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?
Condition: Inflammation; Glucose Metabolism Disorders
MeSH terms: Metabolic Diseases; Glucose Metabolism Disorders; Inflammation
Study type: Interventional

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.
    

Intervention name(s): TNF-alpha; Endotoxin
Intervention type(s): Biological; Biological
Intervention description(s): Study protocol 1: 6 ng/kg/h intraarterial Study protocol 2: 18 ng/kg/h intravenous; Study protocol 2:0,075 ng/kg/h intravenous
Other intervention name(s): Beromun, Boehringer-Ingelheim, Germany; E. coli endotoxin, US standard
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Care Provider)
Keywords: Endotoxin; LPS; TNF-α; insulin resistance; metabolism