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Vps34 PI 3-kinase inactivation enhances insulin sensitivity through reprogramming of mitochondrial metabolism

Author

Listed:
  • Benoit Bilanges

    (University College London)

  • Samira Alliouachene

    (University College London)

  • Wayne Pearce

    (University College London)

  • Daniele Morelli

    (University College London)

  • Gyorgy Szabadkai

    (University College London
    University of Padua)

  • Yuen-Li Chung

    (The Institute of Cancer Research London)

  • Gaëtan Chicanne

    (Institut des Maladies Métaboliques et Cardiovasculaires)

  • Colin Valet

    (Institut des Maladies Métaboliques et Cardiovasculaires)

  • Julia M. Hill

    (University College London)

  • Peter J. Voshol

    (MRC Metabolic Diseases Unit, Wellcome Trust-MRC Institute of Metabolic Science)

  • Lucy Collinson

    (Lincoln’s Inn Fields Laboratories)

  • Christopher Peddie

    (Lincoln’s Inn Fields Laboratories)

  • Khaled Ali

    (University College London)

  • Essam Ghazaly

    (Queen Mary University of London)

  • Vinothini Rajeeve

    (Queen Mary University of London)

  • Georgios Trichas

    (University of Oxford)

  • Shankar Srinivas

    (University of Oxford)

  • Claire Chaussade

    (University College London)

  • Rachel S. Salamon

    (Albert Einstein College of Medicine)

  • Jonathan M. Backer

    (Albert Einstein College of Medicine)

  • Cheryl L. Scudamore

    (Harwell Science and Innovation Campus)

  • Maria A. Whitehead

    (University College London)

  • Erin P. Keaney

    (Novartis Institutes for BioMedical Research)

  • Leon O. Murphy

    (Novartis Institutes for BioMedical Research)

  • Robert K. Semple

    (University of Cambridge, Addenbrooke’s Hospital)

  • Bernard Payrastre

    (Institut des Maladies Métaboliques et Cardiovasculaires)

  • Sharon A. Tooze

    (Lincoln’s Inn Fields Laboratories)

  • Bart Vanhaesebroeck

    (University College London)

Abstract

Vps34 PI3K is thought to be the main producer of phosphatidylinositol-3-monophosphate, a lipid that controls intracellular vesicular trafficking. The organismal impact of systemic inhibition of Vps34 kinase activity is not completely understood. Here we show that heterozygous Vps34 kinase-dead mice are healthy and display a robustly enhanced insulin sensitivity and glucose tolerance, phenotypes mimicked by a selective Vps34 inhibitor in wild-type mice. The underlying mechanism of insulin sensitization is multifactorial and not through the canonical insulin/Akt pathway. Vps34 inhibition alters cellular energy metabolism, activating the AMPK pathway in liver and muscle. In liver, Vps34 inactivation mildly dampens autophagy, limiting substrate availability for mitochondrial respiration and reducing gluconeogenesis. In muscle, Vps34 inactivation triggers a metabolic switch from oxidative phosphorylation towards glycolysis and enhanced glucose uptake. Our study identifies Vps34 as a new drug target for insulin resistance in Type-2 diabetes, in which the unmet therapeutic need remains substantial.

Suggested Citation

  • Benoit Bilanges & Samira Alliouachene & Wayne Pearce & Daniele Morelli & Gyorgy Szabadkai & Yuen-Li Chung & Gaëtan Chicanne & Colin Valet & Julia M. Hill & Peter J. Voshol & Lucy Collinson & Christoph, 2017. "Vps34 PI 3-kinase inactivation enhances insulin sensitivity through reprogramming of mitochondrial metabolism," Nature Communications, Nature, vol. 8(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-01969-4
    DOI: 10.1038/s41467-017-01969-4
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