title: Bioavailability of insulin detemir and human insulin at the level of peripheral interstitial fluid in humans, assessed by open-flow microperfusion.
abstract: OBJECTIVE
  To find an explanation for the lower potency of insulin detemir observed in humans compared with unmodified human insulin by investigating insulin detemir and human insulin concentrations directly at the level of peripheral insulin-sensitive tissues in humans in vivo.
  
  
  METHODS
  Euglycaemic-hyperinsulinaemic clamp experiments were performed in healthy volunteers. Human insulin was administered i.v. at 6 pmol/kg/min and insulin detemir at 60 pmol/kg/min, achieving a comparable steady-state pharmacodynamic action. In addition, insulin detemir was doubled to 120 pmol/kg/min. Minimally invasive open-flow microperfusion (OFM) sampling methodology was combined with inulin calibration to quantify human insulin and insulin detemir in the interstitial fluid (ISF) of subcutaneous adipose and skeletal muscle tissue.
  
  
  RESULTS
  The human insulin concentration in the ISF was ∼115 pmol/l or ∼30% of the serum concentration, whereas the insulin detemir concentration in the ISF was ∼680 pmol/l or ∼2% of the serum concentration. The molar insulin detemir interstitial concentration was five to six times higher than the human insulin interstitial concentration and metabolic clearance of insulin detemir from serum was substantially reduced compared with human insulin.
  
  
  CONCLUSIONS
  OFM proved useful for target tissue measurements of human insulin and the analogue insulin detemir. Our tissue data confirm a highly effective retention of insulin detemir in the vascular compartment. The higher insulin detemir relative to human insulin tissue concentrations at comparable pharmacodynamics, however, indicate that the lower potency of insulin detemir in humans is attributable to a reduced effect in peripheral insulin-sensitive tissues and is consistent with the reduced in vitro receptor affinity.
authors.affiliation: HEALTH, Institute for Biomedicine and Health Sciences, Joanneum Research Forschungsgesellschaft m.b.H, Graz, Austria.
authors.forename: M
authors.initials: M
authors.lastname: Bodenlenz
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, Medical University of Graz, Graz, Austria.
authors.forename: M
authors.initials: M
authors.lastname: Ellmerer
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, Medical University of Graz, Graz, Austria.
authors.forename: L
authors.initials: L
authors.lastname: Schaupp
authors.affiliation: Novo Nordisk A/S, Bagsvaerd, Denmark.
authors.forename: L V
authors.initials: LV
authors.lastname: Jacobsen
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, Medical University of Graz, Graz, Austria.
authors.forename: J
authors.initials: J
authors.lastname: Plank
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, Medical University of Graz, Graz, Austria.
authors.forename: G A
authors.initials: GA
authors.lastname: Brunner
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, Medical University of Graz, Graz, Austria.
authors.forename: A
authors.initials: A
authors.lastname: Wutte
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, Medical University of Graz, Graz, Austria.|Division of General Dermatology, Department of Dermatology and Venereology, Medical University of Graz, Graz, Austria.
authors.forename: B
authors.initials: B
authors.lastname: Aigner
authors.affiliation: HEALTH, Institute for Biomedicine and Health Sciences, Joanneum Research Forschungsgesellschaft m.b.H, Graz, Austria.|Division of Endocrinology and Metabolism, Department of Internal Medicine, Medical University of Graz, Graz, Austria.
authors.forename: S I
authors.initials: SI
authors.lastname: Mautner
authors.affiliation: HEALTH, Institute for Biomedicine and Health Sciences, Joanneum Research Forschungsgesellschaft m.b.H, Graz, Austria.|Division of Endocrinology and Metabolism, Department of Internal Medicine, Medical University of Graz, Graz, Austria.
authors.forename: T R
authors.initials: TR
authors.lastname: Pieber
mesh_terms: D000328:Adult; D001682:Biological Availability; D002138:Calibration; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D045604:Extracellular Fluid / Q000378:metabolism*; D015309:Glucose Clamp Technique; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D007262:Infusions, Intravenous; D000069057:Insulin Detemir / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D061386:Insulin, Regular, Human / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D007444:Inulin / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics; D054878:Lipoylation; D008297:Male; D008657:Metabolic Clearance Rate; D018482:Muscle, Skeletal / Q000378:metabolism; D050151:Subcutaneous Fat / Q000378:metabolism; D014018:Tissue Distribution; D055815:Young Adult
chemical_list: D007004:Hypoglycemic Agents; D061386:Insulin, Regular, Human; D000069057:Insulin Detemir; D007444:Inulin
keywords: adipose tissue; clinical trial; insulin analogues; pharmacodynamics; pharmacokinetics