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 stable isotope approach to simultaneously quantify gluconeogenic and oxidative metabolic fluxes in the liver and kidney. Hepatic gluconeogenesis from phosphoenolpyruvate was disrupted via liver-specific knockout of cytosolic phosphoenolpyruvate carboxykinase (PEPCK-C; KO). 2H/13C isotopes were infused in fasted KO and WT littermate mice, and fluxes were estimated from isotopic measurements of tissue and plasma metabolites using a multicompartment metabolic model. 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. 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 coordinated regulation of gluconeogenic flux through PEPCK-C. Combining stable isotopes with mathematical modeling provides a versatile platform to assess multitissue metabolism in various genetic, pathophysiological, physiological, and pharmacological settings.
Bibliographical noteFunding Information:
We thank the Vanderbilt University MMPC for assistance with some in vivo studies described here. We thank Freyja D. James for performing surgical catherization of mice. We also thank Martha Wall for assisting with genotyping some mice and Allison Albright for preparing some tissue samples for GC-MS analysis. We would like to thank Susan Hajizadeh in the Vanderbilt University MMPC Hormone and Analytical Core for measuring glucagon. This research was supported by NIH grants R01 DK106348 and U01 CA235508, the Integrated Training in Engineering and Diabetes NIH training grant (T32 DK101003), and the Vanderbilt MMPC (NIH grant U24 DK059637).
© 2021, Rahim et al.