Fat Meal Research Articles

Human intestinal lipid storage through sequential meals reveals faster dinner appearance is associated with hyperlipidemia.

BackgroundIt is increasingly recognized that intestinal cells can store lipids after a meal, yet the effect of this phenomenon on lipid absorption patterns in insulin resistance remains unknown.MethodsThe kinetics of meal fat appearance were measured in insulin-sensitive (IS, n = 8) and insulin-resistant (IR, n = 8) subjects after sequential, isotopically labeled lunch and dinner meals. Plasma dynamics on triacylglycerol-rich (TAG-rich) lipoproteins and plasma hormones were analyzed using a nonlinear, non–steady state kinetic model.ResultsAt the onset of dinner, IS subjects showed an abrupt plasma appearance of lunch lipid consistent with the “second-meal effect,” followed by slower appearance of dinner fat in plasma, resulting in reduced accumulation of dinner TAG of 48% compared with lunch. By contrast, IR subjects exhibited faster meal TAG appearance rates after both lunch and dinner. This effect of lower enterocyte storage between meals was associated with greater nocturnal and next-morning hyperlipidemia. The biochemical data and the kinetic analysis of second-meal effect dynamics are consistent with rapid secretion of stored TAG bypassing lipolysis and resynthesis. In addition, the data are consistent with a role for the diurnal pattern of plasma leptin in regulating the processing of dietary lipid.ConclusionThese data support the concept that intestinal lipid storage may be physiologically beneficial in IS subjects.Trial registrationClinicalTrials.gov NCT02020343.FundingThis study was supported by a grant from the American Diabetes Association (grant 1-13-TS-12).

Impact of Fat Intake on Blood Glucose Control and Cardiovascular Risk Factors in Children and Adolescents with Type 1 Diabetes.

Nutrition therapy is a cornerstone of type 1 diabetes (T1D) management. Glycemic control is affected by diet composition, which can contribute to the development of diabetes complications. However, the specific role of macronutrients is still debated, particularly fat intake. This review aims at assessing the relationship between fat intake and glycemic control, cardiovascular risk factors, inflammation, and microbiota, in children and adolescents with T1D. High fat meals are followed by delayed and prolonged hyperglycemia and higher glycated hemoglobin A1c levels have been frequently reported in individuals with T1D consuming high amounts of fat. High fat intake has also been associated with increased cardiovascular risk, which is higher in people with diabetes than in healthy subjects. Finally, high fat meals lead to postprandial pro-inflammatory responses through different mechanisms, including gut microbiota modifications. Different fatty acids were proposed to have a specific role in metabolic regulation, however, further investigation is still necessary. In conclusion, available evidence suggests that a high fat intake should be avoided by children and adolescents with T1D, who should be encouraged to adhere to a healthy and balanced diet, as suggested by ISPAD and ADA recommendations. This nutritional choice might be beneficial for reducing cardiovascular risk and inflammation.

Role of Tim4 in the regulation of ABCA1+ adipose tissue macrophages and post-prandial cholesterol levels

Dyslipidemia is a main driver of cardiovascular diseases. The ability of macrophages to scavenge excess lipids implicate them as mediators in this process and understanding the mechanisms underlying macrophage lipid metabolism is key to the development of new treatments. Here, we investigated how adipose tissue macrophages regulate post-prandial cholesterol transport. Single-cell RNA sequencing and protected bone marrow chimeras demonstrated that ingestion of lipids led to specific transcriptional activation of a population of resident macrophages expressing Lyve1, Tim4, and ABCA1. Blocking the phosphatidylserine receptor Tim4 inhibited lysosomal activation and the release of post-prandial high density lipoprotein cholesterol following a high fat meal. Both effects were recapitulated by chloroquine, an inhibitor of lysosomal function. Moreover, clodronate-mediated cell-depletion implicated Tim4+ resident adipose tissue macrophages in this process. Thus, these data indicate that Tim4 is a key regulator of post-prandial cholesterol transport and adipose tissue macrophage function and may represent a novel pathway to treat dyslipidemia.

Move it or lose it: limb immobilisation results in impaired postprandial skeletal muscle glucose uptake.

Move it or lose it: limb immobilisation results in impaired postprandial skeletal muscle glucose uptake.

