Postprandial State Research Articles

Time-restricted Eating to Improve Metabolic Health: Investigating the Mechanisms Underlying Glycolytic and Lipolytic actions

Time-restricted eating (TRE) is a behavioral intervention approach motivated by the emerging role of circadian rhythms in physiology and metabolism. In this approach, all caloric intake is restricted within a regular interval of less than 12 hours, with no overt attempt to reduce calories. We present a whole-body computational model of TRE that incorporates enzyme and substrate reactions as well as hormonal actions during fasting and postprandial states. The model is divided into seven compartments: brain, heart, skeletal muscle, gastrointestinal tract, liver, adipose tissue, and other tissues. We conducted simulations to test the hypothesis that TRE modulates whole-body glucose balance by improving postprandial hyperglycemia and hypertriglyceridemia, keeping these excursions to a minimum. We simulated different TRE schedules with meals varying in fat and carbohydrate content. Our results highlight the importance of chrono-pharmacological considerations in glycemic control: TRE modulates the interplay between glycogenolysis in the liver, lipolysis in adipose tissue and fatty acid oxidation in other organs to improve glucose control. The alternation of eating and fasting, in particular, could be manipulated to balance blood sugar levels. TRE simulations have also shown beneficial effects on the lipid front, such as lower triglyceride levels and improved lipolytic effciency, meaning the body is better able to use fat stores for fuel. This work was supported by the Canadian Institutes of Health Research (CIHR) and the Natural Sciences and Engineering Research Council of Canada (NSERC) Discovery award. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Postprandial Increase of Adenosine 2B Receptor in Adipose Tissue Promotes Lipotoxicity

Obese adipose tissue is known to have higher basal rates of lipolysis than lean adipose tissue. This chronic outflow of lipids leads to the ectopic deposition of lipids into non-adipose, insulin-sensitive tissues such as the heart, liver, and skeletal muscle. This process, known as lipotoxicty, promotes the development of insulin resistance in these tissues. Therefor developing ways to control lipolysis in obese individuals is a useful intervention that would help curtail the development of type II diabetes. Adenosine, a nucleoside released from cells during metabolic stress or inflammation, may play an important role in this process. Our lab has discovered that adipocytes tightly regulate Adenosine receptor 2B (A2BR) expression during the transition from the postabsorptive (fasting) to postprandial (fed) state. QPCR data has confirmed that A2BR levels increase postprandially and decrease postabsorptively in adipose tissue, but not other insulin-sensitive organs. Administration of an A2BR agonist in mice yields a large lipolytic response in the postprandial, but not postabsorptive state. Genetic deletion of A2BR from adipose tissue confirms that this lipolytic response depends on A2BR signaling in the individual adipocytes. Importantly we have also shown that A2BR levels in obese mouse adipose tissue are constitutively high regardless of nutritional state, suggesting these cells are primed for lipolytic stimulation. Therefore, pharmacological antagonists of A2BR could reduce basal lipolysis in obese individuals and in turn improve whole body insulin sensitivity. 5T32GM139787-03 5R01GM136900-04. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Relationships between Body Composition Measurements and Insulin-Stimulated Plasma Lipoprotein Lipase Activity in Individuals with Varying Degrees of Body Adiposity

Lipoprotein Lipase (LPL) hydrolyzes plasma triglycerides into free fatty acids in the circulation for use and/or storage in tissues (i.e., adipose tissue, skeletal muscle). Impaired LPL activity (LPLa) is associated with unfavorable health outcomes, such as elevated plasma triglyceride concentrations. We sought to determine how plasma LPLa relates to body composition measurements in individuals with varying degrees of adiposity. Eighteen subjects (ages 19 to 45 years) with body mass index (BMI) between 18 and 45 kg/m2 had their body composition measured by dual-energy X-ray absorptiometry (DEXA) and insulin sensitivity estimated from an oral glucose tolerance test by using the Matsuda Index (MI). Subjects ingested a bolus of 5g fat (i.e., whipping cream, 0.2 g fat/kg fat free mass), followed by small boluses of fat over the course of a 3-hour experimental period. This experimental protocol allows for the induction of a postprandial state without perturbation of the plasma triglyceride or insulin concentrations. LPLa was measured in the presence of increased plasma insulin induced by intravenous insulin infusion during the last 30 mins of the 3-hour experimental protocol. Insulin was infused at a rate of 0.5 mU/kg/min for subjects with MI-determined insulin sensitivity < 4 and 1 mU/kg/min for those with MI-determined insulin sensitivity > 4, in order to produce comparable levels of plasma insulin concentrations across subjects. To release endothelial-bound LPL, subjects received an injection of intravenous heparin (75 UI/kg) at the end of the plasma insulin infusion. Plasma samples were collected 10 minutes after the heparin infusion and analyzed for LPL concentration (LPLc) and LPLa using commercially available ELISA kits. Person’s correlation was used to evaluate relationships between several body composition parameters and LPLc as well as LPLa. LPLc was not correlated (P >0.05) with BMI (r = 0.03), total lean body mass (r = -0.20), total body fat (r = -0.02), or android fat (r = - 0.08). However, LPLa was positively correlated (P <0.05) with BMI (r = 0.49) and total lean body mass (r = 0.58), as well as total body fat (r = 0.54, P = 0.02) and android fat (r = 0.58, P = 0.01). In conclusion, increased body fat, including android fat, are associated with increased intravascular LPLa in the presence of insulin. Greater insulin-stimulated intravascular LPLa can enhance the release of triglyceride-associated free fatty acids and their uptake by tissues, resulting in insulin resistance as documented in individuals with increased android fat distribution. American Diabetes Association Grant #7-12-CT-40. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Identifying the time course and contributors for Western diet-induced increase in glycocalyx barrier function

