18:1. The CTRs were 7.03 ± 0.77% and 6.87 ± 0.91%, respectively, in TFA and FFA for [1-(13)C] C16:0, while they were 0.60 ± 0.15% and 0.51 ± 0.11% for [1-(13)C] C18:1 (mean ± sem). By studying the kinetics of lipid excretion from subjects, two groups emerged. The first one showed rapid excretion in stool #1, whereas the second showed slower excretion in stools #2-#3. A significant difference was found in the FFA in stool #1 for C16:0 (p < 0.01) and C18:1 (p < 0.05). Individual excretion kinetics showed marked variability. Nevertheless, the CTR over the 3-day study period was substantial and homogenous for all subjects. These results confirm that the assessment of faecal elimination is of great importance when establishing total lipid distribution during the postprandial period and validate the analysis of cumulative tracer loss during 72 h post-tracer ingestion.

Milk polar lipids favorably alter circulating and intestinal ceramide and sphingomyelin species in postmenopausal women.

BACKGROUNDHigh circulating levels of ceramides (Cer) and sphingomyelins (SM) are associated with cardiometabolic diseases. The consumption of whole fat dairy products, naturally containing such polar lipids (PL), is associated with health benefits, but the impact on sphingolipidome remains unknown.METHODSIn a 4-week randomized controlled trial, 58 postmenopausal women daily consumed milk PL-enriched cream cheese (0, 3, or 5 g of milk PL). Postprandial metabolic explorations were performed before and after supplementation. Analyses included SM and Cer species in serum, chylomicrons, and feces. The ileal contents of 4 ileostomy patients were also explored after acute milk PL intake.RESULTSMilk PL decreased serum atherogenic C24:1 Cer, C16:1 SM, and C18:1 SM species (Pgroup < 0.05). Changes in serum C16+18 SM species were positively correlated with the reduction of cholesterol (r = 0.706), LDL-C (r = 0.666), and ApoB (r = 0.705) (P < 0.001). Milk PL decreased chylomicron content in total SM and C24:1 Cer (Pgroup < 0.001), parallel to a marked increase in total Cer in feces (Pgroup < 0.001). Milk PL modulated some specific SM and Cer species in both ileal efflux and feces, suggesting differential absorption and metabolization processes in the gut.CONCLUSIONMilk PL supplementation decreased atherogenic SM and Cer species associated with the improvement of cardiovascular risk markers. Our findings bring insights on sphingolipid metabolism in the gut, especially Cer, as signaling molecules potentially participating in the beneficial effects of milk PL.TRIAL REGISTRATIONClinicalTrials.gov, NCT02099032, NCT02146339.FUNDINGANR-11-ALID-007-01; PHRCI-2014: VALOBAB, no. 14-007; CNIEL; GLN 2018-11-07; HCL (sponsor).

Are ghrelin and leptin involved in food intake and body mass index in maintenance hemodialysis?

OBJECTIVES: Both leptin and ghrelin (in the forms of acyl ghrelin and des-acyl ghrelin) are involved in food intake, and appear to be dysregulated in chronic kidney disease. This study describes plasma leptin, acyl, and des-acyl ghrelin concentrations in relation to protein intake and body mass index (BMI) in hemodialysis (HD) patients. DESIGN: This was a cross-sectional study. SETTING: This study was conducted during the baseline phase of the French multicenter Influence of a High-Flux Dialyzer on Long-Term Leptin Levels Study. PATIENTS: We studied 125 HD patients (aged 72.5+/-11.7 years; 59% males). MAIN OUTCOME MEASURE: Blood samples were collected during fasting, and before a regular HD session. Plasma ghrelin and leptin were evaluated. The protein equivalents of total nitrogen appearance and BMI were calculated. RESULTS: Patients demonstrated elevated serum leptin (48.0+/-49.0 ng/mL) and des-acyl ghrelin (646.6+/-489.5 pg/mL) levels, and low acyl ghrelin levels (29.8+/-58.5 pg/mL), according to normal values. Acyl ghrelin was negatively correlated with C-reactive protein (r=-0.34, P < .001). The des-acyl to acyl ghrelin ratio was negatively correlated with protein intake, as estimated by normalized Protein Nitrogen Appearance (r=-0.22, P=.01). Serum leptin exhibited its well-described positive correlation with BMI and waist circumference, but the other hormones did not. CONCLUSIONS: This study reports high des-acyl ghrelin and leptin levels and low acyl ghrelin levels in HD patients, a finding potentially associated with inflammation and food intake.

Effect of bile acid supplementation on endogenous lipid synthesis in patients with short bowel syndrome: A pilot study.

BACKGROUND & AIMS: Short bowel syndrome patients (SBS) receiving parenteral nutrition (PN) often have dyslipidaemia and can develop intestinal failure-associated liver disease (IFALD). These patients demonstrate increased cholesterol synthesis and hepatic lipogenesis. These lipid disturbances may be due to a decreased concentration of the bile acid pool or malabsorption. The aim of this pilot study was to evaluate the effect of bile acid administration on lipid synthesis in patients with SBS. METHODS: The 24 h fractional synthesis rate (FSR) of cholesterol and triglycerides was measured by the isotopic method (deuterated water) before and after 4 months of ursodeoxycholic acid (UDCA) treatment (20 mg/kg/day). Five short bowel patients (age: 53.4 ± 19.2 years) who had normal liver function and lipid plasmatic profiles received 1920 ± 300 ml of PN for 151 ± 74 days (mean PN energy intake was 27.0 ± 6.0 kcal/kg body weight, composed with 3.87 ± 1.38 g/kg of carbohydrate, 0.72 ± 0.25 g/kg of fat and 1.10 ± 0.23 g/kg of amino acids). Plasma metabolites, liver enzymes, 7-α-OH-cholesterol and steatosis levels were also evaluated before and after treatment. Student's t-tests were performed, and the results were expressed in means (±SD). RESULTS: After treatment, decreases in the absolute values of cholesterol synthesis (0.31 ± 0.12 mmol L-1 to 0.24 ± 0.11 mmol L-1; p < 0.05), FSR of cholesterol (31.6 ± 4.7% to 26.4 ± 4.7%; p = 0.06) and FSR of triglycerides (12.8 ± 5.8% to 9.2 ± 5.5%; p < 0.01) were observed. Cholesterol and alanine aminotransferase concentrations also decreased (ALT) (p < 0.05). The absolute values of triglyceride synthesis and triglyceride concentrations remained unchanged. CONCLUSIONS: In SBS patients, UDCA decreases the hepatic synthesis of triglycerides and cholesterol. These results suggest that UDCA could prevent the onset of the IFALD.