Growth performance, immune status and intestinal fermentative processes of young turkeys fed diet with additive of full fat meals from Tenebrio molitor and Hermetia illucens

Full-fat insect meals were used in young turkeys feeding as feed additives to exert beneficial changes in the intestinal bacterial ecosystem functioning as well as in the immune and antioxidant systems. Two full-fat insect flours obtained from Tenebrio molitor (TM) and Hermetia illucens (HI) insects were added to the base diet (C) in the amount of 3 g/kg and compared to the control and to the effects following common monensin (MON) addition (dietary treatments: C, MON, TM, and HI). Although, the addition of full-fat insect meals to the diet didn't improve performance results such as monensin, it does exerted anti-inflammatory, immunostimulatory and antioxidant changes in turkeys’ blood. The HI and TM dietary treatments caused beneficial reduction in the blood total cholesterol content as well as increase in phosphorus which was not noted in MON treatment. The results indicated that in comparison to the control diet without any additives, the MON, TM and HI additives showed non-selective bacteriostatic properties, without adverse intensification of protein fermentation and pH digesta rise in the caeca of young turkeys. The addition of TM and HI similar as MON reduced the enzymatic activity of caecal microbiota, and decreased caecal concentration of all short-chain fatty acids, except butyric one. The caecal ammonia and dry matter concentration, and pH value of digesta were not affected by dietary treatments.

708-P: Complexity of Mealtime Insulin Dosing in Free-Living People with T1D: Novel Study with Varied Meal Macronutrient Content

Controlled in-patient studies indicate that high fat/protein meals require more insulin coverage than low fat meals with similar carbohydrate (CHO). However, it is unclear how dietary macronutrient content impacts on glycemic responses and insulin requirements in free-living T1D individuals. Adults with T1D (n=25) (mean±SD age 52±15 yrs, A1C 7.1±0.7%, 39% female) on insulin pump and continuous glucose monitoring (CGM) were enrolled in this 18-week duration study. Participants ate meals with specific macronutrient content (high glycemic index [GI], high fat [HGI-HF]; high GI, low fat [HGI-LF]; low GI, high fat [LGI-HF]; low GI, low fat [LGI-LF]). Meal, CGM, and insulin dosing data were reviewed by the study investigator, who provided dose optimization recommendations. Participants provided dosing and CGM data from 463 meals. Time-in-range (TIR) was similar for all meal types (table, p=0.72). LGI meals required significantly more insulin than HGI meals (p=0.01). Significantly more insulin per gram of CHO was used for LGI-HF vs. all other meal types (mean CHO-to-insulin ratio = 4.5 vs. 8.7 for HGI-HF, 7.6 for HGI-LF, and 5.5 for LGI-LF; p= 0.02). This exploratory study in free-living individuals with T1D highlights the complexity of mealtime insulin dosing, pointing to the need for bolus advisors that incorporate other dietary inputs in addition to CHO.View largeDownload slideView largeDownload slide DisclosureS. S. Edwards: Employee; Self; Eli Lilly and Company, Stock/Shareholder; Self; Eli Lilly and Company. W. Wang: Employee; Self; Eli Lilly and Company. E. Toschi: Consultant; Self; Medtronic. A. Atakov-castillo: None. R. Dewar: None. G. M. Steil: Consultant; Self; Abbott Diabetes, Eli Lilly and Company. H. Wolpert: Employee; Self; Eli Lilly and Company.FundingEli Lilly and Company

Study Protocol: A 2-Month Cross-Over Controlled Feeding Trial Investigating the Effect of Animal and Plant Protein Intake on the Metabolome and Cardiometabolic Health

ObjectivesA dietary shift in favor of plant protein (PP) sources over animal protein (AP) sources has been advocated for both sustainability and health reasons, this dietary transition being noticeably associated to decreased cardiovascular and diabetes risks. The differences in amino acid composition between PP and AP may have several effects on the metabolic pathways, and in turn health impacts, which are still poorly characterized. This project aims at characterizing, with a combination of “omics” approaches, the metabolic reorientations induced by a dietary shift from AP to PP sources and understanding their health effects in a population at cardiometabolic risk. MethodsWe will conduct a cross-over randomized feeding trial (NCT04236518) in 20 healthy overweight males (BMI 25–35), aged 25–55, with an enlarged waist circumference (> 94cm) and high plasma triglycerides (>1.5g/L). Participants will be assigned for 1 month each to 2 diets containing predominantly either AP (65% AP:35% PP) or PP (35% AP:65% PP) in a randomized order, separated by a 2-week wash-out period. Lunch and diner will be directly provided while dietary guidelines will be given for breakfast and snacks. Blood, urine and stool samples will be collected at the fasted state every 2 weeks. At the end of each dietary intervention, blood and urine will be collected following a high fat meal, which challenges metabolism and vascular homeostasis. Plasma and urine non-targeted metabolomics analyses (LC-MS) will be combined with Peripheral Blood Mononuclear Cell (PBMC) transcriptomics and fluxomics analyses (D2O tracer) to get a comprehensive overview of the metabolic phenotype associated with AP or PP intake. Flow-Mediated Dilatation (FMD) and Flow Laser Doppler (FLD) will be used to measure respectively macrovascular endothelial function and microvascular skin blood flow at the fasted state and after the high-fat meal. We will also measure anthropometric parameters and analyze biochemistry and inflammatory markers. ResultsNot applicable (protocols abstract). ConclusionsWe expect the multi-omics fingerprinting to reveal subtle metabolic differences associated to AP or PP intake, with a positive effect of PP intake. Improved inflammatory status and endothelial function are also expected to be associated to PP intake. Funding SourcesINRAE and Roquette Frères.