The endothelial glycocalyx is a dynamic gel-like structure bound to the vascular endothelium composed of glycosaminoglycans, such as hyaluronan. The glycocalyx plays a critical role in cardiovascular health, acting as a physical barrier to the contents of flowing blood, including red blood cells. Interestingly, we have shown that 12 weeks of Western diet (WD), characterized by excess saturated fat and sugar content, results in greater glycocalyx barrier function in the mesenteric microcirculation that is strongly related to blood glucose values. Currently, the time course that WD induces an increase in glycocalyx barrier function is unknown, as are the contributors to that increase. Thus, we first examined glycocalyx barrier function 1, 2, 4, and 12 weeks after initiating WD in non-fasted male and female UM-HET3 mice (n=9-14/group). Glycocalyx barrier function was assessed in the mesenteric microcirculation by determining perfused boundary region (PBR), which represents red blood cell penetration into the glycocalyx. A higher PBR indicates worse glycocalyx barrier function. Compared to age-matched normal chow (NC) control mice, PBR was lower in WD at week 1 (NC: 2.35±0.05 vs. WD: 1.94±0.04 μm, p<0.05), 2 (NC: 2.36±0.04 vs. WD: 2.01±0.07 μm, p<0.05), 4 (NC: 2.38±0.04 vs. WD: 1.91±0.1 μm, p<0.05), and 12 (NC: 2.41±0.03 vs. WD 1.99±0.04 μm, p<0.05). While blood glucose was higher in WD compared to NC mice at week 12 (NC: 166±3 vs. WD 179±4 mg/dL, p<0.05), it was similar between NC and WD at week 1, 2, and 4 (P>0.05). These data indicate that the WD-induced increase in glycocalyx barrier function occurs as early as 1 week after initiating WD and appears to be independent of blood glucose. Because glycocalyx barrier function was assessed in the mesenteric microcirculation in non-fasted mice, we then sought to determine if the WD-induced increase in glycocalyx barrier function was due to postprandial state. Thus, we determined PBR in non-fasted and fasted (6h) male and female UM-HET3 mice 1 week after initiating WD (n=14-16/group). Fasting status did not affect PBR in age-matched NC (non-fasted 2.32±0.05 vs. fasted: 2.25±0.04 μm, P>0.05) or WD mice (non-fasted 1.94±0.04 vs. fasted: 2.06±0.05 μm, P>0.05), though WD had lower PBR than NC mice in non-fasted and fasted states (p<0.05). These data indicate that glycocalyx barrier function is unaffected by fasting status. Given the role of hyaluronan in the glycocalyx, we then sought to determine if the WD-induced increase in glycocalyx barrier function was due to higher hyaluronan content in the glycocalyx. Thus, we examined PBR pre- and 30 min post-hyaluronidase administration (35 U) in male and female UM-HET3 mice 1 week after initiating WD (n=5/group). There was a tendency for hyaluronidase administration to increase PBR in age-matched NC mice (Pre: 2.37±0.07 vs. Post: 2.65±0.12 μm, P=0.11), whereas PBR increased in WD mice after hyaluronidase administration (Pre: 2.13±0.04 vs. Post: 2.53±0.09 μm, p<0.05). Additionally, the difference in PBR between NC and WD mice was no longer present post-hyaluronidase administration (P>0.05). Taken together, these data indicate that glycocalyx barrier function is increased as early as 1 week after initiating WD and appears to be independent of blood glucose or fasting status but is at least partially due to increased hyaluronan content in the glycocalyx. This study was partly funded by a grant from the National Institutes of Health (R00 AT010017). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Adaptive thermogenesis, at the level of resting energy expenditure, after diet alone or diet plus bariatric surgery.

