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

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.

• Authors: 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, 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
• Journal: Nature communications (Nat Commun) Vol. 8 Issue 1 Pg. 1804 (11 27 2017) ISSN: 2041-1723 [Electronic] England
• PMID: 29180704 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Insulin
• Phosphoinositide-3 Kinase Inhibitors
• Class III Phosphatidylinositol 3-Kinases
• PIK3C3 protein, mouse
• AMP-Activated Protein Kinases
• Glucose

Topics

• AMP-Activated Protein Kinases (metabolism)
• Animals
• Autophagy (physiology)
• Cell Line, Tumor
• Class III Phosphatidylinositol 3-Kinases
• Diabetes Mellitus, Type 2 (drug therapy, metabolism)
• Gene Knock-In Techniques
• Glucose (analysis, metabolism)
• Glucose Tolerance Test
• Glycolysis (physiology)
• Hepatocytes
• Heterozygote
• Humans
• Insulin (metabolism)
• Insulin Resistance
• Liver (cytology, metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Mitochondria (metabolism)
• Models, Animal
• Muscle, Skeletal (cytology, metabolism)
• Myoblasts
• Phosphatidylinositol 3-Kinases (genetics, metabolism)
• Phosphoinositide-3 Kinase Inhibitors
• Phosphorylation
• Primary Cell Culture
• Signal Transduction (physiology)