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Metabolomics : Official Journal of the... May 2024Analysis of time-resolved postprandial metabolomics data can improve our understanding of the human metabolism by revealing similarities and differences in postprandial...
INTRODUCTION
Analysis of time-resolved postprandial metabolomics data can improve our understanding of the human metabolism by revealing similarities and differences in postprandial responses of individuals. Traditional data analysis methods often rely on data summaries or univariate approaches focusing on one metabolite at a time.
OBJECTIVES
Our goal is to provide a comprehensive picture in terms of the changes in the human metabolism in response to a meal challenge test, by revealing static and dynamic markers of phenotypes, i.e., subject stratifications, related clusters of metabolites, and their temporal profiles.
METHODS
We analyze Nuclear Magnetic Resonance (NMR) spectroscopy measurements of plasma samples collected during a meal challenge test from 299 individuals from the COPSAC cohort using a Nightingale NMR panel at the fasting and postprandial states (15, 30, 60, 90, 120, 150, 240 min). We investigate the postprandial dynamics of the metabolism as reflected in the dynamic behaviour of the measured metabolites. The data is arranged as a three-way array: subjects by metabolites by time. We analyze the fasting state data to reveal static patterns of subject group differences using principal component analysis (PCA), and fasting state-corrected postprandial data using the CANDECOMP/PARAFAC (CP) tensor factorization to reveal dynamic markers of group differences.
RESULTS
Our analysis reveals dynamic markers consisting of certain metabolite groups and their temporal profiles showing differences among males according to their body mass index (BMI) in response to the meal challenge. We also show that certain lipoproteins relate to the group difference differently in the fasting vs. dynamic state. Furthermore, while similar dynamic patterns are observed in males and females, the BMI-related group difference is observed only in males in the dynamic state.
CONCLUSION
The CP model is an effective approach to analyze time-resolved postprandial metabolomics data, and provides a compact but a comprehensive summary of the postprandial data revealing replicable and interpretable dynamic markers crucial to advance our understanding of changes in the metabolism in response to a meal challenge.
Topics: Humans; Postprandial Period; Male; Female; Metabolomics; Adult; Fasting; Principal Component Analysis; Magnetic Resonance Spectroscopy; Middle Aged; Data Analysis; Metabolome
PubMed: 38722393
DOI: 10.1007/s11306-024-02109-y -
Bio Systems Jun 2024Hepatocyte lipid and glucose metabolism is regulated not only by major hormones like insulin and glucagon but also by many other factors, including calcium ions....
Hepatocyte lipid and glucose metabolism is regulated not only by major hormones like insulin and glucagon but also by many other factors, including calcium ions. Recently, mitochondria-associated membrane (MAM) dysfunction combined with incorrect IP-receptor regulation has been shown to result in abnormal calcium signaling in hepatocytes. This dysfunction could further lead to hepatic metabolism pathology. However, the exact contribution of MAM dysfunction, incorrect IP-receptor regulation and insulin resistance to the calcium-insulin-glucagon interplay is not understood yet. In this work, we analyze the role of abnormal calcium signaling and insulin dysfunction in hepatocytes by proposing a model of hepatocyte metabolic regulatory network with a detailed focus on the model construction details besides the biological aspect. In this work, we analyze the role of abnormal calcium signaling and insulin dysfunction in hepatocytes by proposing a model of hepatocyte metabolic regulatory network. We focus on the model construction details, model validation, and predictions. We describe the dynamic regulation of signaling processes by sigmoid Hill function. In particular, we study the effect of both the Hill function slope and the distance between Hill function extremes on metabolic processes in hepatocytes as a model of nonspecific insulin dysfunction. We also address the significant time difference between characteristic time of glucose hepatic processing and a typical calcium oscillation period in hepatocytes. Our modeling results show that calcium signaling dysfunction results in an abnormal increase in postprandial glucose levels, an abnormal glucose decrease in fasting, and a decreased amount of stored glycogen. An insulin dysfunction of glucose phosphorylation, glucose dephosphorylation, and glycogen breakdown also cause a noticeable effect. We also get some insight into the so-called hepatic insulin resistance paradox, confirming the hypothesis regarding indirect insulin action on hepatocytes via dysfunctional adipocyte lipolysis.