The objective of this study was to compare the magnitude of adaptive thermogenesis (AT), at the level of resting energy expenditure (REE), after a very low-energy diet alone or combined with Roux-en-Y gastric bypass or sleeve gastrectomy, as well as to investigate the association between AT and changes in appetite. A total of 44 participants with severe obesity underwent 10 weeks of a very low-energy diet alone or combined with Roux-en-Y gastric bypass or sleeve gastrectomy. Body weight and composition, REE, subjective appetite feelings, and plasma concentrations of gastrointestinal hormones were measured at baseline and week 11. AT, at the level of REE, was defined as a significantly lower measured versus predicted (using a regression model with baseline data) REE. Participants lost 18.4 ± 3.9 kg of body weight and experienced AT, at the level of REE (-121 ± 188 kcal/day; p < 0.001), with no differences among groups. The larger the AT, at the level of REE, the greater the reduction in fasting ghrelin concentrations and the smaller the reduction in feelings of hunger and desire to eat in the postprandial state. Weight-loss modality does not seem to modulate the magnitude of AT, at the level of REE. The greater the AT, at the level of REE, the greater the drive to eat following weight loss.

Abstract CT131: Effect of rivoceranib administered as 200 mg once daily on the pharmacokinetics of CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 substrates

Abstract Title: Effect of Rivoceranib Administered as 200 mg Once Daily on the Pharmacokinetics of CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 Substrates Background: Rivoceranib is a selective vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor with potent antitumor activity. The purpose of this study is to evaluate the effect of rivoceranib on the pharmacokinetics of various CYP substrates in healthy subjects following administration of rivoceranib 200 mg once daily (QD), which is similar to the proposed rivoceranib dosing regimen (250 mg QD) in combination with camrelizumab for the treatment of hepatocellular carcinoma. Methods: This open-label, fixed-sequence, crossover drug-drug interaction phase 1 study evaluated the impact of multiple oral doses of rivoceranib at 200 mg QD on the pharmacokinetics of single oral doses of CYP enzyme substrates included in the Cooperstown 5+1 cocktail (midazolam 2 mg [CYP3A4/5 substrate], warfarin 10 mg [CYP2C9 substrate]/vitamin K 10 mg, dextromethorphan 30 mg [CYP2D6 substrate], omeprazole 40 mg [CYP2C19 substrate], and caffeine 200 mg [CYP1A2 substrate]). On Day 1, subjects received a single oral dose of the Cooperstown cocktail. Blood samples were collected predose on Day 1 and up to 120 hours post-dose for pharmacokinetic analyses. On Days 6-15, subjects received rivoceranib at 200 mg QD. On Day 11, a single dose of the Cooperstown Cocktail was co-administered with rivoceranib at 200 mg. Each dose was administered under postprandial conditions except for Day 11 when subjects fasted. Blood samples were collected predose on Day 11 and up to 120 hours post cocktail dosing for pharmacokinetic analyses. Subjects returned on any day between Days 21-25 for safety follow-up. Results: Rivoceranib 200 mg QD increased dextromethorphan AUC0-inf by 144% and Cmax by 70%, increased midazolam AUC0-inf by 65% and Cmax by 16%, increased the warfarin AUC0-inf by 28% and Cmax by 5%, increased omeprazole AUC0-inf by 77% and Cmax by 62%, and decreased caffeine AUC0-inf by 20% and Cmax by 7%. Cooperstown Cocktail alone or coadministration of Cooperstown Cocktail and rivoceranib was generally well tolerated. Conclusions:Rivoceranib at 200 mg QD does not substantially affect the exposure of the substrates of CYP3A4/5, CYP2C9, CYP2C19, and CYP1A2. Recommendation of dose adjustment of these CYP substrates is not needed when administered with rivoceranib at 200 mg QD. Rivoceranib may increase the exposure of the substrate of CYP2D6 by approximately 100%, indicating that a dose adjustment of CYP2D6 substrates and/or close monitoring patients should be considered when administered with rivoceranib 200 mg QD. Citation Format: Seong Jang, Xiaohui (Tracey) Wei, Xianzhang Meng, Joseph Reitano, Vinoo Urity, Cheol Hee Park, Bill Strickland, Grace Lee, David Nguyen. Effect of rivoceranib administered as 200 mg once daily on the pharmacokinetics of CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 substrates [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT131.

