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

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.

This study aimed to investigate the causal relationship between PA and T2DM and to explore the underlying molecular mechanisms and potential therapeutic targets.

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.

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.

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.