Topics: Hepatocytes; Glucose; Calcium; Lipid Metabolism; Models, Biological; Calcium Signaling; Humans; Insulin; Animals; Insulin Resistance; Metabolic Networks and Pathways
PubMed: 38718915
DOI: 10.1016/j.biosystems.2024.105227 -
American Journal of Physiology.... Jul 2024Skeletal muscle microvascular blood flow (MBF) plays an important role in glucose disposal in muscle. Impairments in muscle MBF contribute to insulin resistance and...
Skeletal muscle microvascular blood flow (MBF) plays an important role in glucose disposal in muscle. Impairments in muscle MBF contribute to insulin resistance and prediabetes. Animal studies show that short-term (3 day) high-fat feeding blunts skeletal muscle MBF before impairing insulin-stimulated glucose disposal. It is not known whether this occurs in humans. We investigated the temporal impact of a 7-day high-calorie high-fat (HCHF) diet intervention (+52% kJ; 41% fat) on fasting and postprandial cardiometabolic outcomes in 14 healthy adults (18-37 yr). Metabolic health and vascular responses to a mixed-meal challenge (MMC) were measured at pre ()-, mid ()- and post ()-intervention. There were no significant differences in body weight, body fat %, fasting blood glucose, and fasting plasma insulin concentrations at pre-, mid- and postintervention. Compared with preintervention there was a significant increase in insulin (but not glucose) total area under the curve in response to the MMC at midintervention ( = 0.041) and at postintervention ( = 0.028). Unlike at pre- and midintervention, at postintervention muscle MBF decreased at 60 min ( = 0.024) and 120 min ( = 0.023) after the MMC. However, macrovascular blood flow was significantly increased from 0 to 60 min ( < 0.001) and 120 min ( < 0.001) after the MMC at pre-, mid- and postintervention. Therefore, short-term HCHF feeding in healthy individuals leads to elevated postprandial insulin but not glucose levels and a blunting of meal-induced skeletal muscle MBF responses but not macrovascular blood flow responses. This is the first study to investigate skeletal muscle microvascular blood flow (MBF) responses in humans after short-term high-calorie high-fat (HCHF) diet. The main findings were that HCHF diet causes elevated postprandial insulin in healthy individuals within 3 days and blunts meal-induced muscle MBF within 7 days, despite no impairments in postprandial glucose or macrovascular blood flow.
Topics: Humans; Hyperinsulinism; Adult; Male; Muscle, Skeletal; Young Adult; Female; Diet, High-Fat; Adolescent; Postprandial Period; Insulin; Blood Glucose; Regional Blood Flow; Microcirculation; Insulin Resistance; Healthy Volunteers; Microvessels; Fasting
PubMed: 38717363
DOI: 10.1152/ajpendo.00070.2024 -
Brazilian Journal of Medical and... 2024Patients undergoing chemotherapy with cisplatin commonly present gastrointestinal effects such as constipation and gastric emptying (GE) delay. Both the purinergic...
Patients undergoing chemotherapy with cisplatin commonly present gastrointestinal effects such as constipation and gastric emptying (GE) delay. Both the purinergic system and physical exercise modulate the gastrointestinal (GI) tract. In the current study, we investigated the role of ATP, physical exercise, and P2X7 receptor blocking on GE delay induced by cisplatin in rats. Male rats were divided into the following groups: control (C), cisplatin (Cis), exercise (Ex), Brilliant Blue G (BBG), ATP, Cis+Ex, Cis+ATP, Cis+BBG, Cis+Ex+BBG, Cis+Ex+BBG+ATP, and Cis+ATP+BBG. GE delay was induced by treatment with 1 mg/kg cisplatin (1 time/week for 5 weeks, ip). The moderate physical exercise was swimming (1 h/day, 5 days/week for 5 weeks). At the end of the treatment or exercise and 30 min before the GE assessment, some groups received BBG (50 mg/kg, sc) or ATP (2 mg/kg, sc). Then, GE was assessed after a 10-min postprandial period. Chronic use of Cis decreased GE delay (P<0.05) compared to the control group. Both exercise and ATP prevented (P<0.05) GE delay compared to Cis. The pretreatment with BBG significantly inhibited (P<0.05) the effect of exercise and ATP. On the other hand, the association between exercise and ATP reversed (P<0.05) the effect of the BBG and prevented GE delay. Therefore, we suggest that both exercise and treatment with ATP activate P2X7 receptors and prevent GE delay induced by cisplatin in rats.
