Whey vs Casein to Combat Post-inflammatory Protein and Muscle Waste in Acute Disease

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

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).

Study Overview

• Status: Completed
• Conditions: Endotoxemia; Muscle Protein Synthesis; Nutrition; Metabolism; Milk Protein; Whey; Casein
• Intervention / Treatment: Dietary supplement: Casein; Dietary supplement: Whey; Dietary supplement: Leucine-enriched whey

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.

• Study Type: Interventional
• Enrollment (Actual): 10
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Denmark
  • Aarhus, Denmark, 8000
    • Aarhus University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years to 40 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Casein; "LPS + 36 hour fast and bedrest" + Casein (9% leucine) - 0.6 g protein/kg bodyweight, 1/3 as bolus and 2/3 as sipping.	Dietary supplement: Casein; see experimental description
Experimental: Whey; "LPS + 36 hour fast and bedrest" + Whey (11% leucine) - 0.6 g protein/kg bodyweight, 1/3 as bolus and 2/3 as sipping	Dietary supplement: Whey; see experimental description
Experimental: Leucine-enriched whey; "LPS + 36 hour fast and bedrest" + Leucine-enriched whey (16% leucine) - 0.6 g protein/kg bodyweight, 1/3 as bolus and 2/3 as sipping	Dietary supplement: Leucine-enriched whey; see experimental description

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in muscle phenylalanine netbalance over the forearm muscle	Changes of muscle phenylalanine net balance (= arterio(phe conc)-venous(phe conc) x flow) from baseline to 3.5 hours after intervention using the forearm model	Change from baseline to 3.5 hours after intervention

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in whole body protein metabolism measured by a combination of phenylalanine- and tyrosine tracer	Changes in whole body protein synthesis rates (umol/kg/h), breakdown rates (umol/kg/h), phenylalanine to tyrosine conversion rates (umol/kg/h) and net balance (umol/kg/h)	Change from baseline to 3.5 hours after intervention
Blood enrichment of essential amino acids	measures of essential amino acids in the blood	At baseline and every 30 minutes during the intervention period (3.5 hours)
Changes in insulin concentrations	Measures of insulin concentration in blood	At baseline and every 30 minutes during the intervention period (3.5 hours)
Change in Intracellular signalling in muscle measured by western blotting.	Investigating intracellular activity of muscle metabolism pathways by western blotting.	Change from baseline and after 2 hours of intervention
Energy expenditure	Using indirect calorimetry for 15 min	At baseline and after 2.5 hours of intervention
Changes in Glucose, fat and protein oxidation rates	Using indirect calorimetry for 15 min for measuring glucose- (mg/kg/min), fat- (mg/kg/min) and protein oxidation (mg/kg/min)	At baseline and after 2.5 hours of intervention
Change in muscle breakdown and synthesis rates measured by phenylalanine tracer	changes from baseline to 3.5 hours after intervention in Ra(phe)=breakdown (umol/kg/h) and Rd(phe)=synthesis rate (umol/kg/h)	Change from baseline to 3.5 hours after intervention
Changes in Glucagon concentrations	Glucagon concentrations in blood	Change from baseline and to 1 hour and 3.5 hour after the intervention
Changes in GIP concentrations	GIP concentrations in blood	Change from baseline and to 1 hour and 3.5 hour after the intervention
Changes in GLP-1 concentrations	GLP-1 concentrations in blood	Change from baseline and to 1 hour and 3.5 hour after the intervention
Changes in Glucose concentrations	Glucose concentrations in blood	At baseline and every 30 minutes during the intervention period (3.5 hours)
Changes in heart rate profile upon repeated LPS exposure	heart rate (beats/min)	Measured at baseline and 1,2,3,4,5,6 and 24 hours after LPS (6-8 weeks between visit 1,2 and 3)
Changes in temperature profile upon repeated LPS exposure	Axillary temperature (celcius)	Measured at baseline and 1,2,3,4,5,6 and 24 hours after LPS (6-8 weeks between visit 1,2 and 3)
Changes in blood pressure profile upon repeated LPS exposure	blood pressure (mmHg)	Measured at baseline and 1,2,3,4,5,6 and 24 hours after LPS (6-8 weeks between visit 1,2 and 3)
Changes in symptom score profile upon repeated LPS exposure	symptom score (from 0-5) for nausea, back pain, muscle pain, headache and chills. 0=no symptoms, 5=severe symptoms.	Measured at baseline and 1,2,3,4,5,6 and 24 hours after LPS (6-8 weeks between visit 1,2 and 3)
Changes in TNfalfa profile upon repeated LPS exposure	TNfalfa blood concentrations	Measured at baseline and 1, 2, 4, 6 and 24 hours after LPS (6-8 weeks between visit 1,2 and 3)
Changes in IL-1 profile upon repeated LPS exposure	IL-1 blood concentrations	Measured at baseline and 1, 2, 4, 6 and 24 hours after LPS (6-8 weeks between visit 1,2 and 3)
Changes in IL-6 profile upon repeated LPS exposure	IL-6 blood concentrations	Measured at baseline and 1, 2, 4, 6 and 24 hours after LPS (6-8 weeks between visit 1,2 and 3)
Changes in IL-10 profile upon repeated LPS exposure	IL-10 blood concentrations	Measured at baseline and 1, 2, 4, 6 and 24 hours after LPS (6-8 weeks between visit 1,2 and 3)

Collaborators and Investigators

• Sponsor: University of Aarhus
• Collaborators: Arla Food for Health
• Investigators: Principal Investigator: Niels Moeller, Professor, Institute for clinical Medicine

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): December 7, 2017
• Primary Completion (Actual): September 19, 2018
• Study Completion (Actual): September 19, 2018

Study Registration Dates

• First Submitted: October 13, 2017
• First Submitted That Met QC Criteria: October 23, 2017
• First Posted (Actual): October 24, 2017

Study Record Updates

• Last Update Posted (Actual): April 25, 2019
• Last Update Submitted That Met QC Criteria: April 23, 2019
• Last Verified: November 1, 2018

More Information

Terms related to this study

• Keywords: milk protein, endotoxemia, muscle protein synthesis, whey, casein
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Sepsis; Bacteremia; Toxemia; Endotoxemia; Molecular Mechanisms of Pharmacological Action; Chelating Agents; Sequestering Agents; Caseins
• Other Study ID Numbers: theproteinstudy

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No
• IPD Plan Description: We will analyse all data ourselves

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No