Abstract
Metabolic diseases are characterized by a decreased action of insulin. During the course of the disease, usual treatments frequently fail and patients are finally submitted to insulinotherapy. There is thus a need for innovative therapeutic strategies to improve insulin action. Growth factor receptor-bound protein 14 (Grb14) is a molecular adapter that specifically binds to the activated insulin receptor (IR) and inhibits its tyrosine kinase activity. Molecules disrupting Grb14-IR binding are therefore potential insulin-sensitizing agents. We used Structure-Based Virtual Ligand Screening to generate a list of 1000 molecules predicted to hinder Grb14-IR binding. Using an acellular bioluminescence resonance energy transfer (BRET) assay, we identified, out of these 1000 molecules, 3 compounds that inhibited Grb14-IR interaction. Their inhibitory effect on insulin-induced Grb14-IR interaction was confirmed in co-immunoprecipitation experiments. The more efficient molecule (C8) was further characterized. C8 increased downstream Ras-Raf and PI3-kinase insulin signaling, as shown by BRET experiments in living cells. Moreover, C8 regulated the expression of insulin target genes in mouse primary hepatocytes. These results indicate that C8, by reducing Grb14-IR interaction, increases insulin signalling. The use of C8 as a lead compound should allow for the development of new molecules of potential therapeutic interest for the treatment of diabetes.
Highlights
Changes in lifestyle over the last decades resulted in a dramatic increase in the prevalence of metabolic diseases such as obesity and type 2 diabetes, which are characterized by an insulin-resistance state[1]
The first step of insulin action is its binding to its membrane receptor (IR), a member of the tyrosine kinase family of receptors, and the activation of intracellular pathways leading to the final anabolic effects of the hormone[4]
We have scored a collection containing 340 000 compounds (ChemBridge) after structured-based virtual screening performed on the basis of the Growth factor receptor-bound protein 14 (Grb14)(BPS)-IR crystallographic structure[15]
Summary
Changes in lifestyle over the last decades resulted in a dramatic increase in the prevalence of metabolic diseases such as obesity and type 2 diabetes, which are characterized by an insulin-resistance state[1]. To overcome this defect, two different strategies are commonly used, aiming either at increasing insulin secretion or at improving distal insulin action, in order to decrease hepatic glucose production and enhance peripheral glucose utilization[2]. Grb[14] expression is increased in skeletal muscle of obese and insulin-resistant patients and decreased by weight loss, along with increased insulin sensitivity[20] All these data suggest that this protein could be involved in the decrease in insulin signaling observed in metabolic diseases. Three compounds were isolated and further characterized for their activity on insulin signaling
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