Macronutrient Composition of the Meal May Influence Postprandial Plasma IL-6 Concentration in Men With Overweight or Obesity: An Analysis of Pooled Clinical Trial Data

ObjectivesRisk of cardiovascular disease (CVD) is markedly associated with poor diet quality (e.g., a high intake of saturated fats, refined carbohydrates; and a low intake of whole grains, fruits, and vegetables). Numerous clinical studies report that consuming a high-saturated fat meal (HFM) induces postprandial inflammation. However, few studies have evaluated proinflammatory mediators after consuming a HFM compared to an average American meal (AAM). The objective of study was to investigate plasma proinflammatory cytokine levels after consumption of a HFM compared to an AAM in middle-aged men with overweight or obesity. MethodsThis pooled analysis included data from two randomized controlled trials designed to evaluate the anti-inflammatory effect of consuming a spice blend delivered in two different meals with similar calories (∼1000 kcal): (1) a HFM (33% kcal from saturated fat, 36% kcal from carbohydrate, 16% kcal from protein) or (2) an AAM (16% from saturated fat, 49% kcal from carbohydrate, ∼21% kcal from protein). Both meals had a minimal amount of spices added for palatability. The results reported are from subjects in the control group on each trial: a HFM with 1.4 g of garlic powder and an AAM with 0.6 g of a spice blend. Data from non-smoking, middle-aged (40–65 y) men with overweight/obesity (BMI ≥25 and ≤35 kg/m2), elevated waist circumference (≥94 cm), and at least one other risk factor for CVD were included in the analysis (Total n = 26; HFM consumption n = 12, AAM consumption n = 14). Plasma cytokine concentrations (IL-1β, IL-6, IL-8, TNF-α, and MCP-1) were measured at 0, 60,120, 180,240 min after meal consumption. ResultsThere was a significant time-by-meal interaction on plasma IL-6 concentration (P < 0.05). Plasma IL-6 concentration was significantly higher 180 min and 240 min (1189% and 362%, respectively; P < 0.05) after consuming a HFM compared to an AAM. There was no effect of meal or time-by-meal interaction on other plasma cytokines. ConclusionsConsumption of a HFM compared to an AAM resulted in a greater circulating IL-6 in men with overweight or obesity. Macronutrient composition of the meal may influence postprandial inflammatory responses. Funding SourcesMcCormick Science Institute and the National Center for Advancing Translational Sciences, NIH (1UL1TR002014–01).

A Single High Fat Meal Adversely Affects Postprandial Endothelial Function: A Systematic Review and Meta-Analysis

Abstract Objectives High-fat diets are associated with endothelial dysfunction, the first step in the progression to atherosclerosis and cardiovascular disease. We aimed to determine the postprandial endothelial response (flow-mediated dilation (FMD)) to a high-fat meal in various populations and define how the response varies by conducting a systematic review of the literature. Methods Six electronic databases were systematically searched for original research published from database inception to May 2020. Eligible studies measured both fasting and postprandial FMD following consumption of a meal containing ≥ 30 g fat or ≥ 40% energy from fat. A random-effects model was used to analyse the pooled effect size change from the fasting FMD, presented as mean difference. Moderator variables were analysed by meta-regression. Results One-hundred and twenty articles reporting on 3821 adults were included in the review. High fat meal consumption significantly attenuated FMD at 2 hours (MD: −1.61; 95% CI −2.02 −1.19, p &amp;lt; 0.001), 3 hours (−1.73; −2.30 −1.17, p &amp;lt; 0.001) and 4 hours (−1.54; −1.88 −1.20, p &amp;lt; 0.001), though heterogeneity (I2) was &amp;gt; 90%. Meta-regression revealed that fasting FMD significantly impacted the reported effect size (p &amp;lt; 0.0001) at all postprandial timepoints. Age and BMI were inversely correlated with FMD response at 2 and 4 hours (p &amp;lt; 0.0001). Conclusions Younger, healthy-weight participants exhibited a larger postprandial reduction in FMD compared to older, heavier groups after a high-fat meal. Vulnerable populations could be more likely to exhibit endothelial dysfunction, as evident through lower fasting FMD, together with impaired metabolic flexibility. A single high fat meal adversely impacts endothelial function and the magnitude of the impact on postprandial FMD was influenced by fasting FMD, participant age, and BMI. Funding Sources Monash University

Clinical pharmacokinetics of bdtx-189, an inhibitor of allosteric ErbB mutations, in patients with advanced solid malignancies in MasterKey-01 study.

