Postprandial Lipid Research Articles

Acute response in glycemia and lipemia postprandial after resistance and concurrent training in overweight postmenopausal women

Introduction: In postmenopausal women, metabolic responses to lipids during postprandial periods following combined exercise training are unknown. Objective: To examine the acute effects of resistance training (RT) and concurrent training (CT) on postprandial lipemia and glycemia in postmenopausal women. Methods: This quasi-experimental, exposure response study, linked 27 women who were randomly divided into three groups and evaluated for anthropometry, physical fitness, and nutrition status. Two experimental groups did a session of different types of physical activities (RT or CT), and a control group did not do any training activities (only aerobic exercise). At 12 hours post-training, in fasting conditions, a hypercaloric nutritional compound equivalent to 50% of the basal metabolic rate (BMR) of each woman was supplied. Pre and post hypercaloric intake, biochemical markers (lipemia and glycemia) were determined and compared with the control group. Results: A reduction in total energy expenditure was observed due to RT and CT training (p<0.005). The changes are associated with decreased total cholesterol and low-density lipoprotein levels in the RT group, as well as decreased triglyceride levels and increased high-density lipoprotein levels in the CT and aerobic exercise groups. Conclusion: RT and CT performed 12 hours before the consumption of the hyper caloric nutritional compound can change postprandial lipid and glucose levels. Acute physical training could influence the reduction of energy expenditure and the improvement of glycaemia and lipemia in postmenopausal women. Keywords: exercise; fitness; glycemia; lipemia; nutrition; postmenopausal; trainings.

Low-fat dairy consumption improves intestinal immune function more than high-fat dairy in a diet-induced swine model of insulin resistance.

To understand the effects of consuming high-fat and low-fat dairy products on postprandial cardiometabolic risk factors and intestinal immune function, we used an established low birthweight (LBW) swine model of diet-induced insulin resistance. LBW piglets were randomized to consume one of the 3 experimental high fat diets and were fed for a total of 7weeks: (1) Control high fat (LBW-CHF), (2) CHF diet supplemented with 3 servings of high-fat dairy (LBW-HFDairy) and (3) CHF diet supplemented with 3 servings of low-fat dairy (LBW-LFDairy). As comparison groups, normal birthweight (NBW) piglets were fed a CHF (NBW-CHF) or standard pig grower diet (NBW-Chow). At 11weeks of age, all piglets underwent an established modified oral glucose and fat tolerance test. At 12weeks of age, piglets were euthanized and ex vivo cytokine production by cells isolated from mesenteric lymph node (MLN) stimulated with mitogens was assessed. Dairy consumption did not modulate postprandial plasma lipid, inflammatory markers and glucose concentrations. A lower production of IL-2 and TNF-α after pokeweed mitogen (PWM) stimulation was observed in LBW-CHF vs NBW-Chow (P < 0.05), suggesting impaired MLN T cell function. While feeding high-fat dairy had minimal effects, feeding low-fat dairy significantly improved the production of IL-2 and TNF-α after PWM stimulation (P < 0.05). Irrespective of fat content, dairy had a neutral effect on postprandial cardiometabolic risk factors. Low-fat dairy products improved intestinal T cell function to a greater extent than high-fat dairy in this swine model of obesity and insulin resistance.

GLP-1 attenuates intestinal fat absorption and chylomicron production via vagal afferent nerves originating in the portal vein

Background/ObjectiveGLP-1R agonists have been shown to reduce fasting and postprandial plasma lipids, both of which are independent risk factors for the development of cardiovascular disease. However, how endogenous GLP-1 – which is rapidly degraded – modulates intestinal and hepatic lipid metabolism is less clear. A vagal gut-brain-axis originating in the portal vein has been proposed as a possible mechanism for GLP-1’s anti-lipemic effects. Here we sought to examine the relationship between vagal GLP-1 signalling and intestinal lipid absorption and lipoprotein production. MethodsSyrian golden hamsters or C57BL/6 mice received portal vein injections of GLP-1(7-36), and postprandial and fasting plasma TG, TRL TG, or VLDL TG were examined. These experiments were repeated during sympathetic blockade, and under a variety of pharmacological or surgical deafferentation techniques. In addition, hamsters received nodose ganglia injections of a GLP-1R agonist or antagonist to further probe the vagal pathway. Peripheral studies were repeated in a novel GLP-1R KO hamster model and in our diet-induced hamster models of insulin resistance. ResultsGLP-1(7-36) site-specifically reduced postprandial and fasting plasma lipids in both hamsters and mice. These inhibitory effects of GLP-1 were investigated via pharmacological and surgical denervation experiments and found to be dependent on intact afferent vagal signalling cascades and efferent changes in sympathetic tone. Furthermore, GLP-1R agonism in the nodose ganglia resulted in markedly reduced postprandial plasma TG and TRL TG, and fasting VLDL TG and this nodose GLP-1R activity was essential for portal GLP-1s effect. Notably, portal and nodose ganglia GLP-1 effects were lost in GLP-1R KO hamsters and following diet-induced insulin resistance. ConclusionOur data demonstrates for the first time that portal GLP-1 modulates postprandial and fasting lipids via a complex vagal gut–brain–liver axis. Importantly, loss or interference with this signalling axis via surgical, pharmacological, or dietary intervention resulted in the loss of portal GLP-1s anti-lipemic effects. This supports emerging evidence that native GLP-1 works primarily through a vagal neuroendocrine mechanism.

