Association between primary aldosteronism and type 2 diabetes and identification of potential molecular mechanisms.

Background: Primary aldosteronism (PA) is a common cause of secondary hypertension and is associated with an increased risk of cardiovascular and metabolic complications. Emerging evidence suggests a close relationship between PA and type 2 diabetes mellitus (T2DM), with a higher prevalence of impaired glucose metabolism observed in PA patients. However, the underlying molecular mechanisms linking PA and T2DM remain unclear. Purpose: This study aimed to investigate the causal relationship between PA and T2DM and to explore the underlying molecular mechanisms and potential therapeutic targets. Materials and methods: Mendelian randomization (MR) was performed to evaluate the causal association between PA and T2DM. Shared disease-associated genes were identified from public databases, followed by protein-protein interaction (PPI) construction and pathway enrichment analysis. Experimental validation was conducted in NCI-H295R and HepG2 cells. Virtual screening and molecular docking were applied to identify candidate small-molecule compounds targeting key genes. Results: MR suggested a potential positive causal association between PA and T2DM. Integrated bioinformatics and experimental analyses identified SRC as a central regulatory hub gene in PA-associated metabolic dysfunction. Functional experiments showed that aldosterone-induced SRC activation impaired insulin signaling through the AKT-IRS1-GLUT4 axis, while SRC inhibition partially restored insulin response. Pathway analysis highlighted the AGE-RAGE signaling pathway as a key inflammatory mediator linking PA to T2DM. Furthermore, SRC-mediated metabolic signaling and AGE-RAGE-driven inflammatory responses appeared to synergistically contribute to disease progression. Virtual screening identified Grossularine-1 as a promising SRC-targeting compound. Conclusions: Our findings demonstrate a genetic association between PA and T2DM, with SRC identified as a potential key mediator in their pathogenesis. We further highlight the pivotal role of the AGE-RAGE pathway in PA-induced T2DM and propose Grossularine 1 as a promising candidate.