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Endotoxin & Cytokines. Do Protein Loss and Metabolic Effects Depend on Central Nervous System (CNS) Activation of Stress Hormones or on Local Mechanisms in Muscle and Fat?

This study has been completed.
Sponsor:
Collaborators:
University of Aarhus
Lundbeck Foundation
Information provided by (Responsible Party):
Ermina Bosnjak, Aarhus University Hospital
ClinicalTrials.gov Identifier:
NCT01452958
First received: September 22, 2011
Last updated: January 29, 2013
Last verified: January 2013
History of Changes
  Purpose

Main objective :

The purpose of this study is to prove that the effects of bacterial endotoxin and cytokine TNF-α, on protein loss, fatty acid release, and glucose metabolism depend on two mechanisms:

  1. Direct local effects in muscle tissue.
  2. Activation of the hypothalamo-pituitary axis and a stress-hormone response

Study protocols:

  1. Acute metabolic effects of TNF-α(Beromun, Boehringer-Ingelheim Germany) vs placebo perfused into the femoral artery of the leg in 8 healthy subjects.

  2. Acute metabolic effects of

    • placebo(saline)
    • endotoxin(US standard reference E.Coli, endotoxin)
    • TNF-α(Beromun, Boehringer-Ingelheim Germany) given systemically
    • in 8 patients with hypopituitarism(to block stress hormone release) and in 8 healthy subjects all studied thrice.

Condition Intervention
Inflammation
Glucose Metabolism Disorders
 Biological: TNF-alpha
Biological: Endotoxin

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver)
Official Title: Endotoxin & Cytokines. Do Protein Loss and Metabolic Effects Depend on CNS Activation of Stress Hormones or on Local Mechanisms in Muscle and Fat?

Resource links provided by NLM:

U.S. FDA Resources

Further study details as provided by Aarhus University Hospital:

Primary Outcome Measures:
  • Acute metabolic effects of endotoxin and cytokine TNF-α (Study 2) [ Time Frame: 2 hours ] [ Designated as safety issue: No ]

    During a basal period.

    Acute metabolic effects: Glucose metabolism was quantified with raw arterio-venous differences and 3H3-Glucose tracer. Lactate was quantified with raw arterio-venous differences. Lipid metabolism was quantified with [9,10-3H]-Palmitate tracer and amino acid metabolism with 15N-Phenylalanine tracer and 13C-Urea tracer.


  • Acute metabolic effects of endotoxin and cytokine TNF-α (Study 2) [ Time Frame: 4 hours ] [ Designated as safety issue: No ]

    During a hyperinsulinaemic euglycaemic clamp.

    Acute metabolic effects: Glucose metabolism was quantified with raw arterio-venous differences and 3H3-Glucose tracer. Lactate was quantified with raw arterio-venous differences. Lipid metabolism was quantified with [9,10-3H]-Palmitate tracer and amino acid metabolism with 15N-Phenylalanine tracer and 13C-Urea tracer.


  • Acute metabolic effects of cytokine TNF-α (Study 1) [ Time Frame: 3 hours ] [ Designated as safety issue: No ]

    During a basal period.

    Acute metabolic effects: Glucose and lactate were quantified with raw arterio-venous differences; lipid metabolism was quantified with [9,10-3H]-palmitate and amino acid metabolism with 15N-phenylalanine.


  • Acute metabolic effects of cytokine TNF-α (Study 1) [ Time Frame: 3 hours ] [ Designated as safety issue: No ]

    During a hyperinsulinaemic euglycaemic clamp.

    Acute metabolic effects: Glucose and lactate were quantified with raw arterio-venous differences; lipid metabolism was quantified with [9,10-3H]-palmitate and amino acid metabolism with 15N-phenylalanine.