Blood Lipid Responses to Diets Enriched with Cottonseed Oil Compared with Olive Oil in Adults with High Cholesterol in a Randomized Trial

BackgroundIncreasing unsaturated fat intake is beneficial for cardiovascular health, but the type of unsaturated fat to recommend remains equivocal. ObjectivesWe investigated the effects of an 8-week diet intervention that was rich in either cottonseed oil (CSO; PUFA rich) or olive oil (OO; MUFA rich) on blood lipids in hypercholesterolemic adults. MethodsForty-three men and women with hypercholesterolemia (53 ± 10 years; BMI, 27.6 ± 4.8 kg/m2) completed this randomized parallel clinical trial consisting of an 8-week partial outpatient feeding intervention. Participants were given meals and snacks accounting for ∼60% of their daily energy needs, with 30% of energy needs from either CSO (n = 21) or OO (n = 22). At pre- and postdiet intervention visits, participants consumed a high-SFA meal (35% of total energy needs; 70% of energy from fat). The primary outcomes of fasting cholesterol profiles and secondary outcomes of postprandial blood lipids and glycemic markers were assessed over a 5-hour period. ResultsThere were greater reductions from baseline to week 8 in fasting serum total cholesterol (TC; −17.0 ± 3.94 mg/dL compared with −2.18 ± 3.72 mg/dL, respectively; P = 0.008), LDL cholesterol (−19.7 ± 3.94 mg/dL compared with −5.72 ± 4.23 mg/dL, respectively; P = 0.018), non–HDL cholesterol (−20.8 mg/dL ± 4.00 compared with −6.61 ± 4.01 mg/dL, respectively; P = 0.014), and apoB (−11.8 mg/dL ± 2.37 compared with −3.10 ± 2.99 mg/dL, respectively; P = 0.05), in CSO compared with OO. There were also visit effects from baseline to week 8 for increases in HDL cholesterol (CSO, 56.5 ± 2.79 mg/dL to 60.2 ± 3.35 mg/dL, respectively; OO: 59.7 ± 2.63 mg/dL to 64.1 ± 2.24 mg/dL, respectively; P < 0.001), and decreases in the TC:HDL-cholesterol ratio (CSO, 4.30 ± 0.27 mg/dL to 3.78 ± 0.27 mg/dL, respectively; OO, 3.94 ± 0.16 mg/dL to 3.57 ± 0.11 mg/dL, respectively; P < 0.001), regardless of group assignment. In response to the high-SFA meal, there were differences in postprandial plasma glucose (P = 0.003) and triglyceride (P = 0.004) responses and a trend in nonesterified fatty acids (P = 0.11) between groups, showing protection in the postprandial state from an occasional high-SFA fat meal with CSO, but not OO, diet enrichment. ConclusionsCSO, but not OO, diet enrichment caused substantial improvements in fasting and postprandial blood lipids and postprandial glycemia in hypercholesterolemic adults. This trial was registered at clinicaltrials.gov as NCT04397055.

