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

September 22, 2011
January 29, 2013
June 2010
January 2013   (final data collection date for primary outcome measure)
  • 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.

Same as current
Complete list of historical versions of study NCT01452958 on ClinicalTrials.gov Archive Site
  • 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)
Same as current
Not Provided
Not Provided
 
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?
Endotoxin & Cytokines. Do Protein Loss and Metabolic Effects Depend on CNS Activation of Stress Hormones or on Local Mechanisms in Muscle and Fat?

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.

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.

Interventional
Not Provided
Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver)
  • Inflammation
  • Glucose Metabolism Disorders
  • 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
  • Biological: Endotoxin
    Study protocol 2:0,075 ng/kg/h intravenous
    Other Name: E. coli endotoxin, US standard
  • Experimental: TNF-α
    Beromun, Boehringer-Ingelheim, Germany
    Intervention: Biological: TNF-alpha
  • Experimental: Endotoxin
    Intervention: Biological: Endotoxin
Bach E, Nielsen RR, Vendelbo MH, Møller AB, Jessen N, Buhl M, K-Hafstrøm T, Holm L, Pedersen SB, Pilegaard H, Biensø RS, Jørgensen JO, Møller N. Direct effects of TNF-α on local fuel metabolism and cytokine levels in the placebo-controlled, bilaterally infused human leg: increased insulin sensitivity, increased net protein breakdown, and increased IL-6 release. Diabetes. 2013 Dec;62(12):4023-9. doi: 10.2337/db13-0138. Epub 2013 Jul 8.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
24
January 2013
January 2013   (final data collection date for primary outcome measure)

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
Male
18 Years to 70 Years
Yes
Contact information is only displayed when the study is recruiting subjects
Denmark
 
NCT01452958
2010/0604
Yes
Ermina Bosnjak, Aarhus University Hospital
Aarhus University Hospital
  • University of Aarhus
  • Lundbeck Foundation
Principal Investigator: Niels Møller, Professor Aarhus University Hospital
Aarhus University Hospital
January 2013

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP