Mittal Ayushi, Buscaglia Paul, Srivastava Dhiraj, Artemyev Nikolai O, Sebag Julien A
Department of Pharmacology, University of Michigan, Ann Arbor, MI, 48109, USA; Elizabeth Weiser Caswell Diabetes Institute, University of Michigan, Ann Arbor, MI, 48109, USA; Department of Molecular Physiology and Biophysics, University of Iowa, Iowa city, 52242, USA.
Department of Pharmacology, University of Michigan, Ann Arbor, MI, 48109, USA; Elizabeth Weiser Caswell Diabetes Institute, University of Michigan, Ann Arbor, MI, 48109, USA.
Mol Metab. 2025 Aug 7;100:102230. doi: 10.1016/j.molmet.2025.102230.
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.
2型糖尿病的一个标志是葡萄糖转运蛋白4（GLUT4）响应胰岛素向特化细胞的质膜转位受损。确定参与此缺陷的机制对于开发恢复胰岛素敏感性的治疗方法至关重要。我们之前鉴定出一种小分子胰岛素增敏剂C59，它通过与Unc119b结合来改善胰岛素刺激的GLUT4转位，然而，Unc119b介导的GLUT4转运调控的作用和机制尚不清楚。
在此，我们使用体外系统和胰岛素抵抗的啮齿动物模型，并对Unc119b表达进行基因操作，以揭示该蛋白在葡萄糖稳态调节中的作用。
我们证明Unc119b是GLUT4转位的内源性抑制剂，它导致肥胖个体胰岛素抵抗的发生。我们表明Unc119b与Rac1相互作用并抑制胰岛素对其的激活，从而导致GLUT4转位减少。Rac1的异戊二烯化C末端和C59都与Unc119b内的同一位点结合，因此表明C59通过干扰Unc119b对Rac1的作用来增强GLUT4转位。
总体而言，本研究将Unc119b确定为葡萄糖稳态的关键调节因子，揭示了其在GLUT4转运中的作用，并确定了一类新型胰岛素增敏剂的作用机制。