Postprandial triglycerides, endothelial function, and inflammatory cytokines as potential candidates for early risk detection in normal-weight obesity

ProblemNormal-weight obesity (NWO) is associated with increased cardiovascular disease (CVD) risk. However, NWO’s clinical presentation is often unremarkable based on common risk factors. We examined whether CVD risk factors not routinely measured clinically including postprandial triglycerides, flow-mediated dilation (FMD), and inflammatory cytokines would be abnormal in NWO, consistent with their future risk. MethodsIndividuals were recruited into 3 groups (n = 10/ group): controls (Con), NWO, and metabolic syndrome (MetS). Con was defined as a normal body mass index (BMI), < 25% (M) or < 35% (F) body fat, and < 1 International Diabetes Federation (IDF) criteria. NWO were above this body fat cutoff while maintaining a normal BMI and MetS was defined per the IDF. Participants underwent an abbreviated fat tolerance test (i.e., difference in fasting and 4 h triglycerides following a high-fat meal [9 kcal/kg; 73% fat)] and fasting and postprandial lipid and glucose metrics, as well as FMD were measured. A T cell cytokine bioplex was also performed using fasting serum. ResultsNWO and MetS had similar body fat% and both were higher than Con (p < 0.0001). Despite having similar fasting triglycerides to Con, NWO had 4-hour triglycerides 66% greater than Con, but 46% lower than MetS (p < 0.01). FMD decreased in all groups after the high-fat meal (p < 0.0001). MetS displayed lower fasting FMD than Con, and NWO was similar to both groups (p < 0.05). No group differences were observed with postprandial FMD and the majority of fasting cytokines assessed. However, MetS exhibited higher fasting TNF-α than Con (p < 0.05), and NWO was similar to both groups. ConclusionsOverall, NWO was associated with higher postprandial triglycerides than Con, but displayed little evidence of impaired vascular health or inflammation.

Cardiometabolic and Anthropometric Outcomes of Intermittent Fasting Among Civil Servants With Overweight and Obesity: Study Protocol for a Nonrandomized Controlled Trial.

BackgroundOverweight and obesity among adults are a growing global public health threat and an essential risk factor for various noncommunicable diseases. Although intermittent fasting is a generally new dietary approach to weight management that has been increasingly practiced worldwide, the effectiveness of 2 days per week dry fasting remains unclear.ObjectiveThe Cardiometabolic and Anthropometric Outcomes of Intermittent Fasting study aims to determine the cardiometabolic, anthropometric, dietary intake, and quality of life changes among civil servants with overweight and obesity, following combined intermittent fasting and healthy plate (IFHP) and healthy plate (HP) and explore the participants’ experiences.MethodsWe designed a mixed methods quasi-experimental study to evaluate the effectiveness of the IFHP and HP methods among adults with overweight and obesity. A total of 177 participants were recruited for this study, of which 91 (51.4%) were allocated to the IFHP group and 86 (48.6%) to the HP group. The intervention comprised 2 phases: supervised (12 weeks) and unsupervised (12 weeks). Data collection was conducted at baseline, after the supervised phase (week 12), and after the unsupervised phase (week 24). Serum and whole blood samples were collected from each participant for analysis. Data on sociodemographic factors, quality of life, physical activity, and dietary intake were also obtained using questionnaires during data collection.ResultsMost of the participants were female (147/177, 83.1%) and Malay (141/177, 79.7%). The expected outcomes of this study are changes in body weight, body composition, quality of life, physical activity, dietary intake, and cardiometabolic parameters such as fasting blood glucose, 2-hour postprandial blood glucose, hemoglobin A1c, fasting insulin, and lipid profile.ConclusionsThe Cardiometabolic and Anthropometric Outcomes of Intermittent Fasting study is a mixed methods study to evaluate the effectiveness of combined IFHP and HP interventions on cardiometabolic and anthropometric parameters and explore participants’ experiences throughout the study.Trial RegistrationClinicalTrials.gov NCT05034653; https://clinicaltrials.gov/ct2/show/NCT05034653International Registered Report Identifier (IRRID)RR1-10.2196/33801

Pemafibrate improved postprandial TG, Reml-C and ApoB48 in patients with type 2 diabetes (T2D) and hypertriglyceridemia: A post-hoc analysis of the phase 3 clinical trial

Background and Aims : Postprandial increase in TG-rich lipoproteins is a risk factor for atherosclerosis. Pemafibrate, a selective PPARα modulator (SPPARMα), causes profound TG reduction and HDL increase in patients with hypertriglyceridemia. However, there is limited data available about postprandial lipid parameters under pemafibrate treatment in patients with T2D and hypertriglyceridemia. The aim of this study was to examine the effect of pemafibrate on postprandial lipid parameters in this population.