Topics: Animals; Cisplatin; Male; Adenosine Triphosphate; Gastric Emptying; Receptors, Purinergic P2X7; Physical Conditioning, Animal; Rats, Wistar; Antineoplastic Agents; Rats; Purinergic P2X Receptor Antagonists
PubMed: 38716980
DOI: 10.1590/1414-431X2024e13234 -
Cureus Apr 2024Post-prandial hyperglycemia (PPHG) remains a complex aspect in the management of type 2 diabetes mellitus (T2DM) in the Indian population due to uncertainty in the...
BACKGROUND
Post-prandial hyperglycemia (PPHG) remains a complex aspect in the management of type 2 diabetes mellitus (T2DM) in the Indian population due to uncertainty in the optimal utilization of alpha-glucosidase inhibitors (AGIs) either as standalone therapy or in combination, whether initiated initially or as a sequential therapy.
METHODS
This was a post-approval, observational, multicentric clinical study conducted at 50 centers according to principles of the International Council for Harmonisation of Technical Requirements of Pharmaceuticals for Human Use Guideline for Good Clinical Practice (ICH-GCP) and Declaration of Helsinki and local ethics approval. Descriptive and analytical statistics were applied for conclusion and categorical variables using SPSS version 29.0.1.0 (171) (Armonk, NY: IBM Corp.).
RESULTS
Protocol analyses of 515 cases revealed baseline demographics as follows: age 57.35±10.04 years, weight 72.86±10.92 kg, and BMI 28.33±6.07 kg/m. Comorbidities included hypertension (N=169, 32.82%), thyroid disorders (N=99, 19.22%), and heart failure (N=92, 17.86%). Concomitant oral antidiabetics (OADs) prescribed as DPP4i (9.50%), SGLT2i (19.20%), and DPP4i+SGLT2i (7.20%). Study drug reduced glycosylated hemoglobin (HbA1c) by 13.77% (1.25% mean change, p<0.01), fasting blood glucose (FBG) by 23.69% (44.61 mg/dL mean change, p<0.01), post-prandial blood glucose (PPBG) by 24.57% (70.46 mg/dL mean change, p<0.01), and body weight by 4.43% (3.21 kg mean change, p<0.01) over 12 weeks. A total of 161 patients accomplished targeted PPBG of <180 mg/dL (119.13 mg/dL mean change, p<0.01). Regression analysis considering PPBG and HbA1c ≤7.5% showed a weak correlation between them (R-value=0.13, R-squared value=0.02), whereas between PPBG and HbA1c ≤9% yielded moderate positive correlation (R-value=0.53, R-squared value=0.28). There were no adverse events reported or analyzed during the observation period.
CONCLUSION
Voglibose fixed-dose combination (FDC) demonstrates significant effectiveness at the initial dosage when started early in the management of T2DM and high PPBG levels. Moreover, it exhibits good tolerability, thereby contributing to higher compliance among Indian patients who consume a high-carbohydrate diet.
PubMed: 38707131
DOI: 10.7759/cureus.57494 -
European Journal of Pharmaceutical... Jul 2024Physiologically based pharmacokinetic (PBPK) models can help to understand the effects of gastric emptying on pharmacokinetics and in particular also provide a platform...
