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Updated: Aug 17 2022


  • Overview
    • Function
      • de novo glucose synthesis
        • effectively glycolysis in reverse
        • can maintain blood glucose when glycogen stores are exhausted
        • must supply brain and RBCs which utilize glucose for energy
          • is NOT a source of energy for the liver
            • hepatocytes use β-oxidation to supply the energy needed for gluconeogenesis
      • potential substrates
        • all amino acids
          • except for leucine and lysine
          • alanine is transported from muscle to liver, where it undergoes transamination to form pyruvate, which forms the substrate for gluconeogenesis
            • in the process of forming pyruvate from alanine, alpha-ketoglutarate is converted to glutamate via transamination
        • lactate
          • produced in anaerobic glycolysis
        • glycerol-3-phosphate
          • produced in fat catabolism
        • propionyl-CoA
          • produced in odd-carbon fatty acid catabolism
    • Pathway
      • location
        • hepatocytes (primary)
        • kidney
        • enterocytes
        • NOT muscle
          • no glucose-6-phosphatase
            • cannot release free glucose
      • enzymes
        • involves both mitochondrial and cytosolic enzymes
        • several steps of glycolysis are reversible
        • the non-reversible steps must be bypassed with special gluconeogenic enzymes
          • pyruvate carboxylase
            • pyruvate → oxaloacetate
            • requires biotin and ATP
            • activated by acetyl-CoA
              • oxaloacetate must be converted to malate to exit the mitochondria via the malate-aspartate shuttle
            • in mitochondria
          • PEP carboxykinase (PEPCK)
            • oxaloacetate → phosphoenolpyruvate (PEP)
            • requires GTP
            • activated by glucagon and cortisol
            • in both cytosol and mitochondria
          • fructose-1,6-bisphosphatase
            • fructose-1,6-bisphosphate → fructose-6-P
            • important control point of gluconeogenesis
            • activated by ATP, inhibited by AMP and fructose-2,6-bisphosphate
            • in cytosol
          • glucose-6-phosphatase (G6P)
            • glucose-6-P → glucose
            • in ER of hepatocytes
            • clinical relevance
              • von Gierke disease = G6P deficiency
                • see Glycogen metabolism
        • other enzymes
          • lactate dehydrogenase
            • lactate → pyruvate
            • requires free NAD+
      • regulation
        • stimulation
          • glucagon
          • acetyl CoA
          • citrate
        • inhibition
          • high NADH/NAD+ ratio
            • alcohol may cause elevated NADH/NAD+ ratio leading to hypoglycemia
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