A Study of Lifestyle Modifications with and Without Metformin in Prediabetic Subjects

Purpose: Prediabetes is a stage in the natural history of impaired glucose metabolism rather than as a distinctive clinical entity. The primary objective was to compare the effect of lifestyle modifications (LSMs) with and without metformin in prolonging the onset of diabetes mellitus in prediabetics. Materials and Methods: This study is an open label, parallel group comparative study conducted from 2016 to 2020. One hundred and four prediabetic subjects were assigned to two groups: group I (51) LSM and group II (53) metformin 500 mg along with LSM. Baseline investigations included fasting blood sugar (FBS), post-prandial blood sugar (PPBS), HbA1c, and lipid profile, followed up for 12 months. Results: The baseline parameters were comparable between the groups. In both the groups, there was a significant reduction in abdominal circumference, total cholesterol, triglycerides, low-density lipoprotein, FBS, PPBS, and HbA1c between baseline and 1 year. There was no significant difference between groups I and II in reduction of all the above-mentioned parameters. The outcomes of prediabetic subjects after 1 year of treatment in both the groups were comparable. Only one (2.1%) subject had more than 126 mmHg FBS in the LSM group. The adverse effects observed were dizziness, nausea, flatulence, myalgia, abdominal pain, and heart burn, which were mild to moderate in intensity and in most patients it subsided with time. Conclusion: LSM alone was equivalent to LSM along with metformin in effective control of blood sugars. Lipid profile and weight may be significantly reduced.

The Location of Missense Variants in the Human GIP Gene Is Indicative for Natural Selection.

The intestinal hormone, glucose-dependent insulinotropic polypeptide (GIP), is involved in important physiological functions, including postprandial blood glucose homeostasis, bone remodeling, and lipid metabolism. While mutations leading to physiological changes can be identified in large-scale sequencing, no systematic investigation of GIP missense variants has been performed. Here, we identified 168 naturally occurring missense variants in the human GIP genes from three independent cohorts comprising ~720,000 individuals. We examined amino acid changing variants scattered across the pre-pro-GIP peptide using in silico effect predictions, which revealed that the sequence of the fully processed GIP hormone is more protected against mutations than the rest of the precursor protein. Thus, we observed a highly species-orthologous and population-specific conservation of the GIP peptide sequence, suggestive of evolutionary constraints to preserve the GIP peptide sequence. Elucidating the mutational landscape of GIP variants and how they affect the structural and functional architecture of GIP can aid future biological characterization and clinical translation.

ANGPTL3 Is Involved in the Post-prandial Response in Triglyceride-Rich Lipoproteins and HDL Components in Patients With Coronary Artery Disease.

It is well-established that there exists an inverse relationship between high-density lipoprotein (HDL) cholesterol and triglyceride (TG) levels in the plasma. However, information is lacking on the impact of post-prandial triglyceride-rich lipoproteins (TRLs) on the structure of HDL subclasses in patients with coronary artery disease (CAD). In this study, the data of 49 patients with CAD were analyzed to evaluate dynamic alterations in post-prandial lipid profiles using nuclear magnetic resonance-based methods. An enzyme-linked immunosorbent assay was used to quantify the serum angiopoietin-like protein 3 (ANGPTL3). After glucose supplementation, the expression of hepatic ANGPTL3 was evaluated both in vitro and in vivo. Compared to fasting levels, the post-prandial serum TG level of all participants was considerably increased. Although post-prandial total cholesterol in HDL (HDL-C) remained unchanged, free cholesterol in HDL particles (HDL-FC) was significantly reduced after a meal. Furthermore, the post-prandial decrease in the HDL-FC level corresponded to the increase in remnant cholesterol (RC), indicating the possible exchange of free cholesterol between HDL and TRLs after a meal. Moreover, CAD patients with exaggerated TG response to diet, defined as TG increase >30%, tend to have a greater post-prandial increase of RC and decrease of HDL-FC compared to those with TG increase ≤30%. Mechanistically, the fasting and post-prandial serum ANGPTL3 levels were significantly lower in those with TG increase ≤30% than those with TG increase >30%, suggesting that ANGPTL3, the key lipolysis regulator, may be responsible for the different post-prandial responses of TG, RC, and HDL-FC.

A Gene Variation at the ZPR1 Locus (rs964184) Interacts With the Type of Diet to Modulate Postprandial Triglycerides in Patients With Coronary Artery Disease: From the Coronary Diet Intervention With Olive Oil and Cardiovascular Prevention Study.

