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