Vps34 PI 3-kinase inactivation enhances insulin sensitivity through reprogramming of mitochondrial metabolism
Benoit Bilanges
Samira Alliouachene
Wayne Pearce
Daniele Morelli
Gyorgy Szabadkai
Yuen-Li Chung
Gaƫtan Chicanne
Colin Valet
Julia M Hill
Peter J Voshol
Lucy Collinson
Christopher Peddie
Khaled Ali
Essam Ghazaly
Vinothini Rajeeve
Georgios Trichas
Shankar Srinivas
Claire Chaussade
Rachel S Salamon
Jonathan M Backer
Cheryl L Scudamore
Maria A Whitehead
Erin P Keaney
Leon O Murphy
Robert K Semple
Bernard Payrastre
Sharon A Tooze
Bart Vanhaesebroeck
10779/crick.12631052.v1
https://crick.figshare.com/articles/journal_contribution/Vps34_PI_3-kinase_inactivation_enhances_insulin_sensitivity_through_reprogramming_of_mitochondrial_metabolism/12631052
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.
2020-07-15 11:01:30
AMP-Activated Protein Kinases
Animals
Autophagy
Cell Line, Tumor
Class III Phosphatidylinositol 3-Kinases
Diabetes Mellitus, Type 2
Gene Knock-In Techniques
Glucose
Glucose Tolerance Test
Glycolysis
Hepatocytes
Heterozygote
Humans
Insulin
Insulin Resistance
Liver
Male
Mice
Mice, Inbred C57BL
Mice, Transgenic
Mitochondria
Models, Animal
Muscle, Skeletal
Myoblasts
Phosphatidylinositol 3-Kinases
Phosphoinositide-3 Kinase Inhibitors
Phosphorylation
Primary Cell Culture
Signal Transduction
Tooze FC001187
EM