Background and Aimsrs964184 variant in the ZPR1 gene has been associated with blood lipids levels both in fasting and postprandial state and with the risk of myocardial infarction in high-risk cardiovascular patients. However, whether this association is modulated by diet has not been studied.ObjectiveTo investigate whether the type of diet (low-fat or Mediterranean diets) interacts with genetic variability at this loci to modulate fasting and postprandial lipids in coronary patients.Materials and MethodsThe genotype of the rs964184 polymorphism was determined in the Cordioprev Study population (NCT00924937). Fasting and Postprandial triglycerides were assessed before and after 3 years of dietary intervention with either a Mediterranean or a low-fat diet. Postprandial lipid assessment was done by a 4-h oral fat tolerance test (OFTT). Differences in triglycerides levels were identified using repeated-measures ANCOVA.ResultsFrom 523 patients (85% males, mean age 59 years) that completed the OFTT at baseline and after 3 years of intervention and had complete genotype information, 125 of them were carriers of the risk allele G. At the start of the study, these patients showed a higher fasting and postprandial triglycerides (TG) plasma levels. After 3 years of dietary intervention, G-carriers following a Mediterranean Diet maintained higher fasting and postprandial triglycerides, while those on the low-fat diet reduced their postprandial triglycerides to similar values to the population without the G-allele.ConclusionAfter 3 years of dietary intervention, the altered postprandial triglyceride response induced by genetic variability in the rs964184 polymorphism of the ZPR1 gene can be modulated by a low-fat diet, better than by a Mediterranean diet, in patients with coronary artery disease.

SCD1 is nutritionally and spatially regulated in the intestine and influences systemic postprandial lipid homeostasis and gut-liver crosstalk

Stearoyl-CoA desaturase-1 is an endoplasmic reticulum (ER)-membrane resident protein that inserts a double bond into saturated fatty acids, converting them into their monounsaturated counterparts. Previous studies have demonstrated an important role for SCD1 in modulating tissue and systemic health. Specifically, lack of hepatic or cutaneous SCD1 results in significant reductions in tissue esterified lipids. While the intestine is an important site of lipid esterification and assimilation into the body, the regulation of intestinal SCD1 or its impact on lipid composition in the intestine and other tissues has not been investigated. Here we report that unlike other lipogenic enzymes, SCD1 is enriched in the distal small intestine and in the colon of chow-fed mice and is robustly upregulated by acute refeeding of a high-sucrose diet. We generated a mouse model lacking SCD1 specifically in the intestine (iKO mice). These mice have significant reductions not only in intestinal lipids, but also in plasma triacylglycerols, diacylglycerols, cholesterol esters, and free cholesterol. Additionally, hepatic accumulation of diacylglycerols is significantly reduced in iKO mice. Comprehensive targeted lipidomic profiling revealed a consistent reduction in the myristoleic (14:1) to myristic (14:0) acid ratios in intestine, liver, and plasma of iKO mice. Consistent with the reduction of the monounsaturated fatty acid myristoleic acid in hepatic lipids of chow fed iKO mice, hepatic expression of Pgc-1α, Sirt1, and related fatty acid oxidation genes were reduced in chow-fed iKO mice. Further, lack of intestinal SCD1 reduced expression of de novo lipogenic genes in distal intestine of chow-fed mice and in the livers of mice fed a lipogenic high-sucrose diet. Taken together, these studies reveal a novel pattern of expression of SCD1 in the intestine. They also demonstrate that intestinal SCD1 modulates lipid content and composition of not only intestinal tissues, but also that of plasma and liver. Further, these data point to intestinal SCD1 as a modulator of gut-liver crosstalk, potentially through the production of novel signaling lipids such as myristoleic acid. These data have important implications to understanding how intestinal SCD1 may modulate risk for post-prandial lipemia, hepatic steatosis, and related pathologies.

Feeding activates FGF15‐SHP‐TFEB‐mediated lipophagy in the gut

Lysosome‐mediated macroautophagy, including lipophagy, is activated under nutrient deprivation but is repressed after feeding. We show that, unexpectedly, feeding activates intestinal autophagy/lipophagy in a manner dependent on both the orphan nuclear receptor, small heterodimer partner (SHP/NR0B2), and the gut hormone, fibroblast growth factor‐15/19 (FGF15/19). Furthermore, postprandial intestinal triglycerides (TGs) and apolipoprotein‐B48 (ApoB48), the TG‐rich chylomicron marker, were elevated in SHP‐knockout and FGF15‐knockout mice. Genomic analyses of the mouse intestine indicated that SHP partners with the key lysosomal activator, transcription factor‐EB (TFEB) to upregulate the transcription of autophagy/lipolysis network genes after feeding. FGF19 treatment activated lipophagy, reducing TG and ApoB48 levels in HT29 intestinal cells, which was dependent on TFEB. Mechanistically, feeding‐induced FGF15/19 signaling increased the nuclear localization of TFEB and SHP via PKC beta/zeta‐mediated phosphorylation, leading to increased transcription of the TFEB/SHP target lipophagy genes, Ulk1 and Atgl. Collectively, these results demonstrate that paradoxically after feeding, FGF15/19‐activated SHP and TFEB activate gut lipophagy, limiting postprandial TGs. As excess postprandial lipids cause dyslipidemia and obesity, the FGF15/19‐SHP‐TFEB axis that reduces intestinal TGs via lipophagic activation provides promising therapeutic targets for obesity‐associated metabolic disease.

