Neu-P11 Improves Type 2 Diabetes Mellitus Immune Function by Inhibiting the Hippo Signaling Pathway.

OBJECTIVE: Melatonin (Mel) plays a significant role in maintaining bodily homeostasis and regulating insulin resistance (IR) associated with Type 2 diabetes mellitus (T2DM). Neu-P11 is a novel Mel receptor agonist that has been reported to play a critical role in immune function in T2DM. This study aims to investigate the impact of Neu-P11 on the immune function in individuals with T2DM and its potential regulatory pathways. MATERIAL AND METHODS: After inducing IR in 3T3-L1 cells, the study examined the impact of piromelatine (Neu-P11) and XMU-MP-1 (a Hippo pathway inhibitor) on the levels of Hippo pathway proteins, cell viability, extracellular glucose, and GLUT4 expression. After establishing T2DM in rats by a high-fat diet and streptomycin, the effects of Neu-P11 and XMU-MP-1 on glucose metabolism and serum levels of insulin, IgA, IgG, and IgM were investigated. Primary splenocytes isolated from experimental rats were analyzed for the number of immune cells and reactive oxygen species (ROS). RESULTS: In our study, Mel, Neu-P11, and XMU-MP-1 reduced the levels of phospho-MST1/2, phospho-LATS1/LATS1, phospho-YAP/YAP, and phospho-TAZ/TAZ in the Hippo pathway and enhanced cell viability and glucose uptake capability. This effect was more evident in the Neu-P11+XMU-MP-1 group. After treatment with Mel, Neu-P11, and XMU-MP-1, respectively, T2DM rats showed slower weight gain and a decreased spleen index, suppressed splenic ROS, downregulated phosphorylated Hippo pathway proteins, decreased IgA, and increased IgG and IgM, with improved glucose and insulin tolerance. Mel, Neu-P11, and XMU-MP-1 increased the immune cell number (CD3+, CD16+, and CD19+) in T2DM rats. Notably, co-treatment of Neu-P11 and XMU-MP-1 demonstrated superior restoration across all parameters, indicating the efficacy of combinatorial targeting. CONCLUSION: Neu-P11 improves immune function and increases insulin sensitivity in T2DM by inhibiting the Hippo signaling pathway, offering a novel therapeutic avenue for T2DM.