Introduction and Objective: Metformin, the first-line treatment for type 2 diabetes, exerts antidiabetic effects partly through gut microbiota modulation. However, it can also increase Escherichia species capable of inducing endotoxemia via lipopolysaccharide (LPS). This study investigated metabolic endotoxemia, represented by LPS-binding protein (LBP) and its antagonist bactericidal/permeability-increasing protein (BPI), in relation to therapeutic responses to metformin-based therapy.Methods: We recruited 87 subjects from a cohort of type 2 diabetes treated at a medical center in southern Taiwan (from 2016 to 2024). Subjects were stratified into three groups: (1) good control on metformin monotherapy (GM, HbA1c ≤7%), (2) good control with metformin plus dipeptidyl peptidase-4 inhibitors (DPP4i) (GC, HbA1c ≤7% after failure on metformin alone), and (3) poor control on metformin or metformin plus DPP4i (PC, HbA1c >7% but ≤9%). Plasma LBP and BPI levels were measured, and gut microbiota compositions were analyzed via 16S rRNA sequencing.Results: LBP levels were significantly higher in PC compared to GM, in parallel with the higher HOMA-IR in PC. Although BPI levels were similar across groups, elevated LBP in PC indicated greater metabolic endotoxemia. LBP also showed negative correlations with HDL-cholesterol and positive correlations with triglycerides, GPT, CRP, and HOMA-IR. Gut microbiota diversity (Shannon index, representing community evenness) was reduced in GM, with distinct clustering across groups by unweighted UniFrac analysis.Conclusion: Elevated LBP in poorly controlled diabetes highlighted the role of metabolic endotoxemia contributing to insulin resistance. Reduced gut microbiota diversity was observed in type 2 diabetes with durability to metformin monotherapy, suggesting microbial shifts critical to maintaining metformin efficacy. Further analysis of specific microbial changes is warranted.
W. Hung: None. W. Hung: None.
National Science and Technology Council (112-2314-B-037-070-)
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