title: Cardiac PI3K-Akt impairs insulin-stimulated glucose uptake independent of mTORC1 and GLUT4 translocation.
abstract: Impaired insulin-mediated glucose uptake characterizes cardiac muscle in humans and animals with insulin resistance and diabetes, despite preserved or enhanced phosphatidylinositol 3-kinase (PI3K) and the serine-threonine kinase, Akt-signaling, via mechanisms that are incompletely understood. One potential mechanism is PI3K- and Akt-mediated activation of mechanistic target of rapamycin (mTOR) and ribosomal protein S6 kinase (S6K), which may impair insulin-mediated activation of insulin receptor substrate (IRS)1/2 via inhibitory serine phosphorylation or proteasomal degradation. To gain mechanistic insights by which constitutive activation of PI3K or Akt may desensitize insulin-mediated glucose uptake in cardiomyocytes, we examined mice with cardiomyocyte-restricted, constitutive or inducible overexpression of a constitutively activated PI3K or a myristoylated Akt1 (myrAkt1) transgene that also expressed a myc-epitope-tagged glucose transporter type 4 protein (GLUT4). Although short-term activation of PI3K and myrAkt1 increased mTOR and S6 signaling, there was no impairment in insulin-mediated activation of IRS1/2. However, insulin-mediated glucose uptake was reduced by 50-80%. Although longer-term activation of Akt reduced IRS2 protein content via an mTORC1-mediated mechanism, treatment of transgenic mice with rapamycin failed to restore insulin-mediated glucose uptake, despite restoring IRS2. Transgenic activation of Akt and insulin-stimulation of myrAkt1 transgenic cardiomyocytes increased sarcolemmal insertion of myc-GLUT4 to levels equivalent to that observed in insulin-stimulated wild-type controls. Despite preserved GLUT4 translocation, glucose uptake was not elevated by the presence of constitutive activation of PI3K and Akt. Hexokinase II activity was preserved in myrAkt1 hearts. Thus, constitutive activation of PI3K and Akt in cardiomyocytes impairs GLUT4-mediated glucose uptake via mechanisms that impair the function of GLUT4 after its plasma-membrane insertion.
authors.affiliation: Division of Endocrinology, Metabolism, and Diabetes and Program in Molecular Medicine, University of Utah, Salt Lake City, Utah 84112, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhu
authors.forename: Renata O
authors.initials: RO
authors.lastname: Pereira
authors.forename: Brian T
authors.initials: BT
authors.lastname: O'Neill
authors.forename: Christian
authors.initials: C
authors.lastname: Riehle
authors.forename: Olesya
authors.initials: O
authors.lastname: Ilkun
authors.forename: Adam R
authors.initials: AR
authors.lastname: Wende
authors.forename: Tenley A
authors.initials: TA
authors.lastname: Rawlings
authors.forename: Yi Cheng
authors.initials: YC
authors.lastname: Zhang
authors.forename: Quanjiang
authors.initials: Q
authors.lastname: Zhang
authors.forename: Amira
authors.initials: A
authors.lastname: Klip
authors.forename: Ichiro
authors.initials: I
authors.lastname: Shiojima
authors.forename: Kenneth
authors.initials: K
authors.lastname: Walsh
authors.forename: E Dale
authors.initials: ED
authors.lastname: Abel
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003847:Deoxyglucose / Q000378:metabolism; D004789:Enzyme Activation; D005947:Glucose / Q000378:metabolism*; D051275:Glucose Transporter Type 4 / Q000378:metabolism*; D006593:Hexokinase / Q000378:metabolism; D007328:Insulin / Q000502:physiology*; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008822:Mice, Transgenic; D046912:Multiprotein Complexes; D009206:Myocardium / Q000166:cytology / Q000201:enzymology*; D032383:Myocytes, Cardiac / Q000201:enzymology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D021381:Protein Transport; D011506:Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases
chemical_list: D003847:Deoxyglucose; D005947:Glucose; D051275:Glucose Transporter Type 4; D006593:Hexokinase; D007328:Insulin; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D019869:Phosphatidylinositol 3-Kinases; D011506:Proteins; D051057:Proto-Oncogene Proteins c-akt; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; C495693:Slc2a4 protein, mouse; C514862:Akt1 protein, mouse