477-P: Vagal GLP-1–Mediated Reductions in Postprandial Lipids Are Sensitive to Fructose Feeding

Dyslipidemia is a common co-morbidity of insulin resistance, where chronic elevations in hepatic and intestinal lipoproteins are linked to cardiovascular disease. Postprandial production is regulated in-part by gut-derived hormones such as glucagon-like peptide (GLP) -1. Although degradation-resistant analogs of GLP-1 continue to work in diabetic individuals, none have examined whether GLP-1s endogenous neuroendocrine signalling pathways are affected by diet-induced dyslipidemia. Thus, we sought to test whether native GLP-1 could modulate postprandial lipids in a fructose-fed hamster model.Hamsters were fed either a chow or fructose-enriched (FF) diet for 14 days, then received a portal vein injection of either GLP-1 (7-36) or vehicle control to examine if they remained responsive to portal GLP-1. Separately, in hamsters fed either chow or a fat/fructose/cholesterol enriched (FFC) diet we performed nodose ganglia (NG) injections with GLP-1 (7-36) or vehicle. To recapitulate the loss of vagal GLP-1R signalling in the absence of dietary intervention we selectively deafferented GLP-1R containing NG neurons via injection of the cytotoxin saporin conjugated to exendin-4. After treatment, animals received a gavage of olive oil and an intraperitoneal injection of poloxamer to prevent lipoprotein clearance. Postprandial triglyceride-rich lipoproteins isolated via density ultracentrifugation were assessed via blood draws over a 6-hour period.Chow-fed hamsters saw significant reductions in post-prandial lipids after portal GLP-1 injection, whereas FF-fed hamsters were unaffected. Chow-fed hamsters were similarly responsive to GLP-1 (7-36) injection into the NG, displaying reduced postprandial lipids; however, FFC-fed hamsters showed no reduction in plasma lipids. Finally, selective deafferentation of NG GLP-1R-containing neurons caused significant rises in postprandial TG and TRL, underscoring the importance of GLP-1R insensitivity in states of metabolic disease. Disclosure S.S.Hoffman: None. D.C.Alvares: None. K.Adeli: None. Funding CIHR Foundation Grant

29-LB: Investigating the Molecular Basis of the Microbiota-Mediated Regulation of Postprandial Chylomicron Production

Obesity and insulin resistance have been identified as major global health concerns. They are associated with increased intestinal chylomicron production and subsequent remnant lipoprotein accumulation which lead to postprandial dyslipidemia. Dietary composition influences metabolic output of the gut microbiota by digesting dietary nutrients and producing various metabolites, which affects host metabolism. Understanding the mechanistic roles of the microbiota in regulating host lipid metabolism is therefore critical in addressing the pathogenesis of dyslipidemia. In this study, we aimed to investigate the effects of microbiota on lipid and lipoprotein metabolism in Syrian golden hamsters which is a more relevant animal model to human. Microbiota depletion was induced in male and female hamsters given either standard chow or a low fat/high fructose (HF) diet via antibiotic oral gavage administration. The results showed that feeding a HF diet increased plasma triglyceride (TG) and cholesterol (CH) levels while substantially reduced microbiota in antibiotic-administered groups led to significant reduction in circulating TG and CH in both diets. Then, we intended to look at the role of dysbiosis on postprandial lipid accumulation. Interestingly, in both sexes postprandial and TRL-TG levels were dramatically reduced after antibiotic administration; the effect was associated with significantly decreased ApoB48 protein levels. These changes appear to be due to a modulation of genes involved in farnesoid X receptor (FXR) receptor signaling in the ileum. Additionally, some critical genes implicated in lipid synthesis and absorption were also altered in the jejunum, with the most remarkable discovery being the extremely substantial down regulation of Scavenger Receptor Class B type 1“SR-B1” at both the mRNA and protein levels in all antibiotic-treated groups independent of sex and diet. In summary, our results suggest a novel role for the gut microbiota in regulating lipid and lipoprotein metabolism in the gut, urging further studies to determine the underlying mechanisms. Disclosure N. H. S. Abdalqadir: None. K. Adeli: None. Funding Canadian Institutes of Health Research

