NPC86 Increases LncRNA Gas5 In Vivo to Improve Insulin Sensitivity and Metabolic Function in Diet-Induced Obese Diabetic Mouse Model.

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.