Cardiac PI3K-Akt impairs insulin-stimulated glucose uptake independent of mTORC1 and GLUT4 translocation

Yi Zhu, Renata O. Pereira, Brian T. O'Neill, Christian Riehle, Olesya Ilkun, Adam R. Wende, Tenley A. Rawlings, Yi Cheng Zhang, Quanjiang Zhang, Amira Klip, Ichiro Shiojima, Kenneth Walsh, E. Dale Abel

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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 protea-somal 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 cardio-myocytes impairs GLUT4-mediated glucose uptake via mechanisms that impair the function of GLUT4 after its plasma-membrane insertion.

Original languageEnglish (US)
Pages (from-to)172-184
Number of pages13
JournalMolecular Endocrinology
Volume27
Issue number1
DOIs
StatePublished - Jan 7 2013

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Glucose Transporter Type 4
Phosphatidylinositol 3-Kinase
Protein Transport
Insulin
Glucose
Cardiac Myocytes
Insulin Receptor Substrate Proteins
Sirolimus
Proteins
TOR Serine-Threonine Kinases
Ribosomal Protein S6 Kinases
S 6
Hexokinase
mechanistic target of rapamycin complex 1
Protein-Serine-Threonine Kinases
Transgenes
Muscle Cells
Serine
Transgenic Mice
Insulin Resistance

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology

Cite this

Zhu, Y., Pereira, R. O., O'Neill, B. T., Riehle, C., Ilkun, O., Wende, A. R., ... Dale Abel, E. (2013). Cardiac PI3K-Akt impairs insulin-stimulated glucose uptake independent of mTORC1 and GLUT4 translocation. Molecular Endocrinology, 27(1), 172-184. https://doi.org/10.1210/me.2012-1210

Cardiac PI3K-Akt impairs insulin-stimulated glucose uptake independent of mTORC1 and GLUT4 translocation. / Zhu, Yi; Pereira, Renata O.; O'Neill, Brian T.; Riehle, Christian; Ilkun, Olesya; Wende, Adam R.; Rawlings, Tenley A.; Zhang, Yi Cheng; Zhang, Quanjiang; Klip, Amira; Shiojima, Ichiro; Walsh, Kenneth; Dale Abel, E.

In: Molecular Endocrinology, Vol. 27, No. 1, 07.01.2013, p. 172-184.

Research output: Contribution to journalArticle

Zhu, Y, Pereira, RO, O'Neill, BT, Riehle, C, Ilkun, O, Wende, AR, Rawlings, TA, Zhang, YC, Zhang, Q, Klip, A, Shiojima, I, Walsh, K & Dale Abel, E 2013, 'Cardiac PI3K-Akt impairs insulin-stimulated glucose uptake independent of mTORC1 and GLUT4 translocation', Molecular Endocrinology, vol. 27, no. 1, pp. 172-184. https://doi.org/10.1210/me.2012-1210
Zhu, Yi ; Pereira, Renata O. ; O'Neill, Brian T. ; Riehle, Christian ; Ilkun, Olesya ; Wende, Adam R. ; Rawlings, Tenley A. ; Zhang, Yi Cheng ; Zhang, Quanjiang ; Klip, Amira ; Shiojima, Ichiro ; Walsh, Kenneth ; Dale Abel, E. / Cardiac PI3K-Akt impairs insulin-stimulated glucose uptake independent of mTORC1 and GLUT4 translocation. In: Molecular Endocrinology. 2013 ; Vol. 27, No. 1. pp. 172-184.
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