Hepatic glucose production rises with the histological severity of metabolic dysfunction-associated steatohepatitis

Metabolic dysfunction-associated steatotic liver disease (MASLD) and steatohepatitis (MASH) are associated with a high prevalence of type 2 diabetes (T2D). Individuals with MASLD exhibit insulin resistance (IR) and hyperglycemia, but it is unclear whether hepatic glucose production (HGP) is increased with MASLD severity. We evaluated HGP in a cohort of histologically characterized individuals with MASL/MASH using stable isotope infusion (6,6- 2 H 2 -glucose, U- 2 H 5 -glycerol) and liver-specific genome-scale metabolic models (GEMs). Tracer-measured HGP is increased with liver fibrosis and inflammation, but not steatosis, and is associated with lipolysis and IR. The GEM-derived gluconeogenesis is elevated due to high glucogenic/energy metabolite uptakes (lactate, glycerol, and free fatty acid FFA), and the expression of insulin action genes (IRS1, IRS2, and AKT2) is reduced in MASH with fibrosis F2–F4, with/without T2D, suggesting these as putative mechanisms for increased fasting HGP and hyperglycemia. In conclusion, elevated HGP, lipolysis, and IR help to explain the mechanisms for the increased risk of hyperglycemia and T2D in MASH. • Glucose production is higher in individuals with MASH compared to simple steatosis • Glucose production is higher with liver inflammation and fibrosis, not steatosis • Hepatic and adipose insulin resistance contribute to glucose production in MASH • The putative mechanism involves excess glucogenic/energy substrates to the liver Sabatini et al. demonstrate that glucose production is enhanced in individuals with MASH and is associated with hepatic fibrosis and inflammation. These findings reveal altered hepatic glucose metabolism, driven by hepatic and extrahepatic insulin resistance that contributes to the increased risk of hyperglycemia and T2D in individuals with MASH.