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?

Inflammation Clinical Trial

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?

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01452958
• Other study ID #: 2010/0604
• Status: Completed
• Phase: N/A
• First received: September 22, 2011
• Last updated: January 29, 2013
• Start date: June 2010
• Est. completion date: January 2013

Study information

• Verified date: January 2013
• Source: Aarhus University Hospital
• Contact: n/a
• Is FDA regulated: No
• Health authority: Denmark: The Regional Committee on Biomedical Research Ethics
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 24
• Est. completion date: January 2013
• Est. primary completion date: January 2013
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Male
• Age group: 18 Years to 70 Years

Eligibility

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

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver)

Related Conditions & MeSH terms

• Glucose Metabolism Disorders
• Inflammation
• Metabolic Diseases

Intervention

Biological:
• TNF-alpha
Study protocol 1: 6 ng/kg/h intraarterial Study protocol 2: 18 ng/kg/h intravenous
• Endotoxin
Study protocol 2:0,075 ng/kg/h intravenous

Locations

Country	Name	City	State
Denmark	Medical Department MEA, NBG, Aarhus University Hospital	Aarhus

Sponsors (3)

Lead Sponsor	Collaborator
Aarhus University Hospital	Lundbeck Foundation, University of Aarhus

Country where clinical trial is conducted

Denmark, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Acute metabolic effects of endotoxin and cytokine TNF-a (Study 2)	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 hours	No
Primary	Acute metabolic effects of endotoxin and cytokine TNF-a (Study 2)	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.	4 hours	No
Primary	Acute metabolic effects of cytokine TNF-a (Study 1)	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.	3 hours	No
Primary	Acute metabolic effects of cytokine TNF-a (Study 1)	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.	3 hours	No
Secondary	Intracellular insulin signaling, growth hormone signalling and inflammatory signalling pathways.	Musle and fat biopsies during a basal period (120 min. from the beginning of a basal period)	120 min.	No
Secondary	Intracellular insulin signaling, growth hormone signalling and inflammatory signalling pathways.	Musle and fat biopsies during a hyperinsulinaemic euglycaemic clamp (30 min. from the beginning of clamp)	30 min.	No