Gluconeogenesis & Pentose Phosphate Pathway

What is the main source of glucose during the absorptive phase (0–4 hours after eating)?

Exogenous glucose from food intake.

During the postabsorptive phase (4–16 hours), what is the primary source of glucose?

Glycogen breakdown from the liver.

What shift occurs in glucose sources during early starvation (16–28 hours)?

Glycogen use declines, and gluconeogenesis begins to increase.

What is the main glucose source during intermediate starvation (2–16 days)?

Gluconeogenesis using substrates like amino acids, lactate, and glycerol.

What happens to glucose production during prolonged starvation (after 16 days)?

Gluconeogenesis continues at a lower rate; ketone bodies become a major energy source to spare glucose.

When does gluconeogenesis become important?

During periods of starvation or fasting that last longer than one day, when glucose stores are depleted.

Why must the body make glucose during starvation?

Because the brain needs about 120g of glucose per day as its primary energy source.

What molecule is used to make glucose during gluconeogenesis?

Pyruvate → Glucose

What is the overall chemical reaction for gluconeogenesis from pyruvate?

2 Pyruvate + 2 NADH + 4 ATP + 2 GTP + 6 H₂O + 2 H⁺ →
Glucose + 2 NAD⁺ + 4 ADP + 2 GDP + 6 Pi

What energy molecules are consumed during gluconeogenesis from pyruvate?

4 ATP and 2 GTP

What reducing agent is required for gluconeogenesis from pyruvate?

NADH

What does it mean for a molecule to be glucogenic?

It can be converted into pyruvate and then used to make glucose via gluconeogenesis.

What are examples of glucogenic molecules?

Lactate, several amino acids, and glycerol.

Which glycolytic enzymes are irreversible and must be bypassed in gluconeogenesis?

• Hexokinase

• Phosphofructokinase

• Pyruvate kinase

(neg- exergonic)

What are the key enzymes of gluconeogenesis that bypass the irreversible steps of glycolysis?

• Pyruvate carboxylase

• Phosphoenolpyruvate carboxykinase (PEPCK)

• Fructose 1,6-bisphosphatase

• Glucose 6-phosphatase

What are the characteristics of pyruvate carboxylase?

• Metabolically irreversible

• Uses biotin as a cofactor

• Activated by acetyl-CoA

• Anaplerotic (replenishes OAA for the TCA cycle)

• Takes place in the mitochondria

What does PEPCK (Phosphoenolpyruvate carboxykinase) do in gluconeogenesis?

• Converts oxaloacetate (OAA) to phosphoenolpyruvate (PEP)

• Uses GTP

• Expression increases during fasting

• Takes place in the cytosol

Why is oxaloacetate (OAA) converted to malate in gluconeogenesis?

Because OAA cannot cross the mitochondrial membrane; it's converted to malate, transported to the cytosol, and then converted back to OAA.

What enzyme converts pyruvate to oxaloacetate in the mitochondria?

Pyruvate carboxylase.

What enzyme converts oxaloacetate to phosphoenolpyruvate (PEP) in the cytosol?

Phosphoenolpyruvate carboxykinase (PEPCK).

What is the role of glucose 6-phosphatase in gluconeogenesis?

It catalyzes the final step, converting glucose 6-phosphate to free glucose.

Where is glucose 6-phosphatase found in the body?

Only in the liver and kidney.

What does fructose 1,6-bisphosphatase (F1,6BPase) do?

Converts fructose 1,6-bisphosphate to fructose 6-phosphate in gluconeogenesis.

What inhibits fructose 1,6-bisphosphatase?

AMP and fructose 2,6-bisphosphate (F2,6BP).

What are the functions of Glucose 6-phosphate (Glucose 6-P)?

• Precursor for glycogen synthesis and glucose synthesis

Where is glucose 6-phosphatase found and what does it do?

• Found only in liver and kidney

• Maintains blood glucose levels

• Highly regulated in the liver

How many high-energy molecules are used in gluconeogenesis?

6 nucleotide triphosphates (4 ATP + 2 GTP)

Why is gluconeogenesis energetically expensive?

Because it is endergonic and requires 4 extra high-energy phosphate bonds to proceed compared to glycolysis.

How are glycolysis and gluconeogenesis regulated in the liver to prevent simultaneous activity?

They are reciprocally regulated—insulin stimulates glycolysis, glucagon stimulates gluconeogenesis.

What does high AMP indicate in metabolic regulation?

Low energy charge → stimulates glycolysis.

What do high ATP and citrate levels indicate?

High energy state and abundant intermediates → inhibits glycolysis.

What role does fructose 2,6-bisphosphate (F2,6BP) play in metabolism?

It activates PFK-1 (glycolysis) and inhibits FBPase-1 (gluconeogenesis).

What did Carl and Gerty Cori win the Nobel Prize for in 1947?

Discovering the catalytic conversion pathway of glycogen (Cori cycle).

What is the Cori Cycle?

A metabolic cycle where lactate produced by muscles during anaerobic glycolysis is sent to the liver, converted to glucose via gluconeogenesis, and returned to the muscles.

What energy source does the liver use during the Cori Cycle to power gluconeogenesis?

Fatty acid oxidation, which produces ATP.

Why is the Cori Cycle important during intense muscle activity?

It helps clear lactate and recycle it into glucose, allowing continued ATP production in muscle under anaerobic conditions.

Which metabolic fuels does the liver help interconvert?

Carbohydrates, amino acids, and fatty acids

Why is the Cori Cycle essential during intense exercise?

It allows for continued ATP production under low oxygen conditions and prevents lactate accumulation, which would cause acidosis in muscle tissue.

What is the net ATP cost and gain in the Cori Cycle?

Muscle gains 2 ATP per glucose in anaerobic glycolysis. Liver uses 6 ATP to convert lactate to glucose, making the cycle energy-consuming overall.

What happens to the glucose made in the liver?

The glucose is released into the bloodstream and taken up by muscle cells for continued energy production via glycolysis.

How is pyruvate converted to glucose in the liver?

Through gluconeogenesis, pyruvate undergoes multiple steps (involving enzymes like pyruvate carboxylase, PEPCK, FBPase-1, G6Pase) to regenerate glucose.

What happens to lactate once it reaches the liver?

In the liver, LDH converts lactate back to pyruvate, which is then used for gluconeogenesis.

What happens to lactate after it’s formed in the muscle?

Lactate is released into the bloodstream and transported to the liver.

What enzyme reduces pyruvate to lactate in muscle?

Lactate dehydrogenase (LDH) catalyzes the conversion of pyruvate → lactate, regenerating NAD⁺ needed to keep glycolysis running.

What initiates the Cori Cycle in the muscle?

During anaerobic glycolysis in muscle cells, glucose is broken down into pyruvate, which is then converted to lactate due to lack of oxygen.