Introduction and Objective: T2D is characterized by increased rates of endogenous glucose production (VEGP) and hepatic insulin resistance, which are strongly linked with MASLD and potential alterations in hepatic mitochondrial function. Because there is limited direct evidence for this in humans we assessed rates of hepatic mitochondrial oxidation citrate synthase (VCS) flux and contributions of glycerol/glycogen (VGLYC-GLY) and pyruvate carboxylase flux (VPC) to VEGP in humans with poorly controlled T2D using Positional Isotopomer Tracer Analysis (PINTA) as well as rates of lactate and β-OHB turnover. Methods: After an overnight fast 10 individuals with T2D (56±4 yrs, 2F/8M, HbA1c 9.3±1.0%) and 8 age, weight, BMI-matched controls (Cx) (63±5 yrs, 3F/5M, HbA1c 5.5±0.2%) were given a 180 min PINTA infusion: 2H7glucose, 13C4ΒOHB), 3-13Clactate). Liver triglyceride content (LTG) was measured by 1H MRS. Results: Fasting plasma glucose concentrations were 2-fold higher in T2D than in Cx (222±28 vs 100±2 mg/dL, p=0.001). Rates of VEGP were also 2-fold higher in T2D than Cx (1,806±237 vs 766±63 micromol/min; p=0.002) which could be attributed to a 2-fold increase in VGLYC-GLY (T2D:1,276±172 vs. Cx: 510±25 micromol/min; p=0.001) and VPC (T2D: 530±89 vs. Cx: 255±55 micromol/min; p=0.02). Rates of lactate turnover were increased by 50% (p=0.002) while ΒOHB turnover tended to be increased (~80%; p=0.09) in T2D. Finally, VCS was similar in T2D: 241±28 and Cx: 235±45 υmol/min (p=0.92) despite a 3.7-fold increase in LTG (p=0.02). Conclusion: Given that rates of hepatic VGLYC are decreased in poorly controlled T2D these data demonstrate that increased rates of VEGP can mostly be attributed to glycerol-driven gluconeogenesis whereas rates of hepatic VCS are unchanged. These data provide a strong rationale for liver-targeted mitochondrial approaches to increase hepatic fat oxidation to treat MASLD and T2D. Disclosure K. Petersen: Research Support; Current; Merck Current; Village S.S.D.r.l. G. Shulman: Consultant; Current; Novo Nordisk A/S. Research Support; Current; Novo Nordisk A/S. Other - collaboration; Current; Ionis Pharmaceuticals. Advisory Panel; Current; ESPERION Therapeutics, Inc. Research Support; Current; Novo Nordisk Foundation. Advisory Panel; Current; Orsobio. Research Support; Current; Orsobio. Advisory Panel; Current; Village S.S.D. Funding National Institutes of Health R01DK135645
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