fasted state
Recently Published Documents


TOTAL DOCUMENTS

314
(FIVE YEARS 72)

H-INDEX

39
(FIVE YEARS 4)

2022 ◽  
Vol 5 (1) ◽  
Author(s):  
Emine Can ◽  
Jessica A. M. Bastiaansen ◽  
Dominique-Laurent Couturier ◽  
Rolf Gruetter ◽  
Hikari A. I. Yoshihara ◽  
...  

AbstractHyperpolarized [1-13C]pyruvate enables direct in vivo assessment of real-time liver enzymatic activities by 13C magnetic resonance. However, the technique usually requires the injection of a highly supraphysiological dose of pyruvate. We herein demonstrate that liver metabolism can be measured in vivo with hyperpolarized [1-13C]pyruvate administered at two- to three-fold the basal plasma concentration. The flux through pyruvate dehydrogenase, assessed by 13C-labeling of bicarbonate in the fed condition, was found to be saturated or partially inhibited by supraphysiological doses of hyperpolarized [1-13C]pyruvate. The [13C]bicarbonate signal detected in the liver of fasted rats nearly vanished after treatment with a phosphoenolpyruvate carboxykinase (PEPCK) inhibitor, indicating that the signal originates from the flux through PEPCK. In addition, the normalized [13C]bicarbonate signal in fasted untreated animals is dose independent across a 10-fold range, highlighting that PEPCK and pyruvate carboxylase are not saturated and that hepatic gluconeogenesis can be directly probed in vivo with hyperpolarized [1-13C]pyruvate.


2022 ◽  
Vol 8 (1) ◽  
pp. e001206
Author(s):  
Sumona Mandal ◽  
Niall Simmons ◽  
Sidra Awan ◽  
Karim Chamari ◽  
Irfan Ahmed

Intermittent fasting (IF) is an increasingly popular dietary practice, and its implementation is found throughout human civilisation in various cultural, spiritual and religious traditions. Emerging evidence has shown that the health benefits of IF stretch beyond calorie restriction and weight loss. These benefits include metabolic shifts in energy production, the optimisation of peripheral circadian clocks, and overall improvement in physiological markers of metabolic health. IF has been proposed to reduce systemic inflammation and have a role in the prevention and treatment of chronic disease. For the athlete, IF protocols offer a potential new frontier for maintaining performance in the fasted state. They may allow athletes to optimise training adaptions, while respecting individual cultural, religious, and/or spiritual preferences to fast and exercise. Below, we discuss the physiological impact of fasted exercise while highlighting areas for future work to improve our understanding and implementation of the practice for the benefit of both the active general community and sporting populations.


2021 ◽  
Vol 12 ◽  
Author(s):  
Hikari A. I. Yoshihara ◽  
Arnaud Comment ◽  
Juerg Schwitter

As both a consumer and producer of glucose, the kidney plays a significant role in glucose homeostasis. Measuring renal gluconeogenesis requires invasive techniques, and less invasive methods would allow renal gluconeogenesis to be measured more routinely. Magnetic resonance spectroscopy and imaging of infused substrates bearing hyperpolarized carbon-13 spin labels allows metabolism to be detected within the body with excellent sensitivity. Conversion of hyperpolarized 1-13C pyruvate in the fasted rat liver is associated with gluconeogenic flux through phosphoenolpyruvate carboxykinase (PEPCK) rather than pyruvate dehydrogenase (PDH), and this study tested whether this was also the case in the kidney. The left kidney was scanned in fed and overnight-fasted rats either with or without prior treatment by the PEPCK inhibitor 3-mercaptopicolinic acid (3-MPA) following infusion of hyperpolarized 1-13C pyruvate. The 13C-bicarbonate signal normalized to the total metabolite signal was 3.2-fold lower in fasted rats (p = 0.00073) and was not significantly affected by 3-MPA treatment in either nutritional state. By contrast, the normalized [1-13C]aspartate signal was on average 2.2-fold higher in the fasted state (p = 0.038), and following 3-MPA treatment it was 2.8-fold lower in fed rats and 15-fold lower in fasted rats (p = 0.001). These results confirm that, unlike in the liver, most of the pyruvate-to-bicarbonate conversion in the fasted kidney results from PDH flux. The higher conversion to aspartate in fasted kidney and the marked drop following PEPCK inhibition demonstrate the potential of this metabolite as a marker of renal gluconeogenesis.


