Drug-Induced Insulin Autoimmune Syndrome: A FAERS Database and Network Pharmacology Analysis

Introduction: Insulin Autoimmune Syndrome (IAS) is a rare yet clinically significant drug-induced adverse reaction, characterized by hypoglycemic episodes caused by insulin autoantibodies. While individual drug associations are documented in case reports, systematic pharmacovigilance analyses supporting drug-induced IAS are lacking in the literature. This study aims to identify drugs associated with IAS through pharmacovigilance analysis and explore potential molecular mechanisms. Methods: We conducted a comprehensive analysis of IAS reports in the FDA Adverse Event Reporting System (FAERS) database (2004-2024) using multiple disproportionality analysis methods. Drug-gene interaction networks were constructed using DGIdb, GeneCards, and SwissTarget- Prediction databases, with subsequent protein-protein interaction analysis and pathway enrichment performed using STRING and DAVID databases. Results: Analysis of 228 IAS reports revealed significant associations with 17 medications, 16 of which were not documented in the current IAS literature. Captopril showed the strongest association (ROR: 1777, 95% CI: 1051-3005), followed by thiamazole and clopidogrel. Network analysis identified enrichment in the PI3K-Akt signaling pathway, insulin resistance, and AMPK pathways, suggesting these pathways may play a role in the development of IAS. Discussion: This study identified novel drug associations with IAS, highlighting the high risk of captopril in patients with the HLA-DRB1*0406 genotype, and the need for close monitoring of elderly patients on thiamazole or clopidogrel, particularly for hypoglycemia. Additionally, monitoring PI3K-Akt pathway disruption is crucial, as it may impair Treg function and promote the production of autoantibodies against insulin. Conclusions: The study identified 17 medications associated with IAS and emphasized the potential role of the PI3K-Akt pathway, recommending avoidance of certain drugs and enhanced monitoring in high-risk patients.