HCV infection induces dysregulation of glucose-stimulated insulin secretion via the TLR3/TRIF/NF-κB-iNOS-NO axis: Implications for prediabetes in HCV patients.

Hepatitis C virus (HCV) infection induces hyperinsulinemia and is associated with various extrahepatic manifestations, including effects on pancreatic β cells. However, the specific impact of HCV infection on β-cell function remains unclear. This study elucidates the mechanisms of hyperinsulinemia in HCV-infected individuals and its clinical significance in the era of direct-acting antiviral (DAA) therapy. Analysis of 118 non-diabetic HCV-positive patients demonstrated significantly elevated basal insulin levels and C-peptide concentrations compared with 30 healthy controls, with serum/hepatic HCV RNA load positively correlating with insulin secretion. In vitro investigations revealed regulatory effect of HCV on insulin secretion: stimulation under low-glucose conditions via nitric oxide (NO)-dependent pathways, and inhibition under high-glucose conditions. Mechanistically, HCV infection activated the TLR3/TRIF/NF-κB signaling axis to upregulate inducible nitric oxide synthase (iNOS), leading to enhanced NO production that promoted basal insulin release. Pharmacological inhibition of NO or iNOS abrogated HCV-induced insulin hypersecretion without compromising viral replication. Clinically, these findings establish hyperinsulinemia as a pre-diabetic marker in HCV infection and identify the NF-kB/iNOS/NO pathway as a therapeutic target for metabolic comorbidity prevention. Despite HCV curability with DAAs, this work highlights persistent virus-induced β-cell dysfunction and informs integrated strategies for antiviral and metabolic intervention to optimize long-term patient outcomes.