title: Loss of insulin-mediated microvascular perfusion in skeletal muscle is associated with the development of insulin resistance.
abstract: OBJECTIVE
  The aetiology of the development of type 2 diabetes remains unresolved. In the present study, we assessed whether an impairment of insulin-mediated microvascular perfusion occurs early in the onset of insulin resistance.
  
  
  METHODS
  Hooded Wistar rats were fed either a normal diet (ND) or a high-fat diet (HFD) for 4 weeks. Anaesthetized animals were subjected to an isoglycaemic hyperinsulinaemic clamp (3 or 10 mU/min/kg x 2 h), and measurements were made of glucose infusion rate (GIR), hindleg glucose uptake, muscle glucose uptake by 2-deoxy-d-glucose (R'g), glucose appearance (Ra), glucose disappearance (Rd), femoral blood flow (FBF) and hindleg 1-methylxanthine disappearance (1-MXD, an index of microvascular perfusion).
  
  
  RESULTS
  Compared with ND-fed animal, HFD feeding led to a mild increase in fasting plasma glucose and plasma insulin, without an increase in total body weight. During the clamps, HFD rats showed an impairment of insulin-mediated action on GIR, hindleg glucose uptake, R'g, Ra, Rd and FBF, with a greater loss of insulin responsiveness at 3 mU/min/kg than at 10 mU/min/kg. The HFD also impaired insulin-mediated microvascular perfusion as assessed by 1-MXD. Interestingly, 1-MXD was the only measurement that remained unresponsive to the higher dose of 10 mU/min/kg insulin.
  
  
  CONCLUSIONS
  We conclude that the early stage of insulin resistance is characterized by an impairment of the insulin-mediated microvascular responses in skeletal muscle. This is likely to cause greater whole body insulin resistance by limiting the delivery of hormones and nutrients to muscle.
authors.affiliation: Menzies Research Institute, University of Tasmania, Hobart, Australia.
authors.forename: P
authors.initials: P
authors.lastname: St-Pierre
authors.forename: A J
authors.initials: AJ
authors.lastname: Genders
authors.forename: M A
authors.initials: MA
authors.lastname: Keske
authors.forename: S M
authors.initials: SM
authors.lastname: Richards
authors.forename: S
authors.initials: S
authors.lastname: Rattigan
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D004041:Dietary Fats / Q000008:administration & dosage*; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000494:pharmacology*; D007333:Insulin Resistance / Q000502:physiology*; D008297:Male; D008833:Microcirculation / Q000502:physiology*; D018482:Muscle, Skeletal / Q000098:blood supply* / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D012039:Regional Blood Flow / Q000502:physiology
chemical_list: D001786:Blood Glucose; D004041:Dietary Fats; D007004:Hypoglycemic Agents; D007328:Insulin