title: Direct administration of insulin into skeletal muscle reveals that the transport of insulin across the capillary endothelium limits the time course of insulin to activate glucose disposal.
abstract: OBJECTIVE
  Intravenous insulin infusion rapidly increases plasma insulin, yet glucose disposal occurs at a much slower rate. This delay in insulin's action may be related to the protracted time for insulin to traverse the capillary endothelium. An increased delay may be associated with the development of insulin resistance. The purpose of the present study was to investigate whether bypassing the transendothelial insulin transport step and injecting insulin directly into the interstitial space would moderate the delay in glucose uptake observed with intravenous administration of the hormone.
  
  
  METHODS
  Intramuscular injections of saline (n = 3) or insulin (n = 10) were administered directly into the vastus medialis of anesthetized dogs. Injections of 0.3, 0.5, 0.7, 1.0, and 3.0 units insulin were administered hourly during a basal insulin euglycemic glucose clamp (0.2mU x min(-1) x kg(-1)).
  
  
  RESULTS
  Unlike the saline group, each incremental insulin injection caused interstitial (lymph) insulin to rise within 10 min, indicating rapid diffusion of the hormone within the interstitial matrix. Delay in insulin action was virtually eliminated, indicated by immediate dose-dependent increments in hindlimb glucose uptake. Additionally, bypassing insulin transport by direct injection into muscle revealed a fourfold greater sensitivity to insulin of in vivo muscle tissue than previously reported from intravenous insulin administration.
  
  
  CONCLUSIONS
  Our results indicate that the transport of insulin to skeletal muscle is a rate-limiting step for insulin to activate glucose disposal. Based on these results, we speculate that defects in insulin transport across the endothelial layer of skeletal muscle will contribute to insulin resistance.
authors.affiliation: Department of Physiology and Biophysics, University of Southern California, Keck School of Medicine, 1333 San Pablo St., MMR 626, Los Angeles, CA 90033, USA.
authors.forename: Jenny D
authors.initials: JD
authors.lastname: Chiu
authors.forename: Joyce M
authors.initials: JM
authors.lastname: Richey
authors.forename: L Nicole
authors.initials: LN
authors.lastname: Harrison
authors.forename: Edward
authors.initials: E
authors.lastname: Zuniga
authors.forename: Cathryn M
authors.initials: CM
authors.lastname: Kolka
authors.forename: Erlinda
authors.initials: E
authors.lastname: Kirkman
authors.forename: Martin
authors.initials: M
authors.lastname: Ellmerer
authors.forename: Richard N
authors.initials: RN
authors.lastname: Bergman
mesh_terms: D000818:Animals; D001692:Biological Transport; D002196:Capillaries / Q000502:physiology*; D004285:Dogs; D004730:Endothelium, Vascular / Q000502:physiology*; D005947:Glucose / Q000008:administration & dosage / Q000378:metabolism*; D015309:Glucose Clamp Technique; D007262:Infusions, Intravenous; D007273:Injections, Intramuscular; D007328:Insulin / Q000008:administration & dosage / Q000494:pharmacology* / Q000502:physiology*; D008297:Male; D018482:Muscle, Skeletal / Q000098:blood supply* / Q000187:drug effects / Q000502:physiology*
chemical_list: D007328:Insulin; D005947:Glucose