Clinical trial NCT04064268: Anabolic Potential of 3-hydroxybutyrate (3-OHB) and Whey Protein in a Human Catabolic Inflammatory Disease Model
Official title: Anabolic Potential of Adding 3-hydroxybutyrate (3-OHB) to Whey Protein in a Catabolic Inflammatory Disease Model: A Human Randomized Controlled Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Endotoxemia
Muscle Loss
Catabolic State
Protein; Disease
Nutrition Therapy
Keywords: endotoxemia
muscle loss
catabolic state
whey protein
3-hydroxy butyrate
Lead sponsor: University of Aarhus
Sponsor class: OTHER
Collaborators: name: Arla Foods Ingredients
name: Aarhus University Hospital
First posted: 2019-08-21
Enrollment: 8
Sex: MALE
Minimum age (years): 20
Maximum age (years): 40
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
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
Primary purpose: BASIC_SCIENCE

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.

Eligibility criteria: 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

Primary outcomes:
measure: Change in forearm muscle kinetics measured by phenylalanine tracer (Netbalance, rate of disappearence and rate of apperance of phenylanine, nmol/100ml muscle/min)
timeFrame: Change from baseline to 3.5 hours after intervention
Secondary outcomes:
measure: Change in concentration of total aminoacids
timeFrame: Change from baseline to 3.5 hours after intervention
measure: Change in concentration of 3-hydroxybutyrate (mmol/L) )
timeFrame: Measured at baseline and every 30. min throughout the 3.5 hour sipping period
measure: Change in glucose kinetics measured by glucose tracer (rate of apperance and rate of disappearance, mg/kg/min)
timeFrame: Change from baseline to 3.5 hours after intervention
measure: Change in concentration of plasma insulin
timeFrame: Measured at baseline and every 30. min throughout the 3.5 hour sipping period
measure: Change in concentration of plasma glucose
timeFrame: Measured at baseline and every 30. min throughout the 3.5 hour sipping period
measure: Change in concentration of free fatty acids (FFA) levels
timeFrame: Change from baseline to 3.5 hours after intervention
measure: Change in concentration of C-reactive peptide (CRP)
timeFrame: Change from baseline to 3.5 hours after intervention
measure: Change in concentration of blood leucocytes (x10^9/L)
timeFrame: Change from baseline to 3.5 hours after intervention
measure: Change in concentration of stress hormones (glucagon, cortisol, adrenalin, noradrenalin)
timeFrame: Change from baseline to 3.5 hours after intervention
measure: Change in intracellular muscle signalling
timeFrame: Change from baseline to 3.5 hours after intervention
measure: Difference in muscle forearm kinetics measured by phenylalanine tracer (Netbalance, rate of apperance, rate og disappearance) (healthy vs catabolic)
timeFrame: measured at the end of the 3.5 hour basal period
measure: Difference in concentration of total amino acids (healthy vs catabolic)
timeFrame: measured at the end of the 3.5 hour basal period
measure: Difference in glucose kinetics measured with glucose tracer (mg/kg/min) (healthy vs catabolic)
timeFrame: measured at the end of the 3.5 hour basal period
measure: Difference in concentration of free fatty acids (FFA) (healthy vs catabolic)
timeFrame: Measured at the end of the 3.5 hour basal period.
measure: Difference in concentration of C-reactive peptide (CRP) (healthy vs catabolic)
timeFrame: Measured at the end of the 3.5 hour basal period.
measure: Difference in concentration of leucocytes (healthy vs catabolic)
timeFrame: Measured at the end of the 3.5 hour basal period.
measure: Difference in intracellular muscle signalling (healthy vs catabolic)
timeFrame: Measured at the end of the 3.5 hour basal period.
measure: Difference in concentration of 3-hydroxybutyrate (mmol/L) (healthy vs catabolic)
timeFrame: Measured at the end of the 3.5 hour basal period.
measure: Difference in concentration of hormones (insulin, glucagon, cortisol, growth hormone, adrenaline, noradrenalin) (healthy vs catabolic)
timeFrame: Measured at the end of the 3.5 hour basal period.
measure: Difference in whole body protein metabolism (healthy vs catabolic)
timeFrame: Measured at the end of the 3.5 hour basal period.
measure: Difference in concentration of cytokines (healthy vs catabolic)
timeFrame: Measured at baseline and 120 and 240 minutes after LPS administration
measure: Difference in axillary temperature (healthy vs catabolic)
timeFrame: Measured at baseline and 1, 2, 3, 4, 5, 6 and 7 hours after LPS administration
measure: Difference in heart rate (healthy vs catabolic)
timeFrame: Measured at baseline and 1, 2, 3, 4, 5, 6 and 7 hours after LPS administration
measure: Difference in mean arterial pressure (MAP) (healthy vs catabolic)
timeFrame: Measured at baseline and 1, 2, 3, 4, 5, 6 and 7 hours after LPS administration
measure: Difference in symptom score (healthy vs catabolic)
timeFrame: Measured at baseline and 1, 2, 3, 4, 5, 6 and 7 hours after LPS administration
Other outcomes:
Locations:
city: Aarhus
country: Denmark
facility: Medical Research Laboratory, DoH, Aarhus University Hospital
Study officials:
affiliation: Aarhus University Hospital
name: Niels Moeller, Professor
role: PRINCIPAL_INVESTIGATOR
References: