Gluconeogenesis Flashcards
When is gluconeogenesis initiated and where does it occur?
- Initiated during periods of starvation and exercise
- Occurs mainly in liver and to a smaller extent in cortex of the kidney
What are the differences between glycolysis and gluceoneogenesis?
o 3 irreversible reactions occur in glycolysis which need their own reactions in order to return from pyruvate to glucose.
What type of process is gluconeogenesis and what does it require?
- IMPORTANT: it is an energy-consuming process (requires 6 ATP/GTP) and requires a source of carbon
Why is gluconeogenesis needed?
- Brain and erythrocytes need glucose.
- Brain can use ketones but glucose is preferred (uses around 100g per day); erythrocytes have no mitochondria so have to use glucose
- Body maintains blood glucose at around 4.0 to 5.5mmol/L (72-99mg/dL)
- Glycogen degradation is fast and doesn’t use ATP but only have around 100g in liver
- Gluconeogenesis can produce glucose from different starting materials and is the only source of glucose when fasting
What are the three sources of carbon in gluconeogenesis and where do they come from?
o Lactate from muscle (glycolysis)
o Glycerol from fat breakdown (lipolysis)
o Amino acids from proteolysis
What are the sources of energy in gluconeogenesis?
o ATP – from glycolysis and Krebs cycle
o Fatty acids cannot be used as a source of carbon, only broken down to supply ATP
What are the three irreversible steps in pyruvate metabolism and which enzymes are involved?
- 1: G6P -> glucose : glucose-6-phosphatase
- 2: F1,6BP -> F6P: fructose-1,6-bisphosphatase
- 3: pyruvate -> PEP: more complicated
How is the reaction from PEP different in gluconeogenesis and what intermediates are required? What is this process called and why?
- In glycolysis, the reaction from phosphoenolpyruvate (PEP) to pyruvate is a single step reaction. The reverse reaction is a bit more complicated and requires a number of intermediates:
- Oxaloacetate (lacks transporters in the mitochondria)
- Malate (can be transported out of mitochondria)
- Require 1 ATP and 1 GTP molecule
- Two enzymes
- Called the malate cycle: catalysed by malate dehydrogenase.
