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?

NCT ID: NCT01452958

Last Updated: 2013-01-30

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 24 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2010-06-30
• Study Completion Date: 2013-01-31

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.

Conditions

Inflammation; Glucose Metabolism Disorders

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Blinding Strategy: DOUBLE

Study Groups

TNF-α

Beromun, Boehringer-Ingelheim, Germany

Group Type: EXPERIMENTAL

TNF-alpha

Intervention Type: BIOLOGICAL

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

Endotoxin

Group Type: EXPERIMENTAL

Endotoxin

Intervention Type: BIOLOGICAL

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

Interventions

TNF-alpha

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

Intervention Type: BIOLOGICAL

Endotoxin

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

Intervention Type: BIOLOGICAL

Other Intervention Names

Beromun, Boehringer-Ingelheim, Germany; E. coli endotoxin, US standard

Eligibility Criteria

Inclusion Criteria

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

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

Exclusion Criteria

• Diseases
• Allergy

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 70 Years
• Eligible Sex: MALE
• Accepts Healthy Volunteers: Yes

Sponsors

University of Aarhus

OTHER

Sponsor Role: collaborator

Lundbeck Foundation

OTHER

Sponsor Role: collaborator

Aarhus University Hospital

OTHER

Sponsor Role: lead

Responsible Party

Ermina Bosnjak

Medical Doctor, PhD student

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Niels Møller, Professor

Role: PRINCIPAL_INVESTIGATOR

Aarhus University Hospital

Locations

Medical Department MEA, NBG, Aarhus University Hospital

Aarhus, , Denmark

Countries

Denmark

References

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.

Reference Type: DERIVED

PMID: 23835341 (View on PubMed)

Other Identifiers

2010/0604

Identifier Type: -

Identifier Source: org_study_id