Vps34 PI 3-kinase inactivation enhances insulin sensitivity through reprogramming of mitochondrial metabolism.
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Date
2017-11-27ICR Author
Author
Bilanges, B
Alliouachene, S
Pearce, W
Morelli, D
Szabadkai, G
Chung, Y-L
Chicanne, G
Valet, C
Hill, JM
Voshol, PJ
Collinson, L
Peddie, C
Ali, K
Ghazaly, E
Rajeeve, V
Trichas, G
Srinivas, S
Chaussade, C
Salamon, RS
Backer, JM
Scudamore, CL
Whitehead, MA
Keaney, EP
Murphy, LO
Semple, RK
Payrastre, B
Tooze, SA
Vanhaesebroeck, B
Type
Journal Article
Metadata
Show full item recordAbstract
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.
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Subject
Muscle, Skeletal
Liver
Cell Line, Tumor
Mitochondria
Hepatocytes
Myoblasts
Animals
Mice, Inbred C57BL
Mice, Transgenic
Humans
Mice
Diabetes Mellitus, Type 2
Insulin Resistance
Insulin
Glucose
Glucose Tolerance Test
Models, Animal
Signal Transduction
Glycolysis
Phosphorylation
Heterozygote
Autophagy
Male
AMP-Activated Protein Kinases
Gene Knock-In Techniques
Phosphatidylinositol 3-Kinases
Primary Cell Culture
Language
eng
Date accepted
2017-10-30
License start date
2017-11-27
Citation
Nature communications, 2017, 8 (1), pp. 1804 - ?
Publisher
NATURE PUBLISHING GROUP