Platycodi Radix Beverage Improves Postprandial Lipemic Response Associated With Plasma Bacteria-Derived Extracellular Vesicles in Healthy Adults With an Oral Fat Load

ObjectivesThis study aimed to examine the responsiveness of postprandial triglyceride-rich lipoprotein (TRL) metabolism to Platycodi radix beverage (PR) is associated with the alterations in plasma bacteria-derived extracellular vesicles (EVs) composition.MethodsNinety-six healthy and normolipidemic adults were randomly divided into two groups and consumed PR or placebo for 8 weeks. An oral fat tolerance test was performed before and after the 8-week intervention to access the postprandial lipid response. Plasma TG, chylomicron TG (CM-TG), and lipoprotein lipase (LPL) mass levels were measured at fasting, 3, and 6 hours during the oral fat tolerance test and summarized by computing the area under the curve (AUC). EVs isolated from fasting plasma samples were identified using 16S rRNA sequencing. A linear mixed-effect model was used to analyze the difference between the two groups. TLR clearance responder to PR consumption was defined by QUalitative INteraction Trees (QUINT). Lasso regularized generalized linear model (GLM) was used to find genera associated with the responsiveness.ResultsPR consumption for 8 weeks noticeably decreased AUC (0–3h) values for TG and CM-TG compared to the placebo group. Responders for TRL clearance were defined as subjects having higher LPL mass (150.6 ng/mL) and dietary fat intake (38.5 g/day) at baseline. Responders showed remarkable reductions in AUC (0–6h) values for TG and CM-TG in the PR group compared to the placebo group. Furthermore, GLM analysis demonstrated that the responsiveness of postprandial TRL clearance was accurately predicted by the model consisting of changes in the relative abundance of 16 genera, suggesting the close association between them.ConclusionsThese findings suggest that PR consumption modulates postprandial TRL clearance by altering plasma EV composition in normolipidemic adults with habitually higher fat intake over 38.5 g/day.Funding SourcesThis work was supported by the BK21 FOUR (Fostering Outstanding Universities for Research) funded by the Ministry of Education (MOE, Korea) and National Research Foundation of Korea (NRF), and the Bio & Medical Technology Development Program of the National Research Foundation (NRF), funded by the Ministry of Science & ICT (2012M3A9C4048761).

Effects of dapagliflozin on postprandial lipid metabolism in type 2 diabetes mellitus.

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) modulate lipid metabolism and improve cardiovascular morbidity and mortality in patients with type 2 diabetes mellitus (T2DM). The exact cardioprotective mechanism of SGLT2i is unclear. We evaluated the effects of SGLT2i on postprandial lipids, lipoprotein concentrations, glucose and fatty acids. A placebo-controlled randomized, proof-of-concept study. Fourteen male patients with T2DM on intensive insulin regimen were randomly and double-blind allocated to 12 weeks dapagliflozin (10 mg) or placebo. Postprandial effects were assessed with an 8-h standardized oral fat loading test. Mean glycated A1c did not change by dapagliflozin, but the mean daily insulin dose was significantly reduced. Although dapagliflozin did not affect fasting or postprandial levels of glucose and insulin, it increased the postprandial levels of glucagon. While fasting levels of free fatty acids and beta-hydroxybutyrate (bHBA) were unchanged, dapagliflozin significantly increased the postprandial bHBA response. This was seen in the context of increased postprandial glucagon levels by dapagliflozin, without influencing postprandial insulin or glucose levels. Dapagliflozin did not affect fasting or postprandial plasma cholesterol and triglycerides nor postprandial inflammatory markers. Fasting apolipoprotein B48 was decreased without affecting the postprandial response. Markers of inflammation and vascular function did not change. Treatment with dapagliflozin of patients with T2DM led to a reduction of fasting chylomicron remnants and increased postprandial ketone bodies compared to placebo suggesting enhanced hepatic fatty acid oxidation. The latter may have been caused by decreasing the insulin-glucagon ratio. The beneficial clinical effects seen in the trials using dapagliflozin most likely are not due to effects on postprandial inflammation nor postprandial lipemia.

Effect of Acute Intake of Fermented Orange Juice on Fasting and Postprandial Glucose Metabolism, Plasma Lipids and Antioxidant Status in Healthy Human.

