Personalized Medicine · Oct 28, 2026

Clinical and computational exploration of IRS1 and Pancreastatin genetic variants in metabolic response to metformin-sulfonylurea therapy

By Rizvi AA, Abbas M, Faruqui T et al.

BACKGROUND: Individuals with type 2 diabetes mellitus (T2DM) show variable responses to metformin-sulfonylurea therapy. Genetic variation in insulin signaling and metabolic regulation, particularly in insulin receptor substrate-1 (IRS1) and pancreastatin (PST), may contribute to this variability. This study assessed the influence of IRS1 (rs1801278) and PST (rs9658664) polymorphisms on baseline metabolic profiles and response to combination therapy. METHODS: We enrolled 202 diabetic individuals receiving metformin-sulfonylurea therapy. Clinical and biochemical parameters were measured at baseline and follow-up. Genotyping for IRS1 (rs1801278) and PST (rs9658664) was performed using PCR-RFLP and statistically analyzed by SPSS (v.27). Exploratory molecular docking analyses were performed to examine mutation-dependent differences in PST interactions with insulin-signaling proteins. RESULTS: Renal complications were more prevalent among non-responders (p = 0.029). IRS1 and PST genotypes were not associated with therapeutic response. Individuals with IRS1 TT genotype exhibited higher baseline cholesterol, triglyceride, and LDL levels (p = 0.05). Docking analyses suggested mutation-dependent differences in PST interactions with insulin receptor, IRS1, and GRP78. Metformin showed slightly stronger predicted binding to insulin receptor and IRS1 than sulfonylurea. CONCLUSION: Although IRS1 and PST polymorphisms did not show association with treatment response, genotype-based metabolic variability and in silico analyses suggest functional effects on insulin-signaling pathways, highlighting the potential of personalized medicine approaches for optimizing antidiabetic therapy.

doi.org/10.1080/17410541.2026.2753761PubMed 42948864Interventions