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