3097 Background: Allosteric oncogenic mutations occur outside the canonical ATP-binding site of EGFR and HER2, and there are no approved therapies that target such mutations. BDTX-189 is a potent, selective, irreversible inhibitor of 48 allosteric EGFR and HER2 mutant variants under clinical evaluation in the ongoing MasterKey-01 trial (NCT04209465). BDTX-189 was designed to rapidly and irreversibly occupy the active site of targeted ErbB mutants, leading to sustained pharmacodynamic (PD) effects, and with selectivity over EGFR-WT in order to minimize EGFR-WT mediated toxicities. The pharmacokinetic (PK) profile was designed for rapid absorption and fast elimination to maintain target occupancy while minimizing prolonged drug exposure that could contribute to off-target associated toxicities. Methods: In MasterKey-01, BDTX-189 was administered orally once daily in continuous 21-day cycles, taken fasted. Dose escalation included cohorts of 1-2 patients receiving doses between 25 and 200 mg QD followed by 5-7 patients receiving 400 mg, 800 mg, or 1,200 mg QD fasted. The possible effects of a high fat meal on the PK of BDTX-189 were assessed in a subset of patients receiving single doses of 400 mg BDTX-189 fasted and immediately after a high-fat breakfast in a randomized crossover fashion with 3 days between doses. In addition, a dose escalation cohort investigating administration of BDTX-189 non-fasted was enrolled at 800 mg QD. Serial blood samples for analysis of plasma BDTX-189 concentrations were collected after each dose on C1D1 and C1D15. BDTX-189 levels were determined using LC-MS, and data analyzed using non-compartmental methods. Results: After single and multiple doses, BDTX-189 was rapidly absorbed (median tmax 1-2 h), with an elimination t1/2 of 2-6 h. Dose-dependent increases in exposure from 200 to 800 mg QD fasted were observed, with no apparent accumulation or decline in exposures observed at steady-state. Administration of BDTX-189 with a high-fat meal increased AUC approximately 1.7-fold with minimal effect on Cmax, relative to administration in the fasted state. At 800 mg QD, mean AUC was similar in the non-fasting state relative to fasting and was within the target efficacious range defined by mouse models harboring allo-ErbB mutated tumors. Median tmax and t1/2 values were similar after administration in the non-fasted and fasted states. Conclusions: BDTX-189 demonstrated rapid absorption and a short PK half-life consistent with the desired PK/PD profile, with exposures in the efficacious target range based on preclinical data. The pilot high fat food-effect data and non-fasting QD dosing regimen show similar or improved systemic exposure relative to dosing in the fasted state. The MasterKey-01 trial is ongoing, including refinement of the dosing regimen and identification of the recommended phase 2 dose. Clinical trial information: NCT04209465.

TLANDO, a Novel Oral TRT, Improves Sexual and Mental Domain Outcomes in Hypogonadal Men

Male hypogonadism is characterized by symptoms and deficiency (<300 ng/dL) in levels of in total testosterone (TT), a critical hormone for sexual, cognitive, and body function and development. TLANDO, a testosterone undecanoate (TU) comprising lymphatically delivered oral testosterone replacement therapy (TRT) option not requiring dose titration, treatment has demonstrated effective restoration in hypogonadal men of TT levels to the eugonadal range in multiple clinical studies. TLANDO therapy resulted in decreased sex hormone binding globulin with increased free testosterone (FT). TLANDO’s unique delivery system enables consistent restoration of TT regardless of meal fat content. Moreover, TLANDO has shown potential to improve liver health through resolution of fatty liver disease in hypogonadal men and is not known to have any adverse liver effects. However, it is unclear if fixed dose TLANDO therapy without dose adjustment improves symptoms of psychosexual functions. The objective is to assess key sexual and mental domain Patient Reported Outcomes (PRO) post 52 weeks of treatment using TLANDO on the to-be-marketed dosing regimen in comparison with a widely used topical TRT, Androgel 1.62%. Data analysis was performed in in hypogonadal males post TLANDO treatment without dose adjustment, and in patients on the active control from a randomized, multi-center, open label, active controlled 52-week trial (SOAR, NCT02081300). Sexual and mental domain function PROs were measured at baseline (BL) and end of study (EOS) using Psychosexual Daily Questionnaire (PDQ) and Short Form (SF)-36 surveys and compared between TLANDO and active control. Post treatment with TLANDO dosing regimen not requiring dose titration, key sexual domain function PROs at week 52 were significantly (p<0.05) improved from BL: positive mood (BL:4.5 vs EOS:5.1, p<0.001), negative mood (1.8 vs 1.4, p<0.01), overall sexual desire (2.5 vs 3.7, p<0.001), sexual activity (2.5 vs 4.0, p<0.001), highest pleasure with partner (2.0 vs 2.8, p=0.06), highest pleasure without partner (1.8 vs 2.4, p<0.05), weekly maintained erection (3.3 vs 4.5, p<0.001), and weekly full erection % (50.5% vs 68.9%, p<0.001). Most sexual and mental function PROs were comparable to Androgel 1.62. TLANDO therapy was well tolerated through 52 weeks of treatment exposure. In conclusion, TLANDO, a novel easy to use and prescribe TRT not requiring dose titration, demonstrated improvement in sexual and mental PROs, a significant unmet need in hypogonadal males. Further placebo-controlled studies are warranted to better elucidate these improvements.

Efficacy and Safety of TLANDO, A Novel Oral Easy to Prescribe and Use TRT Option

Most widely used testosterone replacement therapy (TRT) products can be inconvenient and cumbersome topical and invasive injectable requiring dose adjustments to attain efficacy. In a pivotal study, a recently approved oral TRT only 26% of patients did not require any dose adjustment. Typically, patients start on a sub-therapeutic dose with gradual dose increases to attain efficacy resulting in additional visit(s) to clinic and pharmacy. Physician research data (N=402) suggested it typically takes 3-6 months of titrations to reach an efficacious dose for majority of patients, a significant barrier in effecting a switch without a period of “efficacy gap”. The requirement of additional visit(s) presents significant challenges for new and current patients desiring to start and to switch to a convenient TRT option, especially in the current COVID-19 pandemic. Recent reports suggest increase of disease severity/mortality in men with low testosterone is possibly due to underlying co-morbidities commonly associated with male hypogonadism. There remains a need for an effective, safe, and easy to use and prescribe product that does not require dose titration. TLANDO is a “triglyceride-free” oral single strength TRT with single dose designed to lymphatically deliver effective and safe levels of testosterone regardless of meal fat content. Moreover, dose titration is prone to some inherent titration decision errors and requires understanding of often complex titration rules. The objective is to assess whether TLANDO, an oral TRT without requiring dose titration, safely restores effective testosterone (T) levels in hypogonadal men. An open-label, single-arm, multicenter study (NCT03242590) was performed with TLANDO in hypogonadal males (N=95). Subjects received orally 225 mg twice a day testosterone undecanoate (TU) for 24 days without dose adjustment. Efficacy was evaluated by % of subjects who achieved daily T Cavg within the eugonadal range. Using 450mg daily dose without dose adjustment, 80% of subjects (95% CI of 72% to 88%) achieved a T Cavg in the normal range and safely restored with mean T Cavg of 476±184 ng/dL post steady state. T restoration was comparable to other non-oral TRT products. TLANDO was well tolerated with no deaths, no drug-related severe AEs, and no hepatic AEs. In conclusion, effective T restoration using TLANDO, an easy to use and prescribe oral TRT option, was confirmed. Minimal AEs were reported with no hepatic AEs. Upon approval, TLANDO will be the first convenient TRT option without requiring dose adjustments; therefore, enabling selection of an efficacious dose from the start of therapy. TLANDO is well suited for new or existing TRT patients desiring a convenient oral option.

Diet and lung disease-Are fruits and vegetables the ideal whole-food intervention?

Diet and lung disease-Are fruits and vegetables the ideal whole-food intervention?

Lipid digestibility and bioaccessibility of a high dairy fat meal is altered when consumed with whole apples: Investigations using static and dynamic in vitro digestion models

It remains unclear how consuming whole apples, as a food matrix containing pectin and polyphenols, influences lipid digestibility and bioaccessibility from dairy-based meals. Pectin and polyphenols modulate lipid digestion in vitro, but their functionality can be altered by gastric pH, which is buffered by co-consuming dairy products. In the present study, a dairy meal containing 3 wt% protein and 10 wt% fat was digested with and without apples using static (i.e., adapted from INFOGEST standardized static model) and dynamic (TIM-1) in vitro methods to investigate the structure, digestibility, and bioaccessibility of milk fat from emulsion droplets in the presence of consumed apples. Furthermore, in the static digestion, the initial gastric pH was adjusted to 3.0 (i.e., acidic digestion, as INFOGEST protocol suggested) or remained unadjusted (pH = 6.5, i.e., neutral digestion, buffered by the dairy meal) to explore the effects of gastric acidity. Emulsion droplet structure and lipid digestibility in the static digestion were primarily influenced by gastric pH [mean lipolysis rate = 99.32 % and 83.95 % (p < 0.05) for the digestions with neutral and acidic pH in the gastric phase, respectively], but not the presence of apple. However, co-consumption of apples reduced the lipid bioaccessibility measured by TIM-1 [mean bioaccessibility = 65.44 % and 98.92 % (p < 0.05) for the digestions with and without apples, respectively]. Discrepancies in the bioaccessibility of individual fatty acids between the static and TIM-1 models were observed, which may be attributed to variations in the experimental parameters, e.g., chyme transit and enzyme concentration. Overall, this study shows the potential to preferentially modify lipid digestibility and bioaccessibility in high-fat meals by co-consuming apples. It also cautions attention to the digestive conditions of in vitro simulation studies when making comparisons to in vivo conditions.