2021 ◽  
Vol 8 (Supplement_1) ◽  
pp. S650-S651
Author(s):  
Mohammad Hossain ◽  
Courtney Tiffany ◽  
Aline Barth ◽  
Aparna Raychaudhuri ◽  
Etienne F Dumont

Abstract Background Gepotidacin, a novel, first-in-class triazaacenaphthylene antibiotic, inhibits bacterial replication and has in vitro and in vivo activity against key pathogens, including drug-resistant strains, associated with a range of infections. Gepotidacin is currently in Phase 3 clinical studies for the treatment of uncomplicated urinary tract infections and gonorrhea. This study (NCT02853435) was designed to assess gepotidacin pharmacokinetics (PK) in Japanese subjects (fasted and fed). Methods A tablet formulation of 750 mg gepotidacin free base was used in the study, which was conducted in two parts: Part 1, gepotidacin PK was assessed following 1500 and 3000 mg single oral doses in the fasted state; and Part 2, gepotidacin PK was assessed following 1500, 2250, and 3000 mg single oral doses in the fed state. Serial blood and urine samples were collected in both study parts. Results Part 1: The area under the plasma drug concentration-time curve from time 0 to infinity (AUC[0–∞]) and maximum observed concentration (Cmax) were slightly higher in Japanese subjects than in Caucasian subjects at the same dose levels and with the same formulation. Following gepotidacin dosing in the fasted state, the 1500 mg dose was tolerated, while the 3000 mg dose was poorly tolerated with mild or moderate gastro-intestinal adverse effects (GI AEs) reported by most subjects shortly after being dosed. Part 2: PK was linear with doses in the range of 1500–3000 mg. Administration of gepotidacin 3000 mg tablets in the fed state slightly reduced Cmax and slightly increased AUC at the 3000 mg dose level. The 1500 and 2250 mg doses were tolerated while the 3000 mg dose was better tolerated compared to the fasted state with fewer and short-lived GI AEs, mostly mild in intensity. After oral administration of 1500–3000 mg, high urine drug concentrations were achieved, remaining above the minimum inhibitory concentration of 4 μg/mL for up to 24 hours. Conclusion The PK of gepotidacin following administration of a single oral dose to Japanese subjects was linear from 1500–3000 mg and food decreased Cmax without impact on exposure (AUC). Administration of gepotidacin with food resulted in an improved GI tolerability profile at the higher dose tested in Japanese subjects. Disclosures Mohammad Hossain, PhD, GlaxoSmithKline plc. (Employee, Shareholder, Former employee of and past/current shareholder in GlaxoSmithKline plc.) Courtney Tiffany, BSc, GlaxoSmithKline plc. (Employee, Shareholder, Former employee of and past/current shareholder in GlaxoSmithKline plc.) Aline Barth, MSC;PHD, GlaxoSmithKline plc. (Employee, Shareholder, Employee of and shareholder in GlaxoSmithKline plc.) Aparna Raychaudhuri, Ph.D., GlaxoSmithKline plc. (Employee, Shareholder, Former employee of and past/current shareholder in GlaxoSmithKline plc.) Etienne F. Dumont, MD, GlaxoSmithKline plc. (Employee, Shareholder, Former employee of and shareholder in GlaxoSmithKline plc.)


