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.
Highlights
Glucose transporter 4 (GLUT4) as a member of glucose transporters (Gluts) family plays a critical role in glucose uptake in several insulin target tissues, such as muscle and adipose [1,2]
The results indicate that Rut is able to dose-dependently enhance both the activities of RXR-response element (RXRE) and PPARresponse element (PPRE) (Fig. 4a, b) without influencing the activities of LXR-response element (LXRE) and FXR-response element (FXRE) (Fig. 4c, d)
Inducers of GLUT4 translocation or expression were found to exert their beneficial effects on sensitizing insulin signal and recovering the dys-regulated gene expressions, eventually resulting in amelioration of metabolic syndrome [15,16,17]
Summary
GLUT4 as a member of glucose transporters (Gluts) family plays a critical role in glucose uptake in several insulin target tissues, such as muscle and adipose [1,2]. Considering the vital role of GLUT4 in the rate-limit step of glucose transport, targeting the pathways associated with GLUT4 has become an attractive strategy for drug discovery against T2DM and other metabolic disorders [13,14]. Recent research has shown that the agents capable of regulating GLUT4 translocation or expression may exhibit their potentials for anti-diabetic treatments. We determined the natural product (+)-Rutamarin (Rut, Fig. 1a) that potently induces both GLUT4 translocation and expression. As a specific inhibitor of protein tyrosine phosphatase 1B (PTP 1B), it stimulates GLUT4 translocation and glucose uptake, while as an RXRa agonist Rut enhances GLUT4 expression in 3T3-L1 adipocytes. Our results have highlighted the potential for this natural product as a promising lead compound in anti-T2MD drug discovery, and as a valuable chemical probe in GLUT4 complicated pathways investigation
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