Clinical trial NCT03319550: Whey vs Casein to Combat Post-inflammatory Protein and Muscle Waste in Acute Disease
Official title: Whey vs Casein to Combat Post-inflammatory Protein and Muscle Waste - Combining Endotoxemia, Immobilisation and Fasting in Healthy Young Males in a New Model of Acute Febrile Disease
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Muscle Protein Synthesis
Endotoxemia
Nutrition
Milk Protein
Metabolism
Whey
Casein
Keywords: milk protein, endotoxemia, muscle protein synthesis, whey, casein
Lead sponsor: University of Aarhus
Sponsor class: OTHER
Collaborators: name: Arla Food for Health
First posted: 2017-10-24
Enrollment: 10
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: Interventions\*:

I. LPS (1 ng/kg as bolus) + 36 h fasting + 36 h bedrest + Casein

II. LPS (1 ng/kg as bolus) + 36 h fasting + 36 h bedrest + Whey

III. LPS (1 ng/kg as bolus) + 36 h fasting + 36 h bedrest + Leucine-enriched whey

\* LPS will be administered on study day 1 and measurements of metabolism will be performed on study day 2 where we see the secondary effects of acute inflammation. The patient will stay at the hospital over night to ensure continues fast and bedrest.

The beverages will be isocaloric and with the same total protein content. The basal period will be 2,5 hour with infusion of tracer. Hereafter a total amount of 0,6 g protein/kg bodyweight will be orally administered, 1/3 as a bolus and 2/3 as sipping over 3,5 hours. Muscle biopsies and blodsampels will be collected during both the basal and the sipping period.
Primary purpose: BASIC_SCIENCE

Brief summary: This study compares three different protein supplements (casein, whey and leucine-enriched whey) and their effect on post-inflammatory muscle waste in a model of acute disease. Each test person will undergo all three interventions.

It is believed that leucine is the primary driver of muscle protein synthesis and therefore we hypothesize that leucine-enriched whey and whey are superior to casein in combating post-inflammatory muscle waste, because of its higher leucine content (16%, 11% and 9% leucine, respectively).

Detailed description: Background:

Acute illness is accompanied by infection/inflammation, anorexia and immobilization all contributing to muscle loss, making nutritional supplement optimization an obvious target for investigation and eventually clinical intervention. In the clinical setting large heterogenicity among patients complicates investigations of muscle metabolism during acute illness. Therefore we introduce a disease model by combining "Inflammation + 36 hour fast and bedrest". Inflammation/febrile illness will be initiated by using the well-established "human endotoxemia model" with a bolus injection of Escherichia coli lipopolysaccharide (LPS), known to cause inflammation comparable with the initial phase of sepsis. The amino acid leucine has shown to be particularly anabolic in performance sports, but little is known about its potential beneficial effects during acute illness. Leucine is a powerful activator of muscle protein synthesis and it seems that protein supplements with the highest leucine content elicit a greater increase in protein synthesis than those with a smaller fraction of leucine.

The protein supplements used most in hospitals contain casein derived protein, which has a much lower leucine content than the whey protein compounds typically used in performance sports.

This study compares three different protein supplements.The study is an open, randomized crossover trial. Laboratory technicians, test subjects and investigators will be blinded.

Interventions:

I. LPS (1 ng/kg as bolus) + 36 h fasting + 36 h bedrest + Casein (9% leucine) II. LPS (1 ng/kg as bolus) + 36 h fasting + 36 h bedrest + Whey (11% leucine) III. LPS (1 ng/kg as bolus) + 36 h fasting + 36 h bedrest + Leucine-enriched whey (16% leucine)

The test objects will be given 0,6 g protein/kg, 1/3 as a bolus and 2/3 as sipping over a period of 3,5 hour. Muscle metabolism will be investigated by phenylalanine tracer using the forearm model and total protein metabolism using a carbamide tracer. Through muscle biopsies intracellular signalling pathways will be investigated.

Eligibility criteria: Inclusion Criteria:

* Healthy Male
* Age between 20-40
* BMI between 20-30
* Normal health examination and blood samples
* Written informed consent

Exclusion Criteria:

* Immobilisation of an extremity, unless a doctor has declared it fully rehabilitated.
* Allergy against lidocain or latex.
* The use of anabolic steroids
* Disease like: Diabetes, epilepsia, infection, cardiovascular disease.