Glu298Asp (rs1799983) Polymorphism Influences Postprandial Vascular Reactivity and the Insulin Response to Meals of Varying Fat Composition in Postmenopausal Women: Findings from the Randomized, Controlled Dietary Intervention and VAScular function (DIVAS)-2 Study

Previous acute studies suggest the Glu298Asp polymorphism (rs1799983) may influence vascular reactivity in response to long-chain n-3 PUFA intake. However, the effects of this genotype on postprandial vascular function after meals rich in SFAs, n-6 PUFAs, and MUFAs are unclear. This study determined the impact of the Glu298Asp polymorphism on changes in vascular function and cardiometabolic risk biomarkers in response to sequential meals of varying fat composition. In a randomized, double-blind, crossover, acute study, 32 postmenopausal women (mean±SD age: 58±5y; BMI: 25.9±4.1kg/m2) consumed mixed meals (breakfast: 0min, 50g fat; lunch: 330min, 30g fat) containing SFAs, n-6 PUFAs, or MUFAs on 3 occasions. Blood samples for cardiometabolic disease risk markers and real-time measures of vascular reactivity [including flow-mediated dilatation (FMD; primary outcome)] were collected/performed before and regularly for 480min after breakfast. Participants were retrospectively genotyped for the Glu298Asp (rs1799983) polymorphism. Data were analyzed using linear mixed models. For the postprandial %FMD response, a test fat × genotype interaction was observed for the AUC (P=0.019) but not incremental AUC (IAUC), with the AUC being ∼24% greater after MUFA- than after SFA- and n-6 PUFA-rich meals in the Glu298 homozygotes (P≤0.026). Test fat × genotype interactions were also evident for postprandial insulin (P≤0.005), with the MUFA-rich meals demonstrating significantly higher AUC (12.8%/14.9%), IAUC (14.6%/20.0%), and maximum concentration (20.0%/34.5%) than the SFA- and n-6 PUFA-rich meals, respectively, in Asp298 carriers (P<0.05). Genotype did not influence other study outcome measures in response to the test fats. Our findings suggest the Glu298Asp polymorphism may represent a potential determinant of the inter-individual variability in postprandial responsiveness of %FMD and insulin to acute meal fat composition in postmenopausal women. Further studies are required to confirm these observations.This trial was registered at clinicaltrials.gov as NCT02144454.

Postprandial Fatty Acid Profile, but Not Cardiometabolic Risk Markers, Is Modulated by Dairy Fat Manipulation in Adults with Moderate Cardiovascular Disease Risk: The Randomized Controlled REplacement of SaturatEd fat in dairy on Total cholesterol (RESET) Study.

ABSTRACTBackgroundChronic consumption of dairy products with an SFA-reduced, MUFA-enriched content was shown to impact favorably on brachial artery flow-mediated dilatation (FMD). However, their acute effect on postprandial cardiometabolic risk biomarkers requires investigation.ObjectiveThe effects of sequential high-fat mixed meals rich in fatty acid (FA)–modified or conventional (control) dairy products on postprandial FMD (primary outcome) and systemic cardiometabolic biomarkers in adults with moderate cardiovascular risk (≥50% above the population mean) were compared.MethodsIn a randomized crossover trial, 52 participants [mean ± SEM age: 53 ± 2 y; BMI (kg/m2) 25.9 ± 0.5] consumed a high-dairy-fat breakfast (0 min; ∼50 g total fat: modified: 25 g SFAs, 20 g MUFAs; control: 32 g SFAs, 12 g MUFAs) and lunch (330 min; ∼30 g total fat; modified: 15 g SFAs, 12 g MUFAs; control: 19 g SFAs, 7 g MUFAs). Blood samples were obtained before and until 480 min after breakfast, with FMD assessed at 0, 180, 300, and 420 min. Data were analyzed by linear mixed models.ResultsPostprandial changes in cardiometabolic biomarkers were comparable between the different dairy meals, with the exception of a tendency for a 4% higher AUC for the %FMD response following the modified-dairy-fat meals (P = 0.075). Plasma total lipid FA analysis revealed that incremental AUC responses were 53% lower for total SFAs, 214% and 258% higher for total cis-MUFAs (predominantly cis-9 18:1), and trans-18:1, respectively, following the modified relative to the control dairy meals (all P < 0.0001).ConclusionsIn adults at moderate cardiovascular risk, acute consumption of sequential high-fat meals containing FA-modified dairy products had little impact on postprandial endothelial function or systemic cardiometabolic biomarkers, but a differential effect on the plasma total lipid FA profile, relative to conventional dairy fat meals.This trial was registered at clinicaltrials.gov as NCT02089035.