Is there a fast track (“Darmstrasse”) for fluids in the small intestine? Evidence from magnetic resonance imaging

BackgroundThe transit and distribution pattern of fluids in the small intestine is a key parameter for the dissolution and absorption of drugs. Although some information is known about the small intestinal water content after administration of fluid volumes and meals, the intestinal transit of orally ingested fluids and solutions has been barely investigated. The aim of this three-arm, cross-over, 9-subject human study was to investigate the transit of orally ingested water in the small intestine under fasting and postprandial conditions using MRI. To identify the ingested water, manganese gluconate, which can be identified with T1-weighted MRI sequences, was added as a marker. Using Horos (DICOM software), quantification of the distribution of Mn2+ ions in the gastrointestinal tract in fasted versus fed state (standard meal by FDA guidance and a light meal) was possible. The distribution and approximate wetted intestinal length was very similar in the fasting and postprandial states, suggesting rapid transport of water ingested after a meal through the chyme-filled small intestine in continuation of the “Magenstrasse” (stomach road). In some subjects, manganese gluconate reached deeper parts of the small intestine even more quickly in the postprandial state than in the fasting arm of the study. A deeper understanding of the behaviour of solutes in the gastrointestinal tract is fundamental to a mechanistic explanation for the kinetic interaction between food and drug intake (food effects).

From classical dualistic antagonism to hormone synergy: potential of overlapping action of glucagon, insulin and GLP-1 for the treatment of diabesity.

The increasing prevalence of 'diabesity', a combination of type 2 diabetes and obesity, poses a significant global health challenge. Unhealthy lifestyle factors, including poor diet, sedentary behaviour, and high stress levels, combined with genetic and epigenetic factors, contribute to the diabesity epidemic. Diabesity leads to various significant complications such as cardiovascular diseases, stroke, and certain cancers. Incretin-based therapies, such as GLP-1 receptor agonists and dual hormone therapies, have shown promising results in improving glycaemic control and inducing weight loss. However, these therapies also come with certain disadvantages, including potential withdrawal effects. This review aims to provide insights into the cross-interactions of insulin, glucagon, and GLP-1, revealing the complex hormonal dynamics during fasting and postprandial states, impacting glucose homeostasis, energy expenditure, and other metabolic functions. Understanding these hormonal interactions may offer novel hypotheses in the development of 'anti-diabesity' treatment strategies. The article also explores the question of the antagonism of insulin and glucagon, providing insights into the potential synergy and hormonal overlaps between these hormones.

Effects of the Fasting-Postprandial State on Arterial Spin Labeling MRI-Based Cerebral Perfusion Quantification in Alzheimer's Disease.

The fasting-postprandial state remains an underrecognized confounding factor for quantifying cerebral blood flow (CBF) in the cognitive assessment and differential diagnosis of Alzheimer's disease (AD). To investigate the effects of fasting-postprandial state on arterial spin labeling (ASL)-based CBF in AD patients. Prospective. Ninety-two subjects (mean age = 62.5 ± 6.4 years; females 29.3%), including 30 with AD, 32 with mild cognitive impairment (MCI), and 30 healthy controls (HCs). Differential diagnostic models were developed with a 4:1 training to testing set ratio. 3-T, T1-weighted imaging using gradient echo and pseudocontinuous ASL imaging using turbo spin echo. Two ASL scans were acquired to quantify fasting state and postprandial state regional CBFs based on an automated anatomical labeling atlas. Two-way ANOVA was used to assess the effects of fasting/postprandial state and disease state (AD, MCI, and HC) on regional CBF. Pearson's correlation analysis was conducted between regional CBF and cognitive scores (Mini-Mental State Examination [MMSE] and Montreal Cognitive Assessment [MoCA]). The diagnostic performances of the fasting state, postprandial state, and mixed state (random mixing of the fasting and postprandial state CBF) in differential diagnosis of AD were conducted using support vector machine and logistic regression models. Two-way ANOVA, Pearson's correlation, and area under the curve (AUC) of diagnostic model were performed. P values <0.05 indicated statistical significance. Fasting-state CBF was correlated with cognitive scores in more brain regions (17 vs. 4 [MMSE] and 15 vs. 9 [MoCA]) and had higher absolute correlation coefficients than postprandial-state CBF. In the differential diagnosis of AD patients from MCI patients and HCs, fasting-state CBF outperformed mixed-state CBF, which itself outperformed postprandial-state CBF. Compared with postprandial CBF, fasting-state CBF performed better in terms of cognitive score correlations and in differentiating AD patients from MCI patients and HCs. 2 TECHNICAL EFFICACY: Stage 3.

