Topic 8: Gluconeogenesis, Cori & Alanine Cycle

Question 1

What is the most important source for Carbon in gluconeogenesis?

Answer 1

BLOOD LACTATE

Question 2

What is the main gluconeogenic organ/tissue?

Answer 2

LIVER!

Question 3

What is the second most important source of C for gluconeogenesis?

Answer 3

Amino Acids:
Most can contribute to glucose –> glucogenic
Some can only to ketones –> ketogenic

Question 4

What are the ketogenic only amino acids?

Answer 4

Leucine and Lysine

Can go into Acteyl-CoA and then Ketones

Question 5

How much gluconeogenesis is from Fatty Acids?

Answer 5

Barely any, only the Glycerol Backbone can be used and 3 C remainder from ODD chain FA’s for proprionate.

Fatty acid chains will be used for fuel rather than gluconeogenesis considering they are utilized generally in times of fasting/starvation

Question 6

What enzyme removes FA’s from the Glycerol backbone?

Answer 6

Lipase

Question 7

What do fatty acids get used to make?

Answer 7

Acetyl CoA for:

ATP (TCA Cycle) or Ketones

Question 8

What do even chain fatty acids make?

Answer 8

Carbons are cleaved 2 at a time –> copious Acetyl CoA

Question 9

What do odd chain fatty acids make?

Answer 9

Mostly Acteyl CoA until 3 C’s are left –> Proprionate!

Proprionate can be anapleurotic in the TCA Cycle to make Succinyl CoA. This can lead to glucose formation.

Question 10

What is proprionate used for in ruminants?

Answer 10

Main gluconeogenic substrate.

Question 11

What are the 4 enzymes that are used to overcome glycolysis so that gluconeogenesis can take place?

Answer 11

1) Pyruvate Carboxylase and 2) PEP Carboxykinase both to overpower Pyruvate Kinase.
3) Fructose-1,6-Bisphosphatase to get past PFK
4) Glucose-6-Phosphatase to get past Hexokinase

Question 12

What is the function of Pyruvate Carboxylase?

Answer 12

Pyruvate –> OAA in the matrix

ATP is used, CO2 is incorporated to make OAA
Requires Biotin/B7

Question 13

What is the function of PEP Carboxykinase?

Answer 13

OAA –> PEP in the cytosol

GTP is used and CO2 is generated.

Question 14

What is Step 1 of gluconeogenesis?

Answer 14

Pyruvate is converted via Pyruvate Carboxylase to OAA.

ATP is used and CO2 is used. Requires B7/Biotin.

OAA via the Malate-Aspartate Shuttle is moved to the cytosol. (NADH used in matrix, NADH made in cytosol)

Question 15

What is Step 2 of gluconeogenesis?

Answer 15

OAA via PEP Carboxykinase is converted to PEP.

GTP is used and CO2 is generated

Question 16

What is Step 3 of gluconeogenesis?

Answer 16

PEP via Enolase makes 2-Phosphoglycerate.

Question 17

What is Step 4 of gluconeogenesis?

Answer 17

2-Phosphoglycerate via Phosphoglyceromutase moves the phosphate to make 3-Phosphoglycerate.

Question 18

What is Step 5 of gluconeogenesis?

Answer 18

3-Phosphoglycerate via Phosphoglycerate kinase makes 1,3-bisphosphoglycerate.

ATP is used.

Question 19

What is Step 6 of gluconeogenesis?

Answer 19

1,3-BPG via Glyceraldehyde-3-Phosphate Dehydrogenase makes Glyceraldehyde-3-Phosphate.

NADH is used, free Phosphate is yielded

Question 20

What is Step 7 of gluconeogenesis?

Answer 20

GA-3-P (or DHAP since Aldolase does convert between the two and F-1,6-BP) via Aldolase is converted to Fructose-1,6-Bisphosphate

Question 21

What is Step 8 of gluconeogenesis?

Answer 21

F-1,6-BP via Fructose-1,6-bisphosphatase to Fructose-6-phosphate.

H20 is used and free Pi (phosphate) is generated.

Question 22

What is Step 9 of gluconeogenesis?

Answer 22

Fructose-6-Phosphate via Glucosephosphate isomerase is converted to Glucose-6-Phosphate.

Question 23

What is Step 10 of gluconeogenesis?