Primary outcomes:
measure: Change in muscle phenylalanine netbalance over the forearm muscle
timeFrame: Change from baseline to 3.5 hours after intervention
Secondary outcomes:
measure: Change in whole body protein metabolism measured by a combination of phenylalanine- and tyrosine tracer
timeFrame: Change from baseline to 3.5 hours after intervention
measure: Blood enrichment of essential amino acids
timeFrame: At baseline and every 30 minutes during the intervention period (3.5 hours)
measure: Changes in insulin concentrations
timeFrame: At baseline and every 30 minutes during the intervention period (3.5 hours)
measure: Change in Intracellular signalling in muscle measured by western blotting.
timeFrame: Change from baseline and after 2 hours of intervention
measure: Energy expenditure
timeFrame: At baseline and after 2.5 hours of intervention
measure: Changes in Glucose, fat and protein oxidation rates
timeFrame: At baseline and after 2.5 hours of intervention
measure: Change in muscle breakdown and synthesis rates measured by phenylalanine tracer
timeFrame: Change from baseline to 3.5 hours after intervention
measure: Changes in Glucagon concentrations
timeFrame: Change from baseline and to 1 hour and 3.5 hour after the intervention
measure: Changes in GIP concentrations
timeFrame: Change from baseline and to 1 hour and 3.5 hour after the intervention
measure: Changes in GLP-1 concentrations
timeFrame: Change from baseline and to 1 hour and 3.5 hour after the intervention
measure: Changes in Glucose concentrations
timeFrame: At baseline and every 30 minutes during the intervention period (3.5 hours)
measure: Changes in heart rate profile upon repeated LPS exposure
timeFrame: Measured at baseline and 1,2,3,4,5,6 and 24 hours after LPS (6-8 weeks between visit 1,2 and 3)
measure: Changes in temperature profile upon repeated LPS exposure
timeFrame: Measured at baseline and 1,2,3,4,5,6 and 24 hours after LPS (6-8 weeks between visit 1,2 and 3)
measure: Changes in blood pressure profile upon repeated LPS exposure
timeFrame: Measured at baseline and 1,2,3,4,5,6 and 24 hours after LPS (6-8 weeks between visit 1,2 and 3)
measure: Changes in symptom score profile upon repeated LPS exposure
timeFrame: Measured at baseline and 1,2,3,4,5,6 and 24 hours after LPS (6-8 weeks between visit 1,2 and 3)
measure: Changes in TNfalfa profile upon repeated LPS exposure
timeFrame: Measured at baseline and 1, 2, 4, 6 and 24 hours after LPS (6-8 weeks between visit 1,2 and 3)
measure: Changes in IL-1 profile upon repeated LPS exposure
timeFrame: Measured at baseline and 1, 2, 4, 6 and 24 hours after LPS (6-8 weeks between visit 1,2 and 3)
measure: Changes in IL-6 profile upon repeated LPS exposure
timeFrame: Measured at baseline and 1, 2, 4, 6 and 24 hours after LPS (6-8 weeks between visit 1,2 and 3)
measure: Changes in IL-10 profile upon repeated LPS exposure
timeFrame: Measured at baseline and 1, 2, 4, 6 and 24 hours after LPS (6-8 weeks between visit 1,2 and 3)
Other outcomes:
Locations:
city: Aarhus
country: Denmark
facility: Aarhus University Hospital
Study officials:
affiliation: Institute for clinical Medicine
name: Niels Moeller, Professor
role: PRINCIPAL_INVESTIGATOR
References:
citation: Mose M, Moller N, Jessen N, Mikkelsen UR, Christensen B, Rakvaag E, Hartmann B, Holst JJ, Jorgensen JOL, Rittig N. beta-Lactoglobulin Is Insulinotropic Compared with Casein and Whey Protein Ingestion during Catabolic Conditions in Men in a Double-Blinded Randomized Crossover Trial. J Nutr. 2021 Jun 1;151(6):1462-1472. doi: 10.1093/jn/nxab010.