2021 ◽  
pp. 1-7
Author(s):  
Ngoc N. Nguyen ◽  
Ruma G. Singh ◽  
Maxim S. Petrov

<b><i>Background:</i></b> The clinical relevance of excess intrapancreatic fat deposition (IPFD) is increasingly appreciated. Leptin and ghrelin are key players in the regulation of food intake, energy balance, and body fat mass. The aim was to investigate the associations of the leptin/ghrelin ratio and its components with IPFD. <b><i>Methods:</i></b> All participants underwent magnetic resonance imaging on a 3T scanner to quantify IPFD. Both fasting and postprandial blood samples were analyzed for leptin and acylated ghrelin. Linear regression analysis was conducted, accounting for visceral/subcutaneous fat volume ratio, glycated hemoglobin, and other covariates. <b><i>Results:</i></b> A total of 94 participants (32 women) with a median age of 56 (interquartile range 44–66) years were studied. Their median IPFD was 9.6% (interquartile range 8.8–10.4%). In the fasted state, the leptin/ghrelin ratio (β = 0.354; 95% confidence interval 0.044–0.663; <i>p</i> = 0.025, in the most adjusted model) and leptin (β = 0.040; 95% confidence interval 1.003–1.078; <i>p</i> = 0.035, in the most adjusted model) were significantly associated with IPFD. Ghrelin in the fasted state was not significantly associated with IPFD. In the postprandial state, the leptin/ghrelin ratio, leptin, and ghrelin were not significantly associated with IPFD. <b><i>Conclusion:</i></b> Fasting circulating levels of leptin are directly associated with IPFD. Purposely designed mechanistic studies are warranted to determine how high leptin may contribute to excess IPFD.


2021 ◽  
pp. 135965352110565
Author(s):  
Edward Gane ◽  
Mina Pastagia ◽  
Ullrich Schwertschlag ◽  
An De Creus ◽  
Christian Schwabe ◽  
...  

Background This Phase I, two-part, first-in-human study assessed safety/tolerability and pharmacokinetics/pharmacodynamics of single-ascending doses (SAD) and multiple doses (MD) of the oral toll-like receptor-7 agonist, JNJ-64794964 (JNJ-4964) in healthy adults. Methods In the SAD phase, participants received JNJ-4964 0.2 ( N = 6), 0.6 ( N = 6), 1.25 ( N = 8) or 1.8 mg ( N = 6) or placebo ( N = 2/dose cohort) in a fasted state. Food effect was evaluated for the 1.25 mg cohort following ≥6 weeks washout. In the MD phase, participants received JNJ-4964 1.25 mg ( N = 6) or placebo ( N = 2) weekly (fasted) for 4 weeks. Participants were followed-up for 4 weeks. Results No serious adverse events (AEs) occurred. 10/34 (SAD) and 5/8 (MD) participants reported mild-to-moderate (≤Grade 2), transient, reversible AEs possibly related to JNJ-4964. Five (SAD) participants had fever/flu-like AEs, coinciding with interferon-α serum levels ≥100 pg/mL and lymphopenia (<1 × 109/L), between 24–48 h after dosing and resolving approximately 96 h after dosing. One participant (MD) had an asymptomatic Grade 1 AE of retinal exudates (cotton wool spots) during follow-up, resolving 6 weeks after observation. JNJ-4964 exhibited dose-proportional pharmacokinetics, with rapid absorption (tmax 0.5–0.75 h) and distribution, and a long terminal half-life (150–591 h). Overall, no significant differences in JNJ-4964 pharmacokinetic parameters were observed in the fed versus fasted state. JNJ-4964 dose-dependently and transiently induced cytokines with potential anti-HBV activity, including interferon-α, IP-10, IL-1 RA, and/or MCP-1, and interferon-stimulated genes (ISG15, MX1, and OAS1) in serum. Conclusions In healthy adults, JNJ-4964 was generally well-tolerated, exhibited dose-proportional pharmacokinetics and induced cytokines/ISGs, with possible anti-HBV activity.


