Background and aims<\/p>\n
Insulin resistance is a common extrahepatic manifestation of hepatitis C virus (HCV) infection (HCVi), but its mechanism is poorly understood. While systemic insulin resistance is documented, portal insulin dynamics, a key regulator of hepatic metabolism, remain unexplored. This study aimed to investigate the relationship between insulin, the gut-liver axis, and immunometabolic changes in patients with HCV.<\/p>\n
Methods<\/p>\n
HCV patients were evaluated before (HCVi; n = 29) and after sustained virologic response (SVR) achieved with sofosbuvir\/velpatasvir treatment (SVR, n = 23) (NCT02400216). Liver biopsies, portal blood, and peripheral blood were collected at both phases. Statistical analyses were conducted using Wilcoxon rank-sum tests, Mann-Whitney tests, and Pearson’s correlation coefficients to assess differences and associations across insulin, glucose, cytokines, metabolites, immune cells, and hepatic liver transcriptomics to elucidate impaired insulin homeostasis in HCVi.<\/p>\n
Results<\/p>\n
HCV patients had significantly reduced portal insulin compared to SVR (p\u00a0= 0.02), while peripheral insulin, portal glucose, and peripheral glucose remained unchanged. Portal insulin correlated positively with proinflammatory cytokines and vascular injury markers and negatively with CD8\/CD62L\/CD45RA\/CD3 cells (naive cytotoxic T-cells) and non-standard nucleotides. Hepatic transcriptomic analysis revealed portal insulin correlated positively with immune and negatively with amino acid pathways, reflecting insulin’s role in the perturbations of immunometabolism during HCVi.<\/p>\n
Conclusions<\/p>\n
Lower portal insulin during HCVi is associated with changes consistent with altered pancreatic insulin secretion and decreased hepatic insulin extraction. The observed correlations support a potential relationship between the immune response and insulin dynamics, indicating an interplay between the immune system, metabolism, and insulin in HCVi, with clinical implications for the management of dysglycemia.<\/p>\n
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