title: Enhancement of insulin-mediated rat muscle glucose uptake and microvascular perfusion by 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside.
abstract: BACKGROUND
  Insulin-induced microvascular recruitment is important for optimal muscle glucose uptake. 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR, an activator of AMP-activated protein kinase), can also induce microvascular recruitment, at doses that do not acutely activate glucose transport in rat muscle. Whether low doses of AICAR can augment physiologic insulin action is unknown. In the present study we used the euglycemic hyperinsulinemic clamp to assess whether insulin action is augmented by low dose AICAR.
  
  
  METHODS
  Anesthetized rats were studied during saline infusion or euglycemic insulin (3 mU/kg/min) clamp for 2 h in the absence or presence of AICAR for the last hour (5 mg bolus followed by 3.75 mg/kg/min). Muscle glucose uptake (R'g) was determined radioisotopically with (14)C-2-deoxyglucose and muscle microvascular perfusion by contrast-enhanced ultrasound with microbubbles.
  
  
  RESULTS
  AICAR did not affect blood glucose, or lower leg R'g, although it significantly (p < 0.05) increased blood lactate levels and augmented muscle microvascular blood volume via a nitric oxide synthase dependent pathway. Insulin increased femoral blood flow, whole body glucose infusion rate (GIR), R'g, hindleg glucose uptake, and microvascular blood volume. Addition of AICAR during insulin infusion increased lactate production, further increased R'g in Type IIA (fast twitch oxidative) and IIB (fast twitch glycolytic) fiber containing muscles, and hindleg glucose uptake, but decreased R'g in the Type I (slow twitch oxidative) fiber muscle. AICAR also decreased GIR due to inhibition of insulin-mediated suppression of hepatic glucose output. AICAR augmented insulin-mediated microvascular perfusion.
  
  
  CONCLUSIONS
  AICAR, at levels that have no direct effect on muscle glucose uptake, augments insulin-mediated microvascular blood flow and glucose uptake in white fiber type muscles. Agents targeted to endothelial AMPK activation are promising insulin sensitizers, however, the decrease in GIR and the propensity to increase blood lactate cautions against AICAR as an acute insulin sensitizer.
authors.affiliation: Menzies Institute for Medical Research, University of Tasmania, Private Bag 23, Hobart, 7001, TAS, Australia. Eloise.Bradley@utas.edu.au.
authors.forename: Eloise A
authors.initials: EA
authors.lastname: Bradley
authors.affiliation: Garvan Institute of Medical Research, Darlinghurst, NSW, Australia. l.zhang@garvan.org.au.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Institute of Sport, Exercise and Active Living (ISEAL), Victoria University, Melbourne, VIC, Australia. Amanda.genders@vu.edu.au.
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Genders
authors.affiliation: School of Medicine, University of Tasmania, Hobart, TAS, Australia. Stephen.Richards@utas.edu.au.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Richards
authors.affiliation: Menzies Institute for Medical Research, University of Tasmania, Private Bag 23, Hobart, 7001, TAS, Australia. S.Rattigan@utas.edu.au.
authors.forename: Stephen
authors.initials: S
authors.lastname: Rattigan
authors.affiliation: Menzies Institute for Medical Research, University of Tasmania, Private Bag 23, Hobart, 7001, TAS, Australia. Michelle.Keske@utas.edu.au.
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Keske
mesh_terms: D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D001783:Blood Flow Velocity; D003287:Contrast Media; D003847:Deoxyglucose / Q000378:metabolism*; D005263:Femoral Artery / Q000187:drug effects / Q000502:physiology; D015309:Glucose Clamp Technique; D006614:Hindlimb; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000494:pharmacology*; D019344:Lactic Acid / Q000097:blood; D008297:Male; D045423:Microbubbles; D008833:Microcirculation / Q000187:drug effects*; D055806:Microvessels / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000502:physiology; D018656:Muscle Fibers, Fast-Twitch / Q000187:drug effects / Q000378:metabolism; D018657:Muscle Fibers, Slow-Twitch / Q000187:drug effects / Q000378:metabolism; D018482:Muscle, Skeletal / Q000098:blood supply* / Q000187:drug effects* / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D017208:Rats, Wistar; D012039:Regional Blood Flow; D012265:Ribonucleotides / Q000494:pharmacology*; D013997:Time Factors; D014463:Ultrasonography
chemical_list: D003287:Contrast Media; D007004:Hypoglycemic Agents; D007328:Insulin; D012265:Ribonucleotides; D019344:Lactic Acid; D000620:Aminoimidazole Carboxamide; D003847:Deoxyglucose; D019001:Nitric Oxide Synthase; C031143:AICA ribonucleotide