Substrates of Gluconeogenesis

Gluconeogenic precursors are molecules that can be used to produce a net synthesis of glucose. The most important gluconeogenic precursors are glycerol, lactate, and α-keto acids obtained from the metabolism of glucogenic amino acids. [Note: All but two amino acids (leucine and lysine) are glucogenic .]
A. Glycerol
Glycerol is released during the hydrolysis of triacylglycerols (TAG) in adipose tissue  and is delivered by the blood to the liver.
Glycerol is phosphorylated by glycerol kinase to glycerol 3-phosphate, which is oxidized by glycerol 3-phosphate dehydrogenase to dihydroxyacetone phosphate, an intermediate of glycolysis and gluconeogenesis.
B. Lactate
Lactate from anaerobic glycolysis is released into the blood by exercising skeletal muscle and by cells that lack mitochondria such as RBC. In the Cori cycle, this lactate is taken up by the liver and oxidized to pyruvate that is converted to glucose, which is released back into the circulation (Fig. 1).

Figure 1:  The intertissue Cori cycle links gluconeogenesis with glycolysis. [Note: Diffusion of lactate and glucose across membranes is facilitated by transport proteins.]
C. Amino acids
Amino acids produced by hydrolysis of tissue proteins are the major sources of glucose during a fast. Their metabolism generates α-keto acids, such as pyruvate that is converted to glucose, or α-ketoglutarate that can enter the tricarboxylic acid (TCA) cycle and form oxaloacetate (OAA), a direct precursor of phosphoenolpyruvate (PEP). [Note: Acetyl coenzyme A (CoA) and compounds that give rise only to acetyl CoA (for example, acetoacetate, lysine, and leucine) cannot give rise to a net synthesis of glucose. This is because of the irreversible nature of the pyruvate dehydrogenase complex (PDHC), which converts pyruvate to acetyl CoA . These compounds give rise instead to ketone bodies  and are termed ketogenic.]