Kharitonova Anna, Patel Rekha S, Osborne Brenna, Krause-Hauch Meredith, Lui Ashley, Vidyarthi Gitanjali, Li Sihao, Cai Jianfeng, Patel Niketa A
James A. Haley Veteran's Hospital, Research Service, 13000 Bruce B Downs Blvd, Tampa, FL 33612, USA.
Department of Chemistry, University of South Florida, Tampa, FL 33620, USA.
Int J Mol Sci. 2025 Apr 14;26(8):3695. doi: 10.3390/ijms26083695.
In the United States, an estimated 38 million individuals (10% of the population) have type 2 diabetes mellitus (T2D), while approximately 97.6 million adults (38%) have prediabetes. Long noncoding RNAs (lncRNAs) are critical regulators of gene expression and metabolism. We were the first to demonstrate that lncRNA Growth Arrest-Specific Transcript 5 (GAS5 (human)/gas5 (mouse)) is decreased in the serum of T2D patients and established GAS5 as a biomarker for T2D diagnosis and onset prediction, now validated by other groups. We further demonstrated that GAS5 depletion impaired glucose uptake, decreased insulin receptor levels, and inhibited insulin signaling in human adipocytes, highlighting its potential as a therapeutic target in T2D. To address this, we developed NPC86, a small-molecule compound that stabilizes GAS5 by disrupting its interaction with UPF-1, an RNA helicase involved in nonsense-mediated decay (NMD) that regulates RNA stability. NPC86 increased GAS5 and insulin receptor (IR) levels, enhanced insulin signaling, and improved glucose uptake in vitro. In this study, we tested the efficacy of NPC86 in vivo in a diet-induced obese diabetic (DIOD) mouse model, and NPC86 treatment elevated gas5 levels, improved glucose tolerance, and enhanced insulin sensitivity, with no observed toxicity or weight changes. A transcriptomics analysis of adipose tissue revealed the upregulation of insulin signaling and metabolic pathways, including oxidative phosphorylation and glycolysis, while inflammatory pathways were downregulated. These findings highlight NPC86's therapeutic potential in T2D.
在美国，估计有3800万人（占人口的10%）患有2型糖尿病（T2D），而约9760万成年人（38%）患有糖尿病前期。长链非编码RNA（lncRNA）是基因表达和代谢的关键调节因子。我们率先证明，lncRNA生长停滞特异性转录本5（GAS5（人类）/gas5（小鼠））在T2D患者血清中减少，并将GAS5确立为T2D诊断和发病预测的生物标志物，目前已得到其他研究团队的验证。我们进一步证明，GAS5缺失会损害人类脂肪细胞的葡萄糖摄取，降低胰岛素受体水平，并抑制胰岛素信号传导，凸显了其作为T2D治疗靶点的潜力。为了解决这一问题，我们开发了NPC86，这是一种小分子化合物，它通过破坏GAS5与UPF-1（一种参与无义介导衰变（NMD）的RNA解旋酶，NMD调节RNA稳定性）之间的相互作用来稳定GAS5。NPC86在体外可提高GAS5和胰岛素受体（IR）水平，增强胰岛素信号传导，并改善葡萄糖摄取。在本研究中，我们在饮食诱导的肥胖糖尿病（DIOD）小鼠模型中测试了NPC86的体内疗效，NPC86治疗可提高gas5水平，改善葡萄糖耐量，并增强胰岛素敏感性，且未观察到毒性或体重变化。对脂肪组织的转录组学分析显示，胰岛素信号传导和代谢途径（包括氧化磷酸化和糖酵解）上调，而炎症途径下调。这些发现凸显了NPC86在T2D治疗中的潜力。
