• Lactate, pyruvate, glycerol and amino acids are used to make glucose
• All precursors must be converted to oxaloacetate, the starting material for gluconeogenesis
• Acetyl-CoA cannot be used to make glucose (no enzymes exist in mammals that reverse the actions of pyruvate dehydrogenase)
• Most likely to occur when [Glucose] in the blood is low

1. Pyruvate Kinase (PK)
2. Phosphofructokinase (PFK)
3. Hexokinase (HK)

1. Pyruvate carboxylase (bypasses PK)

2. PEP carboxykinase (bypasses PK)

3. Fructose 1,6 Bisphosphatase (bypasses PFK)

4. Glucose 6 Phosphatase (bypasses HK)

Regulators of Glycolysis and Gluconeogenesis: Insulin

• Released by pancreatic beta cells in response to hyperglycemia
• Reduces [cAMP] in the liver
• Induces dephosphorylation of glycogen phosphorylase and glycogen synthase 
• Leads to glycogen synthesis

Regulators of Glycolysis and Gluconeogenesis:

Glucagon

• Released by alpha pancreatic cells in response to hypoglycemia
• Increases [cAMP] and therefore PKA activity increases
• Induces phosphorylation of glycogen phosphorylase and glycogen synthase
• Leads to glycogen breakdown

• Favor gluconeogenesis over glycolysis
• Stimulate cAMP production and increases phosphorylase kinase
• Leads to glycogen breakdown to glucose

inhibited by citrate, ATP

fructose 2,6 bisphosphate activates PFK

Regulators of Glycolysis and Gluconeogenesis: Fructose 1,6 Bisphosphatase

• stimulated by ATP and citrate, therefore high energy charge and the availability of metabolites favor gluconeogenesis over glycolysis
• inhibited by fructose 2,6 bisphosphate

• Activates PFK and inhibits F1,6BPase 
• Controlled by the rates of synthesis and degredation of PFK-2 and FBPase-2
• F2,6P in the liver is high when glucagon and cAMP are low (favoring glycolysis and fat storage)
• F2,6P in the liver is low when glucagon and cAMP are high (favoring gluconeogenesis)

Three Enzymes of Glycogen Breakdown

1. Glycogen Phosphorylase (cleaves a1-4 glycosidic bonds by adding a phosphate and forming G1P)

2. Debranching Enzyme (cleaves a1-6 glycosidic bonds without using a phosphate)

3. Phosphoglucomutase (isomerizes G1P to G6P)

Glucagon and catecholamines raise cAMP levels and induce glycogen breakdown

1. phosphoglucomutase (isomerizes G6P to G1P)

2. UDP-glucose pyrophosphorylase (forms UDP-glucose)

3. Glycogen synthase (creates a1-4 glycosidic bonds by removing UDP)

4. Branching enzyme (creates a1-6 glycosidic bonds)

Insulin stimulates glycogen synthesis by reducing cAMP levels, therefore activating phosphatases that dephosphorylate glycogen synthase and glycogen phosphorylase)

Regulators of Glycogen breakdown and synthesis:

Glucose 6 phosphate and AMP

• Glucose 6 Phosphate stimulates glycogen synthase and phosphatase 1
• AMP stimulates glycogen phosphorylase, this ensures that glycogen is rapidly degraded in metabolic emergencies