(+)-Rutamarin as a dual inducer of both GLUT4 translocation and expression efficiently ameliorates glucose homeostasis in insulin-resistant mice

Zhang, Y, Zhang, H, Yao, X, Shen, H, Chen, J, Li, C, Chen, L, Zheng, M, Ye, J, Hu, L, Shen, X and Jiang, H 2012, '(+)-Rutamarin as a dual inducer of both GLUT4 translocation and expression efficiently ameliorates glucose homeostasis in insulin-resistant mice', PLoS ONE, vol. 7, no. 2, e31811, pp. 1-15.


Document type: Journal Article
Collection: Journal Articles

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Title (+)-Rutamarin as a dual inducer of both GLUT4 translocation and expression efficiently ameliorates glucose homeostasis in insulin-resistant mice
Author(s) Zhang, Y
Zhang, H
Yao, X
Shen, H
Chen, J
Li, C
Chen, L
Zheng, M
Ye, J
Hu, L
Shen, X
Jiang, H
Year 2012
Journal name PLoS ONE
Volume number 7
Issue number 2
Article Number e31811
Start page 1
End page 15
Total pages 15
Publisher Public Library of Science
Abstract Glucose transporter 4 (GLUT4) is a principal glucose transporter in response to insulin, and impaired translocation or decreased expression of GLUT4 is believed to be one of the major pathological features of type 2 diabetes mellitus (T2DM). Therefore, induction of GLUT4 translocation or/and expression is a promising strategy for anti-T2DM drug discovery. Here we report that the natural product (+)-Rutamarin (Rut) functions as an efficient dual inducer on both insulin-induced GLUT4 translocation and expression. Rut-treated 3T3-L1 adipocytes exhibit efficiently enhanced insulin-induced glucose uptake, while diet-induced obese (DIO) mice based assays further confirm the Rut-induced improvement of glucose homeostasis and insulin sensitivity in vivo. Subsequent investigation of Rut acting targets indicates that as a specific protein tyrosine phosphatase 1B (PTP1B) inhibitor Rut induces basal GLUT4 translocation to some extent and largely enhances insulin-induced GLUT4 translocation through PI3 kinase-AKT/PKB pathway, while as an agonist of retinoid X receptor ? (RXR?), Rut potently increases GLUT4 expression. Furthermore, by using molecular modeling and crystallographic approaches, the possible binding modes of Rut to these two targets have been also determined at atomic levels. All our results have thus highlighted the potential of Rut as both a valuable lead compound for anti-T2DM drug discovery and a promising chemical probe for GLUT4 associated pathways exploration.
Subject Basic Pharmacology
Keyword(s) Glucose transporter 4
Insulin
Metformin
Natural product
Protein tyrosine phosphatase 1B
Protein tyrosine phosphatase 1B inhibitor
Retinoid X receptor alpha
Rutamarin
Unclassified drug
Adipocyte
Animal cell
Animal experiment
Animal model
Animal tissue
Article
Cell differentiation
Controlled study
Crystallography
Drug activity
Drug protein binding
Drug structure
Drug targeting
Enzyme inhibition
Gene expression
Gene translocation
Glucose homeostasis
Glucose transport
Human
Human cell
In vivo study
Insulin resistance
Insulin sensitivity
Male
Mouse
Nonhuman
Obesity
Oral glucose tolerance test
Protein determination
Protein function
Protein phosphorylation
Protein targeting
Real time polymerase chain reaction
RNA extraction
Signal transduction
Treatment response
DOI - identifier 10.1371/journal.pone.0031811
Copyright notice © 2012 Zhang et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
ISSN 1932-6203
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