title: (+)-Rutamarin as a dual inducer of both GLUT4 translocation and expression efficiently ameliorates glucose homeostasis in insulin-resistant mice.
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 α (RXRα), 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.
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
authors.forename: Haitao
authors.initials: H
authors.lastname: Zhang
authors.forename: Xin-Gang
authors.initials: XG
authors.lastname: Yao
authors.forename: Hong
authors.initials: H
authors.lastname: Shen
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.forename: Chenjing
authors.initials: C
authors.lastname: Li
authors.forename: Lili
authors.initials: L
authors.lastname: Chen
authors.forename: Mingyue
authors.initials: M
authors.lastname: Zheng
authors.forename: Jiming
authors.initials: J
authors.lastname: Ye
authors.forename: Lihong
authors.initials: L
authors.lastname: Hu
authors.forename: Xu
authors.initials: X
authors.lastname: Shen
authors.forename: Hualiang
authors.initials: H
authors.lastname: Jiang
mesh_terms: D000818:Animals; D001578:Benzopyrans / Q000378:metabolism; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D003924:Diabetes Mellitus, Type 2 / Q000628:therapy; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism*; D051275:Glucose Transporter Type 4 / Q000235:genetics / Q000502:physiology*; D057809:HEK293 Cells; D006706:Homeostasis; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D041681:NIH 3T3 Cells; D021381:Protein Transport; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000378:metabolism
chemical_list: D001578:Benzopyrans; D051275:Glucose Transporter Type 4; D007328:Insulin; C495693:Slc2a4 protein, mouse; C022850:rutamarin; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; C516609:Ptpn1 protein, mouse; D005947:Glucose