Abstract PS12-15: Pharmacokinetics of H3B-6545 in patients with locally advanced or metastatic estrogen receptor-positive HER2 negative breast cancer (ER+ and HER2- BC)

Abstract RATIONALE: Addition of CDK 4/6 inhibitors to endocrine therapy has become standard for patients (pts) with ER+ and HER2- BC with improvements in overall survival. However, acquired resistance to front-line therapy is inevitable, and response to later-line therapy is poor. H3B-6545 is a selective, orally available, small molecule covalent antagonist of the estrogen receptor (ERα). H3B-6545 binds covalently to a cysteine residue at position 530 of both wild-type and the constitutively active mutant ERα proteins. H3B-6545 demonstrated significant antitumor activity in multiple PDX breast cancer models, including those with mutated ESR1 (the gene encoding ERα). A phase I-II study was conducted to explore the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics, and efficacy of this agent in advanced ER+ and Her2- breast cancer pts (NCT03250676). METHODS: PK samples in phase I were obtained at day 1 and day 15 of cycle 1 (Predose, 0.5, 1, 2, 4, 6, 8, 10, and 24 h post dose) and sparse PK samples were collected in the phase II part of the trial. For pts enrolled in the food effect sub-study of phase II, plasma samples were collected during cycle 1 on day 15 and day 22 (Predose, 0.5, 1, 2, 4, 6, 8, 10, and 24 h post dose). Nonlinear mixed effect model (NONMEM) was applied for development of population PK models to fit H3B-6545 plasma concentration data with NONMEM® version 7.4 software. R was used for data management, visualization and statistical summaries. RESULTS: This phase I-II trial enrolled 47 pts in phase I part and 83 pts in the phase II part at the recommended phase II dose of 450 mg QD as of May 15, 2020. The 1180 plasma concentrations of H3B-6545 from a total of 103 pts at doses of 100-600 mg available as of January 15, 2020 were included in this analysis, with the following characteristics [n or (median, min-max) unit]: race (n=91/5/1/6 for White/Black/Asian/others), age (62.5, 31-81) yrs, body weight (79.5, 49-140) Kg, BMI (26.9, 17.6-45.6) Kg/m2, albumin (40, 29-52) g/dL, ALP (88.5, 39-917) IU/L, ALT (28, 10-193) IU/L, AST (36.5, 13-259) IU/L, bilirubin (8.6, 1.7-25.7) µM and creatinine clearance (112, 49.5-389) mL/min. The median number of prior therapy in the metastatic setting was 3 (range: 1 - 10). Out of 103 patients, 32 pts received treatment with a single high-fat meal to test food effect on PK over a randomized crossover design. H3B-6545 plasma concentrations were best described with a one compartment disposition PK model, plus a combined first- and zero-order parallel absorption and lag time. The estimated apparent clearance (CL/F) and volume of distribution (V/F) were 31 L/h and 422 L, respectively, with a typical terminal half-life of about 10 hours. H3B-6545 was absorbed fast, with a typical tmax of about 4 hours. A moderate to high variability (40-60%) was identified in major PK parameters (CL/F, V/F, bioavailability [F1]). A high-fat meal increased bioavailability by approximately 45% and prolonged tmax, roughly from 4 hours to 6 hours post dose. No significant effect was identified from other covariates: age, body weight, race, albumin, AST, ALP, ALT, bilirubin and creatinine clearance. CONCLUSIONS: H3B-6545 PK profiles in breast cancer patients were well described by a one-compartment disposition model with no significant effect of demographics, liver and renal function. When administered with a high fat meal, H3B-6545 exposure was modestly increased. Citation Format: Oneeb Majid, Jianjun Alan Xiao, Tarek Sahmoud, Sanae Yasuda, Lisa Cantagallo, Erika P Hamilton, Timothy Pluard, Dejan Juric, Antonio Gualberto, Ziad Husseiin. Pharmacokinetics of H3B-6545 in patients with locally advanced or metastatic estrogen receptor-positive HER2 negative breast cancer (ER+ and HER2- BC) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS12-15.

Effects of high-carbohydrate versus mixed-macronutrient meals on female soccer physiology and performance

Athletes are often told to minimize intakes of fiber, fat, and protein in pre-competition meals to avoid gut distress, but this guidance is based on scant direct evidence. This study evaluated the physiological and perceptual effects of pre-competition mixed-macronutrient (MM) and high-carbohydrate (HCHO) meals in collegiate female soccer players. Fifteen players participated in this randomized, investigator-blinded, crossover study involving two ~ 1000-kcal meals (HCHO and MM) consumed 4h prior to 70-min scrimmages. Assessments included global positioning system (GPS) tracking, heart rate (HR), perceived exertion (RPE), ratings of fatigue (ROF), gut symptoms, and perceptions of satiety, hunger, and fullness. Differences between conditions for HR, RPE, ROF, and gut symptoms were evaluated with Wilcoxon signed-rank tests. GPS data and hunger, satiety, and fullness scores were compared using within-subjects repeated measures ANOVAs. No statistically significant differences were found between the conditions at any time point for HR, RPE, ROF, or gut symptoms. Significant time effects were found for two GPS variables (total distance covered and high-speed running), indicating that participants covered less distance during the second half of the scrimmages in comparison to the first half. However, there were no significant condition or condition × time interactions for GPS data. Finally, there were no condition or condition × time interactions for hunger, fullness, and satiety, though significant time effects were observed. A MM meal consumed 4h prior to 70min of soccer competition does not increase gut symptoms and can be similarly ergogenic as a HCHO meal.

