title: Direct effects of locally administered lipopolysaccharide on glucose, lipid, and protein metabolism in the placebo-controlled, bilaterally infused human leg.
abstract: BACKGROUND
  Accumulating evidence suggests that chronic exposure to lipopolysaccharide (LPS, endotoxin) may create a constant low-grade inflammation, leading to insulin resistance and diabetes. All previous human studies assessing the metabolic actions of LPS have used systemic administration, making discrimination between direct and indirect effects impossible.
  
  
  OBJECTIVE
  We sought to define the direct, placebo-controlled effects of LPS on insulin resistance and protein and lipid metabolism in the infused human leg without systemic interference from cytokines and stress hormones.
  
  
  METHODS
  This was a randomized, placebo-controlled, single-blinded study.
  
  
  METHODS
  We studied 8 healthy volunteers with bilateral femoral vein and artery catheters during a 3-hour basal and 3-hour hyperinsulinemic-euglycemic clamp period with bilateral muscle biopsies in each period during infusion with saline and LPS.
  
  
  RESULTS
  Overall, LPS perfusion significantly decreased leg glucose uptake, and during the clamp LPS decreased glucose arteriovenous differences (0.65 ± 0.07 mmol/L vs 0.73 ± 0.08 mmol/L). Net palmitate release was increased by LPS, and secondary post hoc testing indicated increased palmitate isotopic dilution, although primary ANOVA tests did not reveal significant dilution. Leg blood flows, phenylalanine, lactate kinetics, cytokines, and intramyocellular insulin signaling were not affected by LPS. LPS thus directly inhibits insulin-stimulated glucose uptake and increases palmitate release in the perfused human leg without detectable effects on amino acid metabolism.
  
  
  CONCLUSIONS
  These data strongly suggest that the primary metabolic effect of LPS is increased lipolysis and muscle insulin resistance, which, together with secondary insulin resistance, caused by systemic cytokine and stress hormone release may lead to overt glucose intolerance and diabetes.
authors.affiliation: Medical Research Laboratories, Clinical Institute, Aarhus University, DK-8000, Aarhus, Denmark.
authors.forename: Mads
authors.initials: M
authors.lastname: Buhl
authors.forename: Ermina
authors.initials: E
authors.lastname: Bosnjak
authors.forename: Mikkel H
authors.initials: MH
authors.lastname: Vendelbo
authors.forename: Jakob
authors.initials: J
authors.lastname: Gjedsted
authors.forename: Roni R
authors.initials: RR
authors.lastname: Nielsen
authors.forename: Thomas
authors.initials: T
authors.lastname: K-Hafstrøm
authors.forename: Esben T
authors.initials: ET
authors.lastname: Vestergaard
authors.forename: Niels
authors.initials: N
authors.lastname: Jessen
authors.forename: Else
authors.initials: E
authors.lastname: Tønnesen
authors.forename: Andreas B
authors.initials: AB
authors.lastname: Møller
authors.forename: Steen B
authors.initials: SB
authors.lastname: Pedersen
authors.forename: Henriette
authors.initials: H
authors.lastname: Pilegaard
authors.forename: Rasmus S
authors.initials: RS
authors.lastname: Biensø
authors.forename: Jens O L
authors.initials: JO
authors.lastname: Jørgensen
authors.forename: Niels
authors.initials: N
authors.lastname: Møller
mesh_terms: D000328:Adult; D001692:Biological Transport / Q000187:drug effects; D050260:Carbohydrate Metabolism / Q000187:drug effects; D005947:Glucose / Q000378:metabolism*; D015309:Glucose Clamp Technique; D006801:Humans; D007262:Infusions, Intravenous; D007333:Insulin Resistance; D007700:Kinetics; D007866:Leg; D050356:Lipid Metabolism / Q000187:drug effects*; D008066:Lipolysis / Q000187:drug effects; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000009:adverse effects*; D008297:Male; D009124:Muscle Proteins / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D055550:Protein Stability / Q000187:drug effects; D059748:Proteolysis / Q000187:drug effects; D011865:Radioisotope Dilution Technique; D016037:Single-Blind Method
chemical_list: D008070:Lipopolysaccharides; D009124:Muscle Proteins; D005947:Glucose