Physiologically based pharmacokinetic (PBPK) models can help to understand the effects of gastric emptying on pharmacokinetics and in particular also provide a platform for understanding mechanisms of food effects, as well as extrapolation between different postprandial conditions, whether standardized clinical or patient-oriented, non-clinical conditions. By integrating biorelevant dissolution data from the GastroDuo dissolution model into a previously described mechanistic model of fed-state gastric emptying, we simulated the effects of a high-calorie high-fat meal on the pharmacokinetics of sildenafil, febuxostat, acetylsalicylic acid, theobromine and caffeine. The model was able to simulate the variability in C and t caused by the presence of the stomach road. The main influences investigated to affect the gastric emptying process were drug solubility (theobromine and caffeine), tablet dissolution rate (acetylsalicylic acid) and sensitivity to gastric motility (sildenafil and febuxostat). Finally, we showed how PBPK models can be used to extrapolate pharmacokinetics between different prandial states using theobromine as an example with results from a clinical study being presented.
Topics: Gastric Emptying; Postprandial Period; Humans; Models, Biological; Computer Simulation; Solubility; Febuxostat; Theobromine; Caffeine; Sildenafil Citrate; Drug Liberation; Aspirin
PubMed: 38705421
DOI: 10.1016/j.ejps.2024.106788 -
The American Journal of Clinical... Jul 2024The regulation of postprandial muscle protein synthesis (MPS) with or without physical activity has been an intensely studied area within nutrition and physiology. The... (Review)
Review
The regulation of postprandial muscle protein synthesis (MPS) with or without physical activity has been an intensely studied area within nutrition and physiology. The leucine content of dietary protein and the subsequent plasma leucinemia it elicits postingestion is often considered the primary drivers of the postprandial MPS response. This concept, generally known as the leucine "trigger" hypothesis, has also been adopted within more applied aspects of nutrition. Our view is that recent evidence is driving a more nuanced picture of the regulation of postprandial MPS by revealing a compelling dissociation between ingested leucine or plasma leucinemia and the magnitude of the postprandial MPS response. Much of this lack of coherence has arisen as experimental progress has demanded relevant studies move beyond reliance on isolated amino acids and proteins to use increasingly complex protein-rich meals, whole foods, and mixed meals. Our overreliance on the centrality of leucine in this field has been reflected in 2 recent systematic reviews. In this perspective, we propose a re-evaluation of the pre-eminent role of these leucine variables in the stimulation of postprandial MPS. We view the development of a more complex intellectual framework now a priority if we are to see continued progress concerning the mechanistic regulation of postprandial muscle protein turnover, but also consequential from an applied perspective when evaluating the value of novel dietary protein sources.
Topics: Leucine; Humans; Postprandial Period; Muscle Proteins; Dietary Proteins; Muscle, Skeletal; Diet; Protein Biosynthesis
PubMed: 38705358
DOI: 10.1016/j.ajcnut.2024.04.032 -
Cancer Chemotherapy and Pharmacology May 2024This study assessed effect of food on pharmacokinetics (PK) and safety of fuzuloparib capsules.
PURPOSE
This study assessed effect of food on pharmacokinetics (PK) and safety of fuzuloparib capsules.
METHODS
A randomized, open-label, two-cycle, two-sequence, crossover clinical trial was conducted. 20 subjects were randomly assigned to 2 groups at a 1:1 ratio. The first group subjects were orally administered 150 mg fuzuloparib capsules under fasting condition in first dosing cycle. The same dose of fuzuloparib capsules were taken under postprandial state after a 7-day washout period. The second group was reversed. 3 ml whole blood was collected at each blood collection point until 72 h post dose. PK parameters were calculated. Furthermore, safety assessment was performed.
RESULTS
The time to maximum concentration (T) was prolonged to 3 h and maximum concentration (C) decreased by 18.6% on high-fat diets. 90% confidence intervals (CIs) of geometric mean ratios (GMRs) for C, area under the concentration-time curve from time zero to time t (AUC), and area under the concentration-time curve extrapolated to infinity (AUC) after high-fat meal were 71.6-92.6%, 81.7-102.7% and 81.6-102.5%, respectively. All treatment-emergent adverse events (TEAEs) were grade 1; No serious adverse events (SAEs), serious unexpected suspected adverse reaction (SUSAR) or deaths were reported.
CONCLUSION
Food decreased the absorption rate and slowed time to peak exposure of fuzuloparib capsules, without impact on absorption extent. Dosing with food was found to be safe for fuzuloparib capsules in this study.
