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Completed

NCT Number: NCT01452958

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?

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.

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Key information

Conditions

Inflammation Glucose Metabolism Disorders Hyperinsulinism Insulin Resistance Metabolic Diseases Nutritional and Metabolic Diseases Pathologic Processes Pathological Conditions, Signs and Symptoms

Age range

18 year–70 year

Sex eligibility

Male

Study type

Interventional

Phase

Not applicable

Primary location

Medical Department MEA, NBG, Aarhus University Hospital

Aarhus, 8000, Denmark

About this study

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:

  • Direct local effects in muscle tissue (Study protocol 1)
  • 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.

Who can participate

Healthy volunteers accepted: Yes

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

TNF-alpha

Biological

Study protocol 1: 6 ng/kg/h intraarterial Study protocol 2: 18 ng/kg/h intravenous

Other names: Beromun, Boehringer-Ingelheim, Germany

Endotoxin

Biological

Study protocol 2:0,075 ng/kg/h intravenous

Other names: E. coli endotoxin, US standard

Primary outcomes

  1. Acute metabolic effects of endotoxin and cytokine TNF-α (Study 2)

    Time frame: 2 hours

    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.

  2. Acute metabolic effects of endotoxin and cytokine TNF-α (Study 2)

    Time frame: 4 hours

    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.

  3. Acute metabolic effects of cytokine TNF-α (Study 1)

    Time frame: 3 hours

    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.

  4. Acute metabolic effects of cytokine TNF-α (Study 1)

    Time frame: 3 hours

    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 outcomes

  1. Intracellular insulin signaling, growth hormone signalling and inflammatory signalling pathways.

    Time frame: 120 min.

    Musle and fat biopsies during a basal period (120 min. from the beginning of a basal period)

  2. Intracellular insulin signaling, growth hormone signalling and inflammatory signalling pathways.

    Time frame: 30 min.

    Musle and fat biopsies during a hyperinsulinaemic euglycaemic clamp (30 min. from the beginning of clamp)

Sponsors and collaborators

Lead sponsor

Aarhus University Hospital

Other

Collaborators

  • Lundbeck Foundation
  • University of Aarhus

Registry information

Official study title

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

Important dates

Study start
2010
Primary completion
2013
Study completion
2013
First posted
Oct 17, 2011
Registry last updated
Jan 30, 2013

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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