title: AICAR reverses ketone body mediated insulin resistance in isolated oxidative muscle.
abstract: Recently it was demonstrated that the ketone body β-hydroxybutyrate (BOH) inhibits insulin-mediated glucose transport in isolated oxidative muscle, which was associated with decreased phosphorylation of Akt/protein kinase B. The purpose of the present study was to determine if activation of AMP-dependent protein kinase by the pharmacological activator AICAR could reverse the insulin resistance induced by BOH. Isolated mouse soleus muscle was incubated in vitro in the absence or presence of 5mM BOH for ∼20 h. Following prolonged incubation, insulin increased 2-deoxyglucose glucose (2-DG) uptake 3-fold, but in the presence of BOH most of the insulin response was lost (only ∼30% remained). Addition of 2mM AICAR during the last 2h of prolonged incubation increased the insulin response in the presence of BOH to ∼80% of the normal insulin effect on 2-DG uptake. The AICAR-mediated reversal of the insulin resistance was not associated with a restoration of the insulin effect on Akt/protein kinase B phosphorylation. However, AICAR enhanced the insulin-induced phosphorylation of the Akt substrate, AS160. In conclusion, these data demonstrate that AICAR reverses the negative effect of BOH on insulin-mediated glucose uptake and this is attributed to activation of a late step in insulin signaling.
authors: Department of Physiology and Pharmacology, Karolinska Institutet, 171 77 Stockholm, Sweden.
authors: Niklas
authors: N
authors: Ivarsson
authors: Shi-Jin
authors: SJ
authors: Zhang
authors: Abram
authors: A
authors: Katz
mesh_terms: D020155:3-Hydroxybutyric Acid / Q000378:metabolism*; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D020690:GTPase-Activating Proteins / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D066298:In Vitro Techniques; D007333:Insulin Resistance; D007657:Ketone Bodies / Q000378:metabolism*; D008297:Male; D051379:Mice; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D010766:Phosphorylation; D017856:Phosphotransferases (Phosphate Group Acceptor) / Q000378:metabolism*; D012265:Ribonucleotides / Q000494:pharmacology*
chemical_list: D020690:GTPase-Activating Proteins; D007657:Ketone Bodies; D012265:Ribonucleotides; C505647:Tbc1d4 protein, mouse; D000620:Aminoimidazole Carboxamide; C118888:AMP-dependent kinase (ATP-forming); D017856:Phosphotransferases (Phosphate Group Acceptor); C031143:AICA ribonucleotide; D005947:Glucose; D020155:3-Hydroxybutyric Acid