Apple consumption reduces markers of postprandial inflammation following a high fat meal in overweight and obese adults: A randomized, crossover trial.

High fat meal-induced postprandial inflammation is exacerbated in overweight and obesity and may contribute to cardiovascular disease (CVD) risk. This study aimed to determine the effects of apples, rich in anti-inflammatory polyphenols, on biomarkers of postprandial inflammation in individuals with overweight and obesity. A randomized, crossover trial was conducted with n = 26 participants (17 female/9 male; mean age 45.5 ± 3.12 years; mean BMI 34.1 ± 1.18 kg m-2) to assess the effects of 3 whole Gala apples (∼200 g) on the 2, 4 and 6 h postprandial response to a high fat meal providing 1 g fat per kg body weight. Changes in plasma biomarkers of inflammation (as the primary outcome) and endotoxin exposure, non-esterified fatty acids (NEFA) and total antioxidant capacity (TAC) were measured. Fasting (0 h) and 4 h peripheral blood mononuclear cells (PBMC) were also isolated from whole blood and stimulated with or without a physiological dose (10 ng mL-1) of lipopolysaccharide (LPS) to measure secreted cytokines. Apples modulated postprandial plasma IFN-γ and reduced its peak concentration (-12.8%), and increased both 4 h (14.4%) and peak (10.5%) TAC (P < 0.05). In unstimulated and LPS-stimulated PBMC, apples reduced secreted IL-6 (-49.3% and -17.1%) and TNF-α (-43.3% and -14.7%) and increased IL-4 (93.1% and 15.8%) in both the unstimulated and LPS-stimulated conditions, as well as decreased GM-CSF (-26.0%) and IL-17 (-47.9%) in unstimulated PBMC and G-CSF (-19.8%) in LPS-stimulated PBMC (P < 0.05). These data suggest acute whole Gala apple consumption may be an effective dietary strategy to mitigate high fat meal-induced postprandial inflammation that exacerbates CVD risk in overweight and obesity. This study was registered at clinicaltrials.gov, NCT03523403, The Apple Study: Investigating the Effects of Whole Apple Consumption on Risk Factors for Chronic Metabolic Diseases in Overweight and Obese Adults.

Proof of pharmacology of Org 48775-0, a p38 MAP kinase inhibitor, in healthy volunteers.

To investigate the safety, tolerability, pharmacokinetics and pharmacodynamics of the highly selective oral p38alpha/beta mitogen-activated protein (MAP) kinase inhibitor Org 48,775-0 in a first-in-human study. In the single ascending dosing (SAD) study, an oral dose of Org 48,775-0 (0.3-600 mg) was evaluated in healthy males. In the multiple ascending dosing (MAD) study, levels of 30, 70 and 150 mg were dosed for six consecutive days, twice daily. Both studies were performed in a double-blind, randomized, placebo-controlled, cross-over fashion and evaluated pharmacokinetics, pharmacodynamics (ex vivo inhibition of lipopolysaccharide [LPS]-induced tumor necrosis factor (TNFα) release) and routine clinical and laboratory data. Pharmacokinetic and pharmacodynamic parameters of Org 48,775-0 were compared between healthy males and postmenopausal females, and the effect of a standardized fat meal was evaluated. All adverse events observed in the SAD (16; dizziness and headache, diarrhoea and catheter-related phlebitis) and MAD (43; mainly somnolence, dizziness, headache and nasopharyngitis) cohorts were mild, transient and completely reversible. Pharmacokinetics were linear up to single doses of 400 mg. Median Tmax ranged from 0.5 to 1.8 hours, geometric mean for T1/2 from 7.0 to 14.4 hours. Org 48,775-0 doses equal to and greater than 30 mg significantly inhibited LPS-induced TNFα release (42.3%; 95% CI = -65.2, -4.3) compared to placebo. In the MAD study, Org 48,775-0 treatment inhibited LPS-induced TNFα release during the entire steady-state period. Levels of inhibition amounted 30-75% for 30 mg, 53-80% for 70 mg and 77-92% for 150 mg Org 48,775-0. Org 48,775-0 has the capacity to significantly inhibit MAP kinase activity in humans without safety concerns.