title: Effects of chronic Akt activation on glucose uptake in the heart.
abstract: Acute activation of the serine-threonine kinase Akt is cardioprotective and increases glucose uptake, at least in part, through enhanced expression of GLUT4 on the sarcolemma. The effects of chronic Akt activation on glucose uptake in the heart remain unclear. To address this issue, we examined the effects of chronic Akt activation on glucose uptake, glycogen storage, and relevant glucose transporters in the hearts of transgenic mice. We found that chronic cardiac activation of Akt led to a substantial increase in the rate of basal glucose uptake (P < 0.05) but blunted the response to insulin (1.9 vs. 18.1-fold increase compared with baseline) using NMR in ex vivo perfused heart. Basal glucose uptake was also increased in Akt transgenic mice in vivo (P < 0.005). These changes were associated with an increase on glycogen deposition, examined with histochemical staining, biochemical (>6-fold, P < 0.001) and in vivo radioactive (5-fold, P < 0.01) assays. Studies in chimeric hearts of female X-linked transgenic Akt mice suggested that increased glycogen deposition occurred as a cell autonomous effect of transgene expression. Interestingly, although sarcolemmal GLUT1 was not significantly altered, chronic Akt activation actually decreased plasma membrane GLUT4. Moreover, intracellular pools of GLUT1 were modestly reduced, whereas intracellular GLUT4 was substantially reduced. It seems likely that neither GLUT1 nor GLUT4 explains the increase in basal glucose uptake but that these reductions contribute to the loss of insulin responsiveness that we observed. These data demonstrate that chronic Akt activation increases basal glucose uptake and glycogen deposition while inhibiting the response to insulin.
authors.affiliation: Program in Cardiovascular Gene Therapy, Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA. tmatsui@partners.org
authors.forename: Takashi
authors.initials: T
authors.lastname: Matsui
authors.forename: Tomohisa
authors.initials: T
authors.lastname: Nagoshi
authors.forename: Eun-Gyoung
authors.initials: EG
authors.lastname: Hong
authors.forename: Ivan
authors.initials: I
authors.lastname: Luptak
authors.forename: Kirsten
authors.initials: K
authors.lastname: Hartil
authors.forename: Ling
authors.initials: L
authors.lastname: Li
authors.forename: Naira
authors.initials: N
authors.lastname: Gorovits
authors.forename: Maureen J
authors.initials: MJ
authors.lastname: Charron
authors.forename: Jason K
authors.initials: JK
authors.lastname: Kim
authors.forename: Rong
authors.initials: R
authors.lastname: Tian
authors.forename: Anthony
authors.initials: A
authors.lastname: Rosenzweig
mesh_terms: D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D003847:Deoxyglucose / Q000378:metabolism / Q000493:pharmacokinetics; D005260:Female; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D005947:Glucose / Q000378:metabolism / Q000493:pharmacokinetics*; D051272:Glucose Transporter Type 1 / Q000235:genetics / Q000378:metabolism; D051275:Glucose Transporter Type 4 / Q000235:genetics / Q000378:metabolism; D006003:Glycogen / Q000096:biosynthesis / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006321:Heart / Q000187:drug effects; D006593:Hexokinase / Q000378:metabolism; D007328:Insulin / Q000494:pharmacology; D007425:Intracellular Membranes / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009206:Myocardium / Q000378:metabolism*; D010477:Perfusion; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*
chemical_list: D051272:Glucose Transporter Type 1; D051275:Glucose Transporter Type 4; D007328:Insulin; C495678:Slc2a1 protein, mouse; C495693:Slc2a4 protein, mouse; D006003:Glycogen; D003847:Deoxyglucose; D006593:Hexokinase; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; D005947:Glucose