Substrate metabolism in male astronauts onboard the International Space Station: the ENERGY study

Bedrest shifts fasting and postprandial fuel selection towards carbohydrate use over lipids, potentially affecting astronauts’ performance and health. We investigated whether this change occurs in astronauts after at least 3 months onboard the International Space Station (ISS). We further explored the associations with diet, physical activity (PA), and body composition. Before and during spaceflight, respiratory quotient (RQ), carbohydrate, and fat oxidation were measured by indirect calorimetry before and following a standardized meal in 11 males (age = 45.7 [SD 7.7] years, BMI = 24.3 [2.1] kg m−²). Postprandial substrate use was determined by 0-to-260 min postprandial incremental area under the curve (iAUC) of nutrient oxidation and the difference between maximal postprandial and fasting RQ (ΔRQ). Food quotient (FQ) was calculated from diet logs. Fat (FM) and fat-free mass (FFM) were measured by hydrometry and PA by accelerometry and diary logs. Spaceflight increased fasting RQ (P = 0.01) and carbohydrate oxidation (P = 0.04) and decreased fasting lipid oxidation (P < 0.01). An increase in FQ (P < 0.001) indicated dietary modifications onboard the ISS. Spaceflight-induced RQ changes adjusted for ground RQ correlated with inflight FQ (P < 0.01). In postprandial conditions, nutrient oxidation and ΔRQ were unaffected on average. Lipid oxidation changes negatively correlated with FFM changes and inflight aerobic exercise and positively with FM changes. The opposite was observed for carbohydrate oxidation. ΔRQ changes were negatively and positively related to FM and FFM changes, respectively. In conclusion, fasting substrate oxidation shift observed during spaceflight may primarily result from dietary modifications. Between-astronaut variability in postprandial substrate oxidation depends on body composition changes and inflight PA.

The association between body mass index and metabolite response to a liquid mixed meal challenge: a Mendelian randomization study

BackgroundMetabolite abundance is a dynamic trait that varies in response to environmental stimuli and phenotypic traits, such as food consumption and body mass index (BMI, kg/m2). ObjectivesIn this study, we used the Netherlands Epidemiology of Obesity (NEO) study data to identify observational and causal associations between BMI and metabolite response to a liquid meal. MethodsA liquid meal challenge was performed, and Nightingale Health metabolite profiles were collected in 5744 NEO participants. Observational and one-sample Mendelian randomization (MR) analysis were conducted to estimate the effect of BMI on metabolites (n = 229) in the fasting, postprandial, and response (or change in abundance) states. ResultsWe observed 473 associations with BMI (175 fasting, 188 postprandial, and 110 response) in observational analyses. In MR analyses, we observed 20 metabolite traits (5 fasting, 12 postprandial, and 3 response) to be associated with BMI. MR associations included the glucogenic amino acid alanine, which was inversely associated with BMI in the response state (β: −0.081; SE: 0.023; P = 5.91 × 10−4), suggesting that as alanine increased in postprandial abundance, that increase was attenuated with increasing BMI. ConclusionsOverall, this study showed that MR estimates were strongly correlated with observational effect estimates, suggesting that the broad associations seen between BMI and metabolite variation has a causal underpinning. Specific effects in previously unassessed postprandial and response states are detected, and these may likely mark novel life course risk exposures driven by regular nutrition.

Liver-derived extracellular vesicles improve whole-body glycaemic control via inter-organ communication.

Small extracellular vesicles (EVs) are signalling messengers that regulate inter-tissue communication through delivery of their molecular cargo. Here, we show that liver-derived EVs are acute regulators of whole-body glycaemic control in mice. Liver EV secretion into the circulation is increased in response to hyperglycaemia, resulting in increased glucose effectiveness and insulin secretion through direct inter-organ EV signalling to skeletal muscle and the pancreas, respectively. This acute blood glucose lowering effect occurs in healthy and obese mice with non-alcoholic fatty liver disease, despite marked remodelling of the liver-derived EV proteome in obese mice. The EV-mediated blood glucose lowering effects were recapitulated by administration of liver EVs derived from humans with or without progressive non-alcoholic fatty liver disease, suggesting broad functional conservation of liver EV signalling and potential therapeutic utility. Taken together, this work reveals a mechanism whereby liver EVs act on peripheral tissues via endocrine signalling to restore euglycaemia in the postprandial state.

Loss of testosterone induces postprandial insulin resistance and increases the expression of the hepatic antioxidant flavin-containing monooxygenases in mice exposed to intermittent hypoxia.

