Gluconeogenesis

Question 1

Explain 4 situations in which gluconeogenesis would occur.

Answer 1

. Exercise- lactate produced, which is used as substrate to get extra glucose for muscle contraction using ATP
. Short-term fasting- alanine from muscles is converted to pyruvate by removing its amino group. When glycogen stores are depleted, alanine from fat reserves and muscle (lean body mass) undergoes gluconeogenesis to produce glucose
. Diabetes- cells insensitive to insulin and think they’re starving of glucose, which triggers gluconeogenesis
. Trauma- peripheral insulin resistance can occur which triggers gluconeogenesis in a similar way as above

Question 2

Why isn’t short term fasting sustainable?

Answer 2

Short term fasting triggers gluconeogenesis once glycogen stores have depleted. Gluconeogenesis uses alanine from muscles and fat stores. It is unsustainable to continuously deplete muscle and lean body mass.

Question 3

What are the substrates for gluconeogenesis?

Answer 3

. Lactate, amino acids (alanine), glycerol (triacylglycerols)
. Especially uses alanine and glycerol from FFAs

Question 4

In which tissues does gluconeogenesis occur?

Answer 4

In the cytosol of the kidneys, liver, and small intestine

Question 5

Gluconeogenesis is often described as the reverse of another metabolic process. Give this term.

Answer 5

Reverse glycolysis (essentially converts pyruvate to glucose)

Question 6

Give the three main steps of gluconeogenesis.

Answer 6

. Pyruvate to phosphoenolpyruvate (PEP)
. Fructose-1,6-bisphosphate to fructose-6-phosphate
. Glucose-6-phosphate to glucose

Question 7

Describe the conversion of pyruvate to PEP.

Answer 7

. In the mitochondria, pyruvate is converted to oxaloacetate by pyruvate carboxylase
. Oxaloacetate reduced to malate
. Malate is moved out of the mitochondrion into the cytosol via the malate shuttle
. Malate is oxidised to regenerate oxaloacetate
. Oxaloacetate is converted to PEP by PEP carboxykinase

Question 8

Why is oxaloacetate reduced to malate in the mitochondria?

Answer 8

. Pyruvate carboxylase only found in mitochondrion, but all other reactions occur in cytosol
. Pyruvate to oxaloacetate, oxaloacetate to malate in mitochondrion
. Malate transferred out of mitochondria by malate shuttle, reoxidised to oxaloacetate
–> oxaloacetate to PEP via PEP carboxykinase etc.

Question 9

Which enzyme converts pyruvate to oxaloacetate?

Answer 9

Pyruvate carboxylase

Question 10

Which enzyme converts oxaloacetate to PEP?

Answer 10

PEP carboxykinase (PEPCK)

Question 11

How is fructose-1,6-bisphosphate converted to fructose-6-phosphate?

Answer 11

By fructose-1,6-bisphosphatase

Question 12

How is fructose-1,6-bisphosphatase regulated?

Answer 12

Allosterically activated by citrate, inhibited by AMP and F26BP

Question 13

Name one point at which glycerol can enter gluconeogenesis.

Answer 13

. Glycerol can enter at DHAP, just before fructose-1,6-bisphosphate is converted to fructose-6-phosphate

Question 14

How is glucose-6-phosphate converted to glucose?

Answer 14

By glucose-6-phosphatase

Question 15

Why is it sometimes beneficial to leave glucose phosphorylated in the G6P form?

Answer 15

Glucose is trapped in cell and can be readily converted to glycogen for storage if needed.

Question 16

How are insulin and glucagon involved in hormonal regulation of glycolysis and gluconeogenesis?

Answer 16

. Insulin activates glycolytic enzymes (e.g. PFK) and inhibits synthesis of PEPCK (important in diabetes)
. Glucagon activates PEPCK and fructose-1-6-bisphosphatase

Question 17

What is the Cori Cycle?

Answer 17

The cycle of lactate being converted to pyruvate then to glucose in liver, and then glucose being converted to pyruvate then lactate in muscles.

Question 18

How are amino acids converted to gluconeogenic precursors?

Answer 18

. Amino group removed
. Carbon skeletons can be converted to glucose
. In the case of alanine, the amino group is removed, which forms pyruvate. Pyruvate can then be converted to glucose by the action of PEPCK, F16BPase and G6Pase

Question 19

How can adipose tissue eventually give rise to acetyl CoA and glucose?

Answer 19

. Adipose tissue releases glycerol and FFAs
. Glycerol enters gluconeogenesis at DHAP and is converted to glucose (eventually)
. FFAs undergo beta-oxidation to produce acetyl CoA

Question 20

How does alcohol inhibit gluconeogenesis?

Answer 20

. Metabolism of alcohol gives large increase in cytosolic NADH in the liver
. Lots of NADH means that lots of pyruvate is reduced to lactate and malate, instead of the reverse
. Less glucose produced from gluconeogenesis until concentration of NADH lowers, so that NAD is able to oxidise lactate and malate to pyruvate, then pyruvate can be converted to glucose