Nutrients ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 3557
Author(s):  
Wandia Kimita ◽  
Sakina H. Bharmal ◽  
Juyeon Ko ◽  
Jaelim Cho ◽  
Maxim S. Petrov

Markers of iron metabolism are altered in new-onset diabetes, but their relationship with metabolic signals involved in the maintenance of energy balance is poorly understood. The primary aim was to explore the associations between markers of iron metabolism (hepcidin and ferritin) and markers of energy balance (leptin, ghrelin, and the leptin/ghrelin ratio) in both the fasted and postprandial states. These associations were also studied in the sub-groups stratified by diabetes status. This was a cross-sectional study of individuals without disorders of iron metabolism who were investigated after an overnight fast and, in addition, some of these individuals underwent a mixed meal test to determine postprandial responses of metabolic signals. The associations between hepcidin, ferritin, and leptin, ghrelin, leptin/ghrelin ratio were studied using several multiple linear regression models. A total of 76 individuals in the fasted state and 34 individuals in the postprandial state were included. In the overall cohort, hepcidin was significantly inversely associated with leptin (in the most adjusted model, the β coefficient ± SE was −883.45 ± 400.94; p = 0.031) and the leptin/ghrelin ratio (in the most adjusted model, the β coefficient ± SE was −148.26 ± 61.20; p = 0.018) in the fasted state. The same associations were not statistically significant in the postprandial state. In individuals with new-onset prediabetes or diabetes (but not in those with normoglycaemia or longstanding prediabetes or diabetes), hepcidin was significantly inversely associated with leptin (in the most adjusted model, the β coefficient ± SE was −806.09 ± 395.44; p = 0.050) and the leptin/ghrelin ratio (in the most adjusted model, the β coefficient ± SE was −129.40 ± 59.14; p = 0.037). Leptin appears to be a mediator in the link between iron metabolism and new-onset diabetes mellitus. These findings add to the growing understanding of mechanisms underlying the derangements of glucose metabolism.


Author(s):  
Sarah K Kirschner ◽  
Gabriella A.M. Ten Have ◽  
Marielle P.K.J. Engelen ◽  
Nicolaas E.P. Deutz

The short-chain fatty acids (SCFAs) acetate, propionate, butyrate, isovalerate, and valerate are end products of intestinal bacterial fermentation and important mediators in the interplay between the intestine and peripheral organs. To unravel the transorgan fluxes and mass balance comparisons of SCFAs, we measured their net fluxes across several organs in a translational pig model. In multi-catheterized conscious pigs (n=12, 25.6 (95% CI [24.2, 26.9]) kg, 8-12 weeks old), SCFA fluxes across portal drained viscera (PDV), liver, kidneys, and hindquarter (muscle compartment) were measured after an overnight fast and in the postprandial state, 4 h after administration of a fiber-free, mixed meal. PDV was the main releasing compartment of acetate, propionate, butyrate, isovalerate, and valerate during fasting and in the postprandial state (all P=0.001). Splanchnic acetate release was high due to the absence of hepatic clearance. All other SCFAs were extensively taken up by the liver (all P<0.05). Even though only 7% [4, 10] (propionate), 42% [23, 60] (butyrate), 26% [12, 39] (isovalerate), and 3% [0.4, 5] (valerate) of PDV release were excreted from the splanchnic area in the fasted state, splanchnic release of all SCFAs was significant (all P≤0.01). Splanchnic propionate, butyrate, isovalerate and valerate release remained low but significant in the postprandial state (all P<0.01). We identified muscle and kidneys as main peripheral SCFA metabolizing organs, taking up the majority of all splanchnically released SCFAs in the fasted state and in the postprandial state. We conclude that the PDV is the main SCFA releasing and the liver the main SCFA metabolizing organ. Splanchnically released SCFAs appear to be important energy substrates to peripheral organs not only in the fasted but also in the postprandial state.


Sign in / Sign up

Export Citation Format

Share Document