Clinical trial 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?
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?
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Inflammation
Glucose Metabolism Disorders
Keywords: Endotoxin
LPS
TNF-α
insulin resistance
metabolism
Lead sponsor: Aarhus University Hospital
Sponsor class: OTHER
Collaborators: name: University of Aarhus
name: Lundbeck Foundation
First posted: 2011-10-17
Enrollment: 24
Sex: MALE
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL

Brief summary: 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.

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 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

Primary outcomes:
measure: Acute metabolic effects of endotoxin and cytokine TNF-α (Study 2)
timeFrame: 2 hours
measure: Acute metabolic effects of endotoxin and cytokine TNF-α (Study 2)
timeFrame: 4 hours
measure: Acute metabolic effects of cytokine TNF-α (Study 1)
timeFrame: 3 hours
measure: Acute metabolic effects of cytokine TNF-α (Study 1)
timeFrame: 3 hours
Secondary outcomes:
measure: Intracellular insulin signaling, growth hormone signalling and inflammatory signalling pathways.
timeFrame: 120 min.
measure: Intracellular insulin signaling, growth hormone signalling and inflammatory signalling pathways.
timeFrame: 30 min.
Other outcomes:
Locations:
city: Aarhus
country: Denmark
facility: Medical Department MEA, NBG, Aarhus University Hospital
Study officials:
affiliation: Aarhus University Hospital
name: Niels Møller, Professor
role: PRINCIPAL_INVESTIGATOR
References:
citation: Bach E, Nielsen RR, Vendelbo MH, Moller AB, Jessen N, Buhl M, K-Hafstrom T, Holm L, Pedersen SB, Pilegaard H, Bienso RS, Jorgensen JO, Moller N. Direct effects of TNF-alpha 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.