We tested the hypothesis that low testosterone alters the effects of intermittent hypoxia (IH) on glucose homeostasis, hepatic oxidative stress, and transcriptomic profile in male mice. We used sham-operated or orchiectomized (ORX) mice exposed to normoxia (Nx) or IH for 2 weeks. We performed fasting insulin and glucose tolerance tests and assessed fasting and postprandial insulin resistance with the HOMA-IR. The activity of hepatic prooxidant (NADPH oxidase-NOX), antioxidant enzymes (superoxide dismutase, catalase, and glutathione peroxidase-SOD, Cat, GPx), lipid peroxidation (MDA concentration), and the total concentration of glutathione (GSH) were measured under postprandial conditions. mRNA sequencing and pathway enrichment analyses were used to identify hepatic genes underlying the interactions between IH and testosterone. In Sham mice, IH improves fasting insulin sensitivity and glucose tolerance, while there are no effects of IH in ORX mice. In ORX mice, IH induces postprandial hyperinsulinemia, insulin resistance, and a prooxidant profile of enzyme activity (low SOD activity) without altering hepatic MDA and GSH content. ORX and IH altered the expression of genes involved in oxidoreductase activities, cytochromes-dependent pathways, and glutathione metabolism. Among the genes upregulated in ORX-IH mice, the flavin-containing monooxygenases (FMO) are particularly relevant since these are potent hepatic antioxidants that could help prevent overt oxidative stress in ORX-IH mice. Low levels of testosterone in male mice exposed to IH induce post-prandial hyperinsulinemia and insulin resistance and determine the mechanisms by which the liver handles IH-induced oxidative stress.

Acute ingestion of a ketone monoester, whey protein, or their co-ingestion in the overnight postabsorptive state elicit a similar stimulation of myofibrillar protein synthesis rates in young males: a double-blind randomized trial

BackgroundKetone bodies may have anabolic effects in skeletal muscle via their capacity to stimulate protein synthesis. Whether orally ingested exogenous ketones can stimulate postprandial myofibrillar protein synthesis (MyoPS) rates with and without dietary protein co-ingestion is unknown. ObjectivesThis study aimed to evaluate the effects of ketone monoester intake and elevated blood β-hydroxybutyrate (β-OHB) concentration, with and without dietary protein co-ingestion, on postprandial MyoPS rates and mechanistic target of rapamycin complex 1 (mTORC1) pathway signaling. MethodsIn a randomized, double-blind, parallel group design, 36 recreationally active healthy young males (age: 24.2 ± 4.1 y; body fat: 20.9% ± 5.8%; body mass index: 23.4 ± 2 kg/m2) received a primed continuous infusion of L-[ring-2H5]-phenylalanine and ingested one of the following: 1) the ketone monoester (R)-3-hydroxybutyl (R)-3-hydroxybutyrate (KET), 2) 10 g whey protein (PRO), or 3) the combination of both (KET+PRO). Blood and muscle biopsy samples were collected during basal and postprandial (300 min) conditions to assess β-OHB, glucose, insulin, and amino acid concentrations, MyoPS rates, and mTORC1 pathway signaling. ResultsCapillary blood β-OHB concentration increased similarly during postprandial conditions in KET and KET+PRO, with both being greater than PRO from 30 to 180 min (treatment × time interaction: P < 0.001). Postprandial plasma leucine and essential amino acid (EAA) incremental area under the curve (iAUC) over 300 min was greater (treatment: both P < 0.001) in KET+PRO compared with PRO and KET. KET, PRO, and KET+PRO stimulated postprandial MyoPS rates (0–300 min) higher than basal conditions [absolute change: 0.020%/h; (95% CI: 0.013, 0.027%/h), 0.014%/h (95% CI: 0.009, 0.019%/h), 0.019%/h (95% CI: 0.014, 0.024%/h), respectively (time: P < 0.001)], with no difference between treatments (treatment: P = 0.383) or treatment × time interaction (interaction: P = 0.245). mTORC1 pathway signaling responses did not differ between treatments (all P > 0.05). ConclusionsAcute oral intake of a ketone monoester, 10 g whey protein, or their co-ingestion in the overnight postabsorptive state elicit a similar stimulation of postprandial MyoPS rates in healthy young males.This trial was registered at clinicaltrials.gov as NCT04565444 (https://clinicaltrials.gov/study/NCT04565444).

Pharmacokinetics and Bioequivalence of Apremilast Tablets in Chinese Healthy Subjects Under Fasting and Postprandial States.

