Integrated Metabolomic and Transcriptomic Profiling of Hepatic Gluconeogenesis under Insulin Resistance Conditions

Background: Hepatic gluconeogenesis is a tightly regulated metabolic pathway essential for maintaining glucose homeostasis during fasting and energy stress. Under insulin-resistant conditions, as seen in type 2 diabetes and metabolic syndrome, this pathway becomes aberrantly activated, contributing to fasting hyperglycemia and overall dysglycemia. Deciphering the molecular networks driving this dysregulation requires an integrated, systems-level approach combining high-throughput transcriptomic and metabolomic data. Methods and Results: This review synthesizes current findings from multi-omics studies investigating hepatic gluconeogenesis in models of insulin resistance, including genetic mouse models, dietary interventions, and human liver biopsies. Transcriptomic analyses reveal upregulation of key gluconeogenic genes such as PCK1, G6PC, and PGC-1α, alongside altered expression of transcription factors including FOXO1 and HNF4α that mediate insulin resistance-driven transcriptional programs. In parallel, untargeted and targeted metabolomic profiling has uncovered disruptions in intermediates of the TCA cycle, amino acid metabolism, and redox balance that support excessive glucose production. Integration of omics datasets has revealed coordinated regulation of enzyme expression, metabolite pools, and signaling pathways (e.g., AKT, AMPK, SIRT1) that converge on the hepatic gluconeogenic machinery. Notably, the rewiring of metabolic fluxes toward glycerol and amino acid-derived substrates, and the persistence of elevated NADH/NAD⁺ ratios, exacerbate hepatic glucose output under insulin-resistant states. Systems biology approaches combining fluxomics, machine learning, and network analysis are uncovering novel regulatory nodes and potential biomarkers for early diagnosis and intervention. Conclusion: Integrated metabolomic and transcriptomic profiling has advanced our understanding of the complex regulation of hepatic gluconeogenesis in insulin resistance. These insights provide a framework for identifying therapeutic targets aimed at restoring metabolic flexibility and controlling hyperglycemia in metabolic disease.