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Inhibition of Unc119b improves insulin sensitivity through potentiation of Rac1 activation in skeletal muscle and brown adipose tissue
Journal article   Open access   Peer reviewed

Inhibition of Unc119b improves insulin sensitivity through potentiation of Rac1 activation in skeletal muscle and brown adipose tissue

Ayushi Mittal, Paul Buscaglia, Dhiraj Srivastava, Nikolai O. Artemyev and Julien A. Sebag
Molecular metabolism (Germany), Vol.100, 102230
10/2025
DOI: 10.1016/j.molmet.2025.102230
PMCID: PMC12791835
PMID: 40754229
url
https://doi.org/10.1016/j.molmet.2025.102230View
Published (Version of record) Open Access

Abstract

A hallmark of type II diabetes is an impairment of the glucose transporter GLUT4 translocation to the plasma membrane of specialized cells in response to insulin. Identifying mechanisms involved in this defect is critical to developing treatments that restore insulin sensitivity. We previously identified a small molecule insulin sensitizer, C59, which improves insulin-stimulated GLUT4 translocation through binding to Unc119b, however, the role and mechanism of Unc119b-mediated regulation of GLUT4 trafficking is unknown. Here we use in vitro systems and rodent models of insulin resistance with genetic manipulations of Unc119b expression to uncover the role of this protein in the regulation of glucose homeostasis. We demonstrate that Unc119b is an endogenous inhibitor of GLUT4 translocation which contributes to the development of insulin resistance in obese individuals. We show that Unc119b interacts with Rac1 and inhibits its activation by insulin, resulting in reduced GLUT4 translocation. Both the prenylated C-terminus of Rac1 and C59 bind to the same site within Unc119b, thus suggesting that C59 enhances GLUT4 translocation by interfering with the action of Unc119b on Rac1. Overall, this study identifies Unc119b as a critical regulator of glucose homeostasis, uncovers its role in GLUT4 trafficking and identifies the mechanism of action of a new class of insulin sensitizers. •Unc119b negatively regulates insulin-stimulated GLUT4 translocation•Increased expression of Unc119b in obesity contributes to insulin resistance•Pharmacological or genetic Inhibition of Unc119b improve insulin sensitivity•Unc119b interacts with and prevents activation of Rac1•Inhibition of Unc119b is a promising strategy to treat insulin resistance and type II diabetes
 Diabetes glucose tolerance GLUT4 translocation insulin sensitivity Rac1 Unc119b

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