Mice with AS160/TBC1D4-Thr649Ala knockin mutation are glucose intolerant with reduced insulin sensitivity and altered GLUT4 trafficking.

Chen S, Wasserman DH, MacKintosh C, Sakamoto K
Cell Metab. 2011 13 (1): 68-79

PMID: 21195350 · PMCID: PMC3081066 · DOI:10.1016/j.cmet.2010.12.005

AS160 has emerged as a key player in insulin-mediated glucose transport through controlling GLUT4 trafficking, which is thought to be regulated by insulin-stimulated phosphorylation of sites including the 14-3-3 binding phospho-Thr649 (equivalent to Thr642 in human AS160). To define physiological roles of AS160-Thr649 phosphorylation and 14-3-3 binding in glucose homeostasis, we substituted this residue by a nonphosphorylatable alanine by knockin mutation in mice. The mutant protein was expressed at normal levels, while insulin-stimulated AS160 binding to 14-3-3s was abolished in homozygous knockin mice. These animals displayed impaired glucose disposal and insulin sensitivity, which were associated with decreased glucose uptake in vivo. Insulin-stimulated glucose transport and cell surface GLUT4 content were reduced in isolated muscles, but not in adipocytes. These results provide genetic evidence that insulin-induced AS160-Thr649 phosphorylation and/or its binding to 14-3-3 play an important role in regulating whole-body glucose homeostasis, at least in part through regulating GLUT4 trafficking in muscle.

Copyright © 2011 Elsevier Inc. All rights reserved.

MeSH Terms (22)

14-3-3 Proteins Adipocytes Animals Biological Transport Blood Glucose Cell Membrane Female Gene Knock-In Techniques Glucose Glucose Tolerance Test Glucose Transporter Type 4 GTPase-Activating Proteins Insulin In Vitro Techniques Male Mice Mice, Transgenic Muscle, Skeletal Mutation Phosphorylation Protein Binding Protein Transport

Connections (1)

This publication is referenced by other Labnodes entities:

Links