Higher postprandial plasma glucose and lipemia, and oxidative and inflammatory responses, are considered important cardiovascular risk factors. Fermentation of fruits has generated products with high concentrations of bioactive compounds. The aim of this study was to evaluate the potential acute effects that fermented orange juice (FOJ) can exert in healthy humans by modulating postprandial response, and inflammatory/antioxidant status, compared with orange juice (OJ). Nine volunteers were recruited for a randomized, controlled, and crossover study. Participants ingested 500 mL of FOJ. At 4 h post intake, subjects consumed a standardized mixed meal. Blood samples were collected at 0–8 h hours post intake. The subjects repeated the protocol with OJ following a 2-week washout period. Glucose and lipid metabolism, plasma antioxidant capacity (ORAC, FRAP), endogenous antioxidants (albumin, bilirubin, uric acid), C-reactive protein and fibrinogen were measured in plasma samples. There was a trend of a smaller increase in LDL-C after FOJ intake compared with OJ, a significant decrease in apo-B and significant increase in ORAC. The glycemic and triglyceride response of meal was attenuated with FOJ. No differences were obtained in endogenous antioxidants and inflammation status between the treatments. The acute consumption of FOJ could play a protective role against cardiovascular risk factors.

GLP-2 Regulation of Dietary Fat Absorption and Intestinal Chylomicron Production via Neuronal Nitric Oxide Synthase (nNOS) Signaling.

Postprandial dyslipidemia is a metabolic condition commonly associated with insulin-resistant states, such as obesity and type 2 diabetes. It is characterized by the overproduction of intestinal chylomicron particles and excess atherogenic chylomicron remnants in circulation. We have previously shown that glucagon-like peptide 2 (GLP-2) augments dietary fat uptake and chylomicron production in insulin-resistant states; however, the underlying mechanisms remain unclear. Previous studies have implicated nitric oxide (NO) in the absorptive actions of GLP-2. In this study, we report a novel role for neuronal NO synthase (nNOS)-mediated NO generation in lipid uptake and chylomicron formation based on studies in C57BL/6J mice, nNOS-/- mice, and Syrian golden hamsters after intraduodenal and oral fat administration. GLP-2 treatment in wild-type (WT) mice significantly increased postprandial lipid accumulation and circulating apolipoprotein B48 protein levels, while these effects were abolished in nNOS-/- mice. nNOS inhibition in Syrian golden hamsters and protein kinase G (PKG) inhibition in WT mice also abrogated the effect of GLP-2 on postprandial lipid accumulation. These studies demonstrate a novel mechanism in which nNOS-generated NO is crucial for GLP-2-mediated lipid absorption and chylomicron production in both mouse and hamster models. Overall, our data implicate an nNOS-PKG-mediated pathway in GLP-2-mediated stimulation of dietary fat absorption and intestinal chylomicron production.

Insulin Requirement and Complications Associated With Serum C-Peptide Decline in Patients With Type 1 Diabetes Mellitus During 15 Years After Diagnosis

ObjectiveC-peptide is conventionally used in assessing pancreatic function in patients with diabetes mellitus. The clinical significance of this molecule during the course of type 1 diabetes mellitus (T1DM) has been recently revisited. This study aimed to investigate the natural course of C-peptide in T1DM patients over the period of 15 years and analyze the association between the residual C-peptide and diabetes complications.MethodsThis retrospective study included a total of 234 children and adolescents with T1DM. Patient data including sex, age at diagnosis, anthropometric measures, daily insulin dose, serum HbA1c, post-prandial serum C-peptide levels, lipid profiles, and diabetic complications at the time of diagnosis and 1, 3, 5, 10, and 15 years after diagnosis were retrospectively collected.ResultsAmong the 234 patients, 101 were men and 133 were women, and the mean patient age at initial diagnosis was 8.3 years. Serum C-peptide decreased constantly since the initial diagnosis, and showed a significant decline at 3 years after diagnosis. At 15 years after diagnosis, only 26.2% of patients had detectable serum C-peptide levels. The subgroup with older patients and patients with higher BMI standard deviation score showed higher mean serum C-peptide, but the group-by-time results were not significant, respectively. Patients with higher serum C-peptide required lower doses of insulin and had fewer events of diabetic ketoacidosis.ConclusionSerum C-peptide decreased consistently since diagnosis of T1DM, showing a significant decline after 3 years. Patients with residual C-peptide required a lower dose of insulin and had a lower risk for diabetic ketoacidosis.