CLINICAL TRIAL REGISTRATION
This study was registered with chinadrugtrials.org.cn (identifier: CTR20221498).
PubMed: 38703321
DOI: 10.1007/s00280-024-04672-6 -
Obesity Surgery Jun 2024In recent years, numerous studies have tried to decode the way bariatric surgery works toward weight reduction by the use of food preference questionnaires. The...
BACKGROUNDS
In recent years, numerous studies have tried to decode the way bariatric surgery works toward weight reduction by the use of food preference questionnaires. The intragastric balloon has gained popularity, mainly due to its limited invasiveness, in patients with obesity not fulfilling criteria for bariatric surgery. However, there is no study assessing the changes in food preferences [FP]. We decided to analyze the FP of individuals prior to intragastric balloon insertion and following its removal, on the strict condition that participants must complete the 6-month treatment period and attend at least 4 of the 7 follow-up interviews.
METHODS
Patients were asked to rate the frequency of consumption of 63 food items before balloon insertion, at monthly intervals and after balloon removal. The food categories were protein, carbohydrates, fruit and vegetables, and sweets and fats.
RESULTS
The questionnaires of 320 participants were analyzed. A reduced frequency in consumption of meat and meat products, high-fat, and high-carbohydrate/sugary products and an increase in raw vegetables and fruit was found in all individuals.
CONCLUSION
The intragastric balloon seems to exert analogically similar mechanisms to bariatric surgery for weight loss, both functioning through alterations in FP. These are dictated by the anatomical re-configuration of the stomach, but mainly by counseling of dieticians and the self-education of the patient after experiencing unpleasant postprandial discomfort.
Topics: Humans; Gastric Balloon; Female; Male; Food Preferences; Adult; Obesity, Morbid; Weight Loss; Surveys and Questionnaires; Middle Aged; Feeding Behavior
PubMed: 38703243
DOI: 10.1007/s11695-024-07233-1 -
Gut Jun 2024Postprandial, or meal-related, symptoms, such as abdominal pain, early satiation, fullness or bloating, are often reported by patients with disorders of gut-brain... (Review)
Review
Postprandial, or meal-related, symptoms, such as abdominal pain, early satiation, fullness or bloating, are often reported by patients with disorders of gut-brain interaction, including functional dyspepsia (FD) or irritable bowel syndrome (IBS). We propose that postprandial symptoms arise via a distinct pathophysiological process. A physiological or psychological insult, for example, acute enteric infection, leads to loss of tolerance to a previously tolerated oral food antigen. This enables interaction of both the microbiota and the food antigen itself with the immune system, causing a localised immunological response, with activation of eosinophils and mast cells, and release of inflammatory mediators, including histamine and cytokines. These have more widespread systemic effects, including triggering nociceptive nerves and altering mood. Dietary interventions, including a diet low in fermentable oligosaccharides, disaccharides, monosaccharides and polyols, elimination of potential food antigens or gluten, IgG food sensitivity diets or salicylate restriction may benefit some patients with IBS or FD. This could be because the restriction of these foods or dietary components modulates this pathophysiological process. Similarly, drugs including proton pump inhibitors, histamine-receptor antagonists, mast cell stabilisers or even tricyclic or tetracyclic antidepressants, which have anti-histaminergic actions, all of which are potential treatments for FD and IBS, act on one or more of these mechanisms. It seems unlikely that food antigens driving intestinal immune activation are the entire explanation for postprandial symptoms in FD and IBS. In others, fermentation of intestinal carbohydrates, with gas release altering reflex responses, adverse reactions to food chemicals, central mechanisms or nocebo effects may dominate. However, if the concept that postprandial symptoms arise from food antigens driving an immune response in the gastrointestinal tract in a subset of patients is correct, it is paradigm-shifting, because if the choice of treatment were based on one or more of these therapeutic targets, patient outcomes may be improved.
Topics: Humans; Postprandial Period; Brain-Gut Axis; Irritable Bowel Syndrome; Dyspepsia; Abdominal Pain; Gastrointestinal Microbiome
PubMed: 38697774
DOI: 10.1136/gutjnl-2023-331833