Answer 23

Glucose-6-Phosphate via Glucose-6-Phosphatase is turned into the final product: GLUCOSE!! YAY, we did it!

Used H2O and yields a free Phosphate (Pi)

Question 24

How is gluconeogenesis regulated by insulin and glucagon?

Answer 24

Insulin –> inhibition
Glucagon –> activation

the 4 special enzymes are up-regulated:
1) Pyruvate Carboxylase 2) PEP CarboxyKinase 3) Fructose-1,6-Bisphosphatase 4) Glucose-6-Phosphatase

Question 25

What else stimulates gluconeogenesis?

Answer 25

Catecholamines (Epi and NorE) AND Glucocorticoids (cortisol)

Question 26

What cells can perform Gluconeogenesis?

Answer 26

Mitochondria containing cells Pyruvate carboxylase is in the mitochondrial matrix

Question 27

What tissues perform gluconeogenesis the most?

Answer 27

LIVER of course Kidney somewhat Small Intestine a bit Only tissues capable of releasing glucose to the blood.

Question 28

Does the brain make glucose?

Answer 28

NO NO NO NO -- (that means no! not nitric oxide)

Question 29

How does skeletal muscle indirectly contribute to gluconeogenesis?

Answer 29

Lactic Acid Cycle (Cori Cycle) AND Glucose-Alanine Cycle

Question 30

How does the Lactic Acid Cycle/Cori Cycle Work?

Answer 30

Lactic Acid is released from skeletal muscle in times of anaerobic metabolism. Liver takes up Lactate and Oxidizes it to form pyruvate --> TCA Cycle+ETC or Gluconeogenesis. Glucose released is picked up, turned into pyruvate --> cycle continues

Question 31

How does the Glucose-Alanine Cycle work?

Answer 31

When muscle has no glucose/glycogen and needs energy, AA's are burned in muscle. Amino group is transaminated to Pyruvate to make Alanine. Alanine is released, liver picks up, deaminates to make pyruvate --> TCA Cycle+ETC or Gluconeogenesis. Glucose released is picked up, turned into pyruvate --> cycle continues.

Question 32

What is Cushing's Syndrome?

Answer 32

Hyperadrenocorticism

Question 33

What does hyperadrenocorticism do?

Answer 33

Excess Gluconeogenesis --> AAs begin to contribute --> skeletal muscle degrades, heart muscle degrades, collagen in tendons degrade --> why we see weak skin, hair, pendulous abdomen, and fat buildup (hyperglycemia) Literally converting muscle to fat. Hyperglycemia brings on PU/PD from osmotic imbalance as well.

Question 34

What does lactic acidosis do?

Answer 34

Comes from over production or under utilization of lactic acid. Happens when > 5 mM (normal is 1.2mM) Decreased blood pH (acidosis) and HCO3

Question 35

What causes lactic acidosis?

Answer 35

Disrupted TCA Cycle or ETC Liver Disease (can't utilize Lactate) Ethanol (competition for NAD+) Various drugs - phenformin

Question 36

Why does ethanol compete for NAD+?

Answer 36

Ethanol metabolism takes precedence in the liver uses up NAD+. Cannot perform gluconeogenesis in presence of alcohol/ethanol since it requires NAD+ for Malate-Aspartate Shuttle and Lactate to Pyruvate.

Question 37

Why do we care about alcohol poisoning in veterinary medicine?

Answer 37

4-Methylpyrazole (Fomepizole) used to inhibit Alcohol Dehydrogenase (enzyme that metabolizes ethanol) for: Methanol (wood alcohol) --> Formaldehyde Ethylene glycol (antifreeze) --> Oxalic acid --> precipitates with Ca++ in the kidney --> rapid renal failure

Question 38

Why is ingesting alcohol after exercise a bad idea?

Answer 38

You've already used up your glycogen stores and built up Lactic Acid. NAD+ is used up by alcohol --> blocking gluconeogenesis = bad idea!

Question 39

What vitamin is crucial for gluconeogenic enzymes to function properly? Which enzymes require it?

Answer 39

Vitamin B7/Biotin ``` Pyruvate Carboxylase (Step 1) Propionyl-CoA Carboxylase (Ruminant gluconeogenesis to make Succinyl-CoA from Proprionate) ```