Gluconeogenesis: Glucose Synthesis

• Gluconeogenesis occurs in the liver and maintains blood glucose during fasting.
• The liver can use glycogenolysis (breakdown of glycogen) or gluconeogenesis to maintain glucose levels.
• Gluconeogenesis forms glucose from noncarbohydrate sources like lactate, amino acids, and glycerol.
• Glucagon and epinephrine promote gluconeogenesis, while insulin inhibits it.
• Glycogen reserves decrease dramatically within the first 12 hours of fasting, increasing gluconeogenesis.
• Gluconeogenesis is the only glucose source after 24 hours.
• Substrates for gluconeogenesis include glycerol 3-phosphate, lactate (from anaerobic glycolysis), and gluconeogenic amino acids (from muscle protein).

Gluconeogenesis Bypass Reactions

• Gluconeogenesis circumvents irreversible steps in glycolysis using specific enzymes.
• It is not possible to convert acetyl-CoA to glucose in humans.
• Most fatty acids are metabolized to acetyl-CoA and therefore are not a major source of glucose.
• Odd-numbered carbon fatty acids are exceptions, yielding a small amount of propionyl-CoA that is gluconeogenic.
• Dietary fructose and galactose can be converted to glucose in the liver.
• Lactate is oxidized to pyruvate by lactate dehydrogenase.
• The gluconeogenic amino acid alanine is converted to pyruvate by alanine aminotransferase (ALT or GPT).
• Glycerol 3-phosphate is oxidized to dihydroxyacetone phosphate (DHAP) by glycerol 3-phosphate dehydrogenase.
• Most enzymes are required to catalyze reactions that circumvent irreversible steps.

Pyruvate Carboxylase

• Pyruvate carboxylase, a mitochondrial enzyme requiring biotin, is activated by acetyl-CoA
• The product, oxaloacetate (OAA), cannot leave the mitochondria directly.
• OAA is reduced to malate, which can exit the mitochondria via the malate shuttle.
• In the cytoplasm, malate is reoxidized to OAA.

Phosphoenolpyruvate Carboxykinase (PEPCK)

• PEPCK is induced by glucagon and cortisol in the cytoplasm.
• It converts OAA to phosphoenolpyruvate (PEP) in a GTP-dependent reaction.
• PEP continues in the pathway to fructose 1,6-bisphosphate.

Fructose-1,6-Bisphosphatase

• Fructose-1,6-bisphosphatase in the cytoplasm is a key control point in gluconeogenesis.
• It hydrolyzes phosphate from fructose 1,6-bisphosphate.
• It is activated by ATP and inhibited by AMP and fructose 2,6-bisphosphate.
• Fructose 2,6-bisphosphate, produced by PFK-2, controls both gluconeogenesis and glycolysis (in the liver).

Glucose-6-Phosphatase

• Glucose-6-phosphatase is in the lumen of the endoplasmic reticulum.
• Glucose 6-phosphate is transported into the ER.
• Free glucose is transported back into the cytoplasm, then leaves the cell.
• Glucose-6-phosphatase is only in the liver.
• Skeletal muscle lacks glucose-6-phosphatase, so muscle glycogen cannot serve as a blood glucose source.

Amino Acids

• While alanine is the main gluconeogenic amino acid, 18 of 20 amino acids (excluding leucine and lysine) are gluconeogenic.
• Hepatic gluconeogenesis does not represent an energy source for the liver.
• Gluconeogenesis requires ATP, which that is provided by β-oxidation of fatty acids
• Hepatic gluconeogenesis is always dependent on β-oxidation of fatty acids in the liver.
• Adipose tissue releases fatty acids during hypoglycemia by breaking down triglycerides.
• Acetyl-CoA cannot be converted to glucose, but it can be converted to ketone bodies.
• Ketone bodies are an alternative fuel for cells, including the brain.
• Chronic hypoglycemia is often accompanied by an increase in ketone bodies.

Regulation by Acetyl-CoA

• Pyruvate carboxylase and pyruvate dehydrogenase are major mitochondrial enzymes that use pyruvate.
• Both are regulated by acetyl-CoA.
• Between meals, fatty acids are oxidized in the liver for energy.
• Accumulating acetyl-CoA activates pyruvate carboxylase and gluconeogenesis, inhibiting PDH.
• The inhibition of PDH prevents conversion of lactate and alanine to acetyl-CoA.
• In the well-fed state, accumulating acetyl-CoA is shuttled into the cytoplasm for fatty acid synthesis with the help of OAA.

Cori and Alanine Cycles

• During fasting, lactate from red blood cells (and possibly exercising skeletal muscle) is converted to glucose in the liver.
• The glucose is returned to the red blood cell or muscle, composing the Cori cycle.
• In the alanine cycle, muscle releases alanine

Alcohol and Hypoglycemia

• Alcoholics are susceptible to hypoglycemia.
• High amounts of cytoplasmic NADH from alcohol metabolism interfere with gluconeogenesis.
• High NADH levels favor the formation of lactate from pyruvate, malate from OAA, and glycerol 3-phosphate from DHAP.
• Excessive alcohol consumption can result in severe hypoglycemia after running a marathon.
• The effect of high amounts of cytoplasmic NADH is to divert important gluconeogenic substrates from entering the pathway
• There is muscle cramping and pain due to lactic acid buildup in muscle.
• NAD is required by lactate dehydrogenase to oxidize lactate to pyruvate for gluconeogenesis.
• The available NAD is used for ethanol metabolism, not lactate oxidation.
• The result is metabolic acidosis and hypoglycemia.