Secondary Outcome Measures:
  • Intracellular insulin signaling, growth hormone signalling and inflammatory signalling pathways. [ Time Frame: 120 min. ] [ Designated as safety issue: No ]
    Musle and fat biopsies during a basal period (120 min. from the beginning of a basal period)

  • Intracellular insulin signaling, growth hormone signalling and inflammatory signalling pathways. [ Time Frame: 30 min. ] [ Designated as safety issue: No ]
    Musle and fat biopsies during a hyperinsulinaemic euglycaemic clamp (30 min. from the beginning of clamp)


Enrollment: 24
Study Start Date: June 2010
Study Completion Date: January 2013
Primary Completion Date: January 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: TNF-α
Beromun, Boehringer-Ingelheim, Germany
 Biological: TNF-alpha
Study protocol 1: 6 ng/kg/h intraarterial Study protocol 2: 18 ng/kg/h intravenous
Other Name: Beromun, Boehringer-Ingelheim, Germany
Experimental: Endotoxin Biological: Endotoxin
Study protocol 2:0,075 ng/kg/h intravenous
Other Name: E. coli endotoxin, US standard

Detailed Description:

PURPOSE:

Knowledge about the effects of bacterial endotoxin and cytokines (and inflammation in general) in humans on protein, glucose and lipid metabolism and intracellular signalling in muscle and fat is sporadic and it is uncertain whether endotoxin and cytokines act directly in fat and muscle tissue or indirectly via central nervous system (CNS) mediated stress hormone release.

The investigators hypothesize that the metabolic effects of endotoxin and cytokine TNF-α, including protein loss, fatty acid release and decreased glucose uptake depend on two mechanisms:

  1. Direct local effects in muscle tissue (Study protocol 1)
  2. Activation of the hypothalamo-pituitary axis and generalized stress hormone response (Study protocol 2)

METHODOLOGY:

Study protocol 1:

Acute metabolic effects of TNF-α (Beromun, Boehringer-Ingelheim, Germany) versus placebo perfused into the femoral artery of the leg in 8 healthy subjects, studied once. Femoral vein sampling allows assessment of local metabolic events in the leg. The vessels were cannulated using the Seldinger technique. Each study comprises a 3 hour basal period and a 3 hour Hyperinsulinemic-Euglycemic Clamp. Muscle biopsies were obtained simultaneously from both lateral vastus muscles.

Study protocol 2:

Acute metabolic effects of (i)placebo (saline), (ii)endotoxin (US standard reference E.Coli, endotoxin) and (iii)TNF-α (Beromun, Boehringer-Ingelheim, Germany) given systemically intravenously (i.v.) in 8 patients with hypopituitarism (to block stress hormone release) and in 8 healthy subjects all studied thrice. Every study comprises a 4 hour basal period and a 2 hour Hyperinsulinemic-Euglycemic Clamp. Muscle and fat biopsies were obtained.

Study protocol 1 and Study protocol 2:

Assays: Mass spectrometry (15N-phenylalanine, 13C-urea), 3H-glucose, 3H-palmitate quantification, hormone and metabolite analysis, cytokine assays, intracellular signaling.

  Eligibility

Ages Eligible for Study:   18 Years to 70 Years
Genders Eligible for Study:   Male
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria 1. group:

  • Male
  • 19 < BMI < 28
  • 18 ≤ Age ≤ 50
  • Healthy

Inclusion Criteria 2. group:

  • Male
  • 20 < BMI < 30
  • Age > 25
  • Healthy

Exclusion Criteria:

  • Diseases
  • Allergy
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01452958

Locations
Denmark
Medical Department MEA, NBG, Aarhus University Hospital
Aarhus, Denmark, 8000
Sponsors and Collaborators
Aarhus University Hospital
University of Aarhus
Lundbeck Foundation
Investigators
Principal Investigator: Niels Møller, Professor Aarhus University Hospital
  More Information

No publications provided

Responsible Party: Ermina Bosnjak, Medical Doctor, PhD student, Aarhus University Hospital
ClinicalTrials.gov Identifier: NCT01452958     History of Changes
Other Study ID Numbers: 2010/0604
Study First Received: September 22, 2011
Last Updated: January 29, 2013
Health Authority: Denmark: The Regional Committee on Biomedical Research Ethics

Keywords provided by Aarhus University Hospital:
Endotoxin
LPS
TNF-α
insulin resistance
metabolism

Additional relevant MeSH terms:
Inflammation
Metabolic Diseases
Glucose Metabolism Disorders
Pathologic Processes

ClinicalTrials.gov processed this record on May 23, 2013