Endotoxemia, Muscle Loss, Catabolic State, Protein; Disease, Nutrition Therapy
Conditions
Keywords
endotoxemia, muscle loss, catabolic state, whey protein, 3-hydroxy butyrate
Brief summary
This study aims to investigate the muscle anabolic potential of adding ketone (3-hydroxybutyrate) to whey protein compared with isocaloric, isonitrogenous whey protein in a human model of inflammatory catabolic disease. Further, this study aims to investigate whether the same amount of whey protein has different effects on muscles in an catabolic inflammatory setting compared with a healthy setting.
Detailed description
Background: Muscle wasting during hospitalization is caused by a combination of immobilization (bed rest), hypocaloric diet and inflammation (e.g. sepsis), and preventive measures are needed. Whey protein is particularly potent in inducing muscle protein synthesis compared with other proteins, at least in healthy populations. Further, the ketone body 3-hydroxybutyrate (3-OHB) effectively preserved muscle in a model of acute inflammatory disease. However, little is known about whether 3-OHB can potentiate the effects of whey protein in a catabolic inflammatory setting. Aim: This study aims to investigate the muscle anabolic potential of adding ketone (3-OHB) to whey protein compared with isocaloric, isonitrogenous whey protein in a human model of catabolic inflammatory disease. Further, this study aims to investigate whether the same amount of whey protein has different effects on muscles in an catabolic inflammatory setting compared with a healthy setting. Hypothesis: 1. 3-OHB potentiates the effect of whey protein in maintaining muscle mass in a catabolic inflammatory setting. 2. The same amount of whey protein will have decreased muscle anabolic effects during catabolic inflammatory conditions compared with healthy conditions Interventions: In a randomized crossover design, eight healthy, lean, young men will undergo either: i) Healthy conditions (overnight fast) + whey protein\^ ii) Catabolic conditions (Inflammation (LPS) + 36-hour fast and bed rest\*) + whey protein\^ iii) Catabolic conditions (Inflammation (LPS) + 36-hour fast and bed rest\*) + 3-OHB/whey protein\^ \*LPS will be administered (1 ng/kg) the day prior to the study together with fast and bed rest. On the study day LPS (0.5 ng/kg) will be injected. \^Beverages will be isonitrogenous and isocaloric (fat will be added) with 45 g whey protein + 20 g maltodextrin. Bolus/sip administration will be applied (1/3 bolus, 1/2 sip) 50 grams of 3-OHB will be orally administered (1/2 bolus, 1/2 sip) Before each study day: The participants arrive fasting (only tap water allowed) by taxi on the study days. They have been without febrile disease the week prior to investigation, and have not performed exercise for 24 hours.
Interventions
DIETARY_SUPPLEMENTWhey
45 g whey + 20 g maltodextrin
DIETARY_SUPPLEMENT3-OHB + Whey
50 g ketone + 45 g whey + 20 g maltodextrin
Sponsors
Arla Foods Ingredients
Aarhus University Hospital
University of Aarhus
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
NONE
Intervention model description
In a randomized crossover design, eight healthy lean young men will undergo either: i) Healthy conditions (overnight fast) + whey protein ii) Catabolic conditions (Inflammation (LPS) + 36-hour fast and bed rest) + whey protein iii) Catabolic conditions (Inflammation (LPS) + 36-hour fast and bed rest) + 3-OHB/whey protein
Eligibility
Sex/Gender
MALE
Age
20 Years to 40 Years
Healthy volunteers
Yes
Inclusion criteria
* Between 20-40 years of age * Body mass index between 20-30 kg/m\^2 * Healthy * Oral and written consent forms obtained prior to study day
Exclusion criteria
* Recent immobilization of an extremity that is not fully rehabilitated * Lactose, lidocain or rubber allergies * Current disease * Use of anabolic steroids * Smoking * Former major abdominal surgery (Or current problems with the GI tract) * \>10 hours of exercise/weak * Present ketogenic diets or high-protein diets * Blood doner that does not want to discontinue blood donations until study completion * Pending MR scan
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in forearm muscle kinetics measured by phenylalanine tracer (Netbalance, rate of disappearence and rate of apperance of phenylanine, nmol/100ml muscle/min) | Change from baseline to 3.5 hours after intervention | Changes of forearm muscle phenylalanine kinetics from baseline to 3.5 hours after intervention using the forearm model |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in concentration of 3-hydroxybutyrate (mmol/L) ) | Measured at baseline and every 30. min throughout the 3.5 hour sipping period | Change in blood BHB levels from baseline to the end of the 3.5 hour sipping period (iAUC) |
| Change in glucose kinetics measured by glucose tracer (rate of apperance and rate of disappearance, mg/kg/min) | Change from baseline to 3.5 hours after intervention | Change in glucose kinetics from baseline to to the end of the 3.5 hour sipping period |
| Change in concentration of plasma insulin | Measured at baseline and every 30. min throughout the 3.5 hour sipping period | Change in plasma insulin levels from baseline to the end of the 3.5 hour sipping period (iAUC) |
| Change in concentration of plasma glucose | Measured at baseline and every 30. min throughout the 3.5 hour sipping period | Change in glucose levels from baseline and after 3.5 hour sipping period expressed as iAUC. |
| Change in concentration of free fatty acids (FFA) levels | Change from baseline to 3.5 hours after intervention | Change in FFA from baseline to the end of the sipping period |
