The liver is the major source of glucose production during fasting under normal physiological conditions. However, the kidney may also contribute to maintaining glucose homeostasis in certain circumstances. To test the ability of the kidney to compensate for impaired hepatic glucose production in vivo, we developed a novel stable isotope approach to simultaneously quantify hepatic and renal gluconeogenic and oxidative metabolic fluxes. Hepatic gluconeogenesis from phosphoenolpyruvate was disrupted via liver-specific knockout of cytosolic PEPCK (KO). Experiments were performed in fasted (~18hr) KO and wild-type (WT) littermate mice (n≥4, per group) fitted with jugular vein and carotid artery catheters. A multi-compartment metabolic model was used to assess fluxes using the isotopic enrichment of plasma and tissue metabolites from mice infused with 2H/13C isotopes. Hepatic gluconeogenesis and glucose production were reduced in KO mice, yet whole-body glucose production and arterial glucose were unaffected. Glucose homeostasis was maintained by a compensatory rise in renal glucose production and gluconeogenesis of 17 and 30-fold, respectively. This was consistent with a ~2-fold rise in PEPCK-C and mitochondrial PEPCK protein expression in the kidneys. Renal oxidative metabolic fluxes of KO mice increased to sustain the energetic and metabolic demands of elevated gluconeogenesis. These results show the reciprocity of the liver and kidney in maintaining glucose homeostasis by regulating gluconeogenic flux through PEPCK-C. This reciprocity creates a layer of redundancy that protects glucose homeostasis in the event that hepatic glucose production is impaired. Combining stable isotopes with mathematical modeling provides a versatile platform to assess multi-tissue metabolism in various genetic, (patho)physiological, and pharmacological settings.


M. Rahim: None. C. M. Hasenour: Employee; Self; Eli Lilly and Company. T. Bednarski: None. C. C. Hughey: None. D. Wasserman: None. J. Young: Consultant; Self; Pfizer Inc., Stock/Shareholder; Self; Metalytics.


National Institutes of Health (R01DK106348, U01CA235508, T32DK101003, U24DK059637)

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