This study compared the pharmacokinetics, safety and bioequivalence (BE) of generic and original apremilast tablets in healthy Chinese subjects under fasting and postprandial conditions, providing sufficient evidence for abbreviated new drug application. A randomized, open-label, two-formulation, single-dose, two-period crossover pharmacokinetic study was performed. Thirty-two eligible healthy Chinese subjects were enrolled in fasting and postprandial studies, respectively. In each trial, subjects received a single 30-mg dose of the test or reference apremilast tablet, followed by a 7-day washout interval between periods. Serial blood samples were obtained for up to 48 h post-intake in each period, and the plasma concentrations of apremilast were determined by a validated method. The primary pharmacokinetic (PK) parameters, including the maximum plasma concentration (Cmax), the areas under the plasma concentration-time curve (AUC0-t, AUC0-∞), were calculated using the non-compartmental method. The geometric mean ratios of the two formulations and the corresponding 90% confidence intervals (CIs) were acquired for bioequivalence analysis. The safety of both formulations was also evaluated. Under fasting and postprandial states, the PK parameters of the test drug were similar to those of the reference drug. The 90% CIs of the geometric mean ratios of the test to reference formulations were 94.09-103.44% for Cmax, 94.05-103.51% for AUC0-t, and 94.56-103.86% for AUC0-∞ under fasting conditions, and 99.18-112.48% for Cmax, 98.79-106.02% for AUC0-t, and 98.95-105.89% for AUC0-∞ under postprandial conditions, all of which were within the bioequivalence range of 80.00-125.00%. Both formulations were well tolerated, and no serious adverse events occurred during the study. The trial confirmed that the PK parameters of the generic and original apremilast tablets were bioequivalent in healthy Chinese subjects under fasting and postprandial states, which met the predetermined regulatory standards. Both formulations were safe and well tolerated. chinaDrugtrials.org.cn, identifier CTR20191056 (July 30, 2019); chictr.org.cn, identifier ChiCTR2300076806 (October 19, 2023).

Glucosamine substituted sulfonylureas: IRS-PI3K-PKC-AKT-GLUT4 insulin signalling pathway intriguing agent.

Normally, skeletal muscle accounts for 70-80% of insulin-stimulated glucose uptake in the postprandial hyperglycemia state. Consequently, abnormalities in glucose uptake by skeletal muscle or insulin resistance (IR) are deemed as initial metabolic defects in the pathogenesis of type 2 diabetes mellitus (T2DM). Globally, T2DM is growing in exponential proportion. The majority of T2DM patients are treated with sulfonylureas in combination with other drugs to improve insulin sensitivity. Glycosylated sulfonylureas (sulfonylurea-glucosamine analogues) are modified analogues of sulfonylurea that have been previously reported to possess antidiabetic activity. The aim of this study was to evaluate the impact of glycosylated sulfonylureas on the insulin signalling pathway at the molecular level using L6 skeletal muscle cell (in vitro) and extracted soleus muscle (ex vivo) models. To create an in vitro model, insulin resistance was established utilizing a high insulin-glucose approach in differentiated L6 muscle cells from Rattus norvegicus. Additionally, for the ex vivo model, extracted soleus muscles, adult Sprague-Dawley rats were subjected to a solution containing 25 mmol L-1 glucose and 100 mmol L-1 insulin for 24 hours to induce insulin resistance. After insulin resistance, compounds under investigation and standard medicines (metformin and glimepiride) were tested. The differential expression of PI3K, IRS-1, PKC, AKT2, and GLUT4 genes involved in the insulin signaling pathway was evaluated using qPCR. The evaluated glycosylated sulfonylurea analogues exhibited a significant increase in the gene expression of insulin-dependent pathways both in vitro and ex vivo, confirming the rejuvenation of the impaired insulin signaling pathway genes. Altogether, glycosylated sulfonylurea analogues described in this study represent potential therapeutic anti-diabetic drugs.

Evaluation of bioequivalence and safety analysis of capecitabine tablets and Xeloda® under postprandial dosing conditions in Chinese patients with solid tumor

ABSTRACT Objectives To compare the pharmacokinetic and safety of the test group capecitabine tablets (0.5 g) and the reference group capecitabine tablets (0.5 g). Methods This study was registered at www.chinadrugtrials.org.cn under the registration number CTR20220138. 48 subjects with solid tumor were recruited and randomized to receive either the test group or the reference group at a dose of 2 g per cycle for three cycles of the entire trial. Results The point estimate of the geometric mean ratio of Cmax for the subject and reference groups was 1.0670, which was in the range of 80.00%-125.00%. And the upper limit of 95% confidence interval was −0.0450 < 0. The statistics of geometric mean ratio of AUC0-t and AUC0-∞ (test group/reference group) and their 90% confidence intervals were in the range of 80.00%-125.00%, thus the test group was bioequivalent to the reference group under the conditions of this postprandial test. There were no major or serious adverse events. Conclusion: The pharmacokinetic profiles of capecitabine under postprandial conditions were consistent between the two groups. The two groups were bioequivalent and had a similar favorable safety profile in Chinese patients with solid tumor.

Postprandial Triglyceride-Rich Lipoproteins-Induced Lysosomal Dysfunction and Impaired Autophagic Flux Contribute to Inflammation in White Adipocytes

BackgroundObesity and postprandial hypertriglyceridemia, characterized by an increase in triglyceride-rich lipoproteins (TRLs), cause chronic low-grade inflammation. It is unclear how postprandial TRLs affect inflammation in white adipocytes. ObjectivesThe objectives of the study were to explore the inflammatory response of postprandial TRLs in white adipocytes and investigate the possible mechanism. MethodsWe measured postprandial triglyceride (TG) and high-sensitivity C-reactive protein (hsCRP) concentrations in 204 recruited subjects and treated white adipocytes from mice with postprandial TRLs from above patients with hypertriglyceridemia. ResultsSerum hsCRP concentrations and BMI were positively related to TG concentrations in the postprandial state. Postprandial TRLs increased mRNA and protein expression of inflammatory factors, including interleukin-1β, via the NOD-like receptor protein 3 (NLRP3)/Caspase-1 pathway, and impaired autophagy flux in white adipocytes of mice. TRLs also induced lysosomal damage as evidenced by the reduced protein expression of lysosome-associated membrane proteins-1 and Cathepsin L. Inhibition of Cathepsin B, NLRP3, and mTOR signaling improved autophagy/lysosome dysfunction and inhibited the activation of the NLRP3/Caspase-1 pathway and inflammatory factors induced by TRLs in white adipocytes. ConclusionsOur results suggest that postprandial hypertriglyceridemia causes chronic inflammation in adipocytes through TRL-induced lysosomal dysfunction and impaired autophagic flux in an mTOR-dependent manner.

Long-chain n-3 PUFA ingestion for the stimulation of muscle protein synthesis in healthy older adults.

This review aims to critically evaluate the efficacy of long-chain ո-3 PUFA ingestion in modulating muscle protein synthesis (MPS), with application to maintaining skeletal muscle mass, strength and function into later life. Ageing is associated with a gradual decline in muscle mass, specifically atrophy of type II fibres, that is exacerbated by periods of (in)voluntary muscle disuse. At the metabolic level, in otherwise healthy older adults, muscle atrophy is underpinned by anabolic resistance which describes the impaired MPS response to non-pharmacological anabolic stimuli, namely, physical activity/exercise and amino acid provision. Accumulating evidence implicates a mechanistic role for n-3 PUFA in upregulating MPS under stimulated conditions (post-prandial state or following exercise) via incorporation of EPA and DHA into the skeletal muscle phospholipid membrane. In some instances, these changes in MPS with chronic ո-3 PUFA ingestion have translated into clinically relevant improvements in muscle mass, strength and function; an observation evidently more prevalent in healthy older women than men. This apparent sexual dimorphism in the adaptive response of skeletal muscle metabolism to EPA and DHA ingestion may be related to a greater propensity for females to incorporate ո-3 PUFA into human tissue and/or the larger dose of ingested ո-3 PUFA when expressed relative to body mass or lean body mass. Future experimental studies are warranted to characterise the optimal dosing and duration of ո-3 PUFA ingestion to prescribe tailored recommendations regarding n-3 PUFA nutrition for healthy musculoskeletal ageing into later life.

Electrogastrography in patients with gastric motility disorders.

Electrogastrography (EGG) is a novel diagnostic modality for assessing the gastrointestinal tract (GI) that generates spontaneous electrical activity and monitors gastric motility. The aim of this study was to compare patients with functional dyspepsia (FD) and diabetic gastroparesis (D-GP) with healthy controls (CT) to use established findings on abnormalities of gastric motility based on EGG characteristics. In this study, 50 patients with FD, 50 D-GP patients, and 50 CT subjects were studied to compare EGG with discrete wavelet transform models (DWT) to extract signal characteristics using a variety of different qualitative and quantitative metrics from pre-prandial and postprandial states. As a result, higher statistically significant (p < 0.05*) were found in the DWT models based on power spectral density (PSD) analysis in both states. We also present that the correlations between EGG metrics and the presence of FD, D-GP, and CT symptoms were inconsistent. This paper represents that EGG assessments of FD and D-GP patients differ from healthy controls in terms of abnormalities of gastric motility. Additionally, we demonstrate that diverse datasets showed adequate gastric motility responses to a meal. We anticipate that our method will provide a comprehensive understanding of gastric motility disorders for better treatment and monitoring in both clinical and research settings. In conclusion, we present potential future opportunities for precise gastrointestinal electrophysiological disorders.