| Change in concentration of C-reactive peptide (CRP) | Change from baseline to 3.5 hours after intervention | Change in CRP from baseline to the end of the sipping period |
| Change in concentration of blood leucocytes (x10^9/L) | Change from baseline to 3.5 hours after intervention | Change in leucocytes from baseline to the end of the sipping period |
| Change in concentration of stress hormones (glucagon, cortisol, adrenalin, noradrenalin) | Change from baseline to 3.5 hours after intervention | Change in hormones from baseline and after 3.5 hour sipping period |
| Change in intracellular muscle signalling | Change from baseline to 3.5 hours after intervention | Change in muscle signalling in muscle biopsies by western blot from baseline to the sipping period |
| Difference in muscle forearm kinetics measured by phenylalanine tracer (Netbalance, rate of apperance, rate og disappearance) (healthy vs catabolic) | measured at the end of the 3.5 hour basal period | Phenylalanine forearm kinetics measured by phenylalanine tracer at the end of the 3.5 hour basal period in healthy vs catabolic (pooled mean of the two catabolic days, if there is no difference between the first and second time of LPS exposure) |
| Difference in concentration of total amino acids (healthy vs catabolic) | measured at the end of the 3.5 hour basal period | Total amino acids measured at the end of the 3.5 hour basal period in healthy vs catabolic conditions (pooled mean of the two catabolic days, if there is no difference between the first and second time of LPS exposure) |
| Difference in glucose kinetics measured with glucose tracer (mg/kg/min) (healthy vs catabolic) | measured at the end of the 3.5 hour basal period | Glucose kinetics measured by glucose tracer at the end of the 3.5 hour basal period in healthy vs catabolic conditions (pooled mean of the two catabolic days, if there is no difference between the first and second time of LPS exposure) |
| Change in concentration of total aminoacids | Change from baseline to 3.5 hours after intervention | Change in total aminoacids from baseline to the end of the 3.5 hour sipping period |
| Difference in concentration of C-reactive peptide (CRP) (healthy vs catabolic) | Measured at the end of the 3.5 hour basal period. | CRP measured at the end of the basal period in healthy vs catabolic (pooled mean of the two catabolic days) |
| Difference in concentration of leucocytes (healthy vs catabolic) | Measured at the end of the 3.5 hour basal period. | Leucocytes measured at the end of the basal period in healthy vs catabolic (pooled mean of the two catabolic days) |
| Difference in intracellular muscle signalling (healthy vs catabolic) | Measured at the end of the 3.5 hour basal period. | Muscle signalling measured in muscle biopsies by western blot during the 3.5 hour basal period in healthy vs catabolic (pooled mean of the two catabolic days) |
| Difference in concentration of 3-hydroxybutyrate (mmol/L) (healthy vs catabolic) | Measured at the end of the 3.5 hour basal period. | 3-hydroxybutyrate measured at the end of the basal period in healthy vs catabolic (pooled mean of the two catabolic days) |
| Difference in concentration of hormones (insulin, glucagon, cortisol, growth hormone, adrenaline, noradrenalin) (healthy vs catabolic) | Measured at the end of the 3.5 hour basal period. | Hormones (insulin, glucagon, cortisol, growth hormone, adrenaline, noradrenalin) measured at the end of the basal period in healthy vs catabolic (pooled mean of the two catabolic days) |
| Difference in whole body protein metabolism (healthy vs catabolic) | Measured at the end of the 3.5 hour basal period. | Difference in whole body protein metabolism measured with tyrosine tracers at the end of the basal period in healthy vs catabolic (pooled mean of the two catabolic days) |
| Difference in concentration of cytokines (healthy vs catabolic) | Measured at baseline and 120 and 240 minutes after LPS administration | Cytokines (TNFalfa, IL-10, IL-6 and IL-1beta) measured between healthy and catabolic conditions (iAUC, a pooled mean of the two catabolic days, if there is no difference between the first and second time of LPS exposure)) |
| Difference in axillary temperature (healthy vs catabolic) | Measured at baseline and 1, 2, 3, 4, 5, 6 and 7 hours after LPS administration | Change in axillary temperature (iAUC). A pooled mean of the two catabolic days, if there is no difference between the first and second time of LPS exposure. |
| Difference in heart rate (healthy vs catabolic) | Measured at baseline and 1, 2, 3, 4, 5, 6 and 7 hours after LPS administration | Change in heart rate (iAUC). A pooled mean of the two catabolic days, if there is no difference between the first and second time of LPS exposure. |
| Difference in mean arterial pressure (MAP) (healthy vs catabolic) | Measured at baseline and 1, 2, 3, 4, 5, 6 and 7 hours after LPS administration | Change in MAP (iAUC). A pooled mean of the two catabolic days, if there is no difference between the first and second time of LPS exposure. |
| Difference in symptom score (healthy vs catabolic) | Measured at baseline and 1, 2, 3, 4, 5, 6 and 7 hours after LPS administration | Change from baseline and throughout the experiment (iAUC). A pooled mean of the two catabolic days, if there is no difference between the first and second time of LPS exposure. Scale 0-5, 0=no symptoms and 5=severe symptoms |
| Difference in concentration of free fatty acids (FFA) (healthy vs catabolic) | Measured at the end of the 3.5 hour basal period. | FFA measured at the end of the basal period in healthy vs catabolic (pooled mean of the two catabolic days) |
Countries
Denmark
Outcome results
None listed