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

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.

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.

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.

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.

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.