title: Modest hyperglycemia prevents interstitial dispersion of insulin in skeletal muscle.
abstract: Insulin injected directly into skeletal muscle diffuses rapidly through the interstitial space to cause glucose uptake, but this is blocked in insulin resistance. As glucotoxicity is associated with endothelial dysfunction, the observed hyperglycemia in diet-induced obese dogs may inhibit insulin access to muscle cells, and exacerbate insulin resistance. Here we asked whether interstitial insulin diffusion is reduced in modest hyperglycemia, similar to that induced by a high fat diet.
  
  
  METHODS
  During normoglycemic (100 mg/dl) and moderately hyperglycemic (120 mg/dl) clamps in anesthetized canines, sequential doses of insulin were injected into the vastus medialis of one hindlimb; the contra-lateral limb served as a control. Plasma samples were collected and analyzed for insulin content. Lymph vessels of the hind leg were also catheterized, and lymph samples were analyzed as an indicator of interstitial insulin concentration.
  
  
  RESULTS
  Insulin injection increased lymph insulin in normoglycemic animals, but not in hyperglycemic animals. Muscle glucose uptake was elevated in response to hyperglycemia, however the insulin-mediated glucose uptake in normoglycemic controls was not observed in hyperglycemia. Modest hyperglycemia prevented intra-muscularly injected insulin from diffusing through the interstitial space reduced insulin-mediated glucose uptake.
  
  
  CONCLUSIONS
  Hyperglycemia prevents the appearance of injected insulin in the interstitial space, thus reducing insulin action on skeletal muscle cells.
authors.affiliation: Department of Physiology and Biophysics, University of Southern California, Los Angeles, CA. Electronic address: Cathryn.Kolka@cshs.org.
authors.forename: Cathryn M
authors.initials: CM
authors.lastname: Kolka
authors.affiliation: Department of Physiology and Biophysics, University of Southern California, Los Angeles, CA.
authors.forename: Ana Valeria B
authors.initials: AV
authors.lastname: Castro
authors.affiliation: Department of Physiology and Biophysics, University of Southern California, Los Angeles, CA.
authors.forename: Erlinda L
authors.initials: EL
authors.lastname: Kirkman
authors.affiliation: Department of Physiology and Biophysics, University of Southern California, Los Angeles, CA.
authors.forename: Richard N
authors.initials: RN
authors.lastname: Bergman
mesh_terms: D065567:Absorption, Physiological; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D004058:Diffusion; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005110:Extracellular Space / Q000737:chemistry; D005947:Glucose / Q000378:metabolism; D015309:Glucose Clamp Technique; D006614:Hindlimb; D006943:Hyperglycemia / Q000097:blood / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics* / Q000627:therapeutic use; D007273:Injections, Intramuscular; D007333:Insulin Resistance; D061389:Insulin, Regular, Pork / Q000008:administration & dosage / Q000032:analysis / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008196:Lymph / Q000737:chemistry / Q000187:drug effects; D008297:Male; D052097:Quadriceps Muscle / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D012720:Severity of Illness Index; D014018:Tissue Distribution
chemical_list: D007004:Hypoglycemic Agents; D061389:Insulin, Regular, Pork; D005947:Glucose
keywords: Endothelium; Glucose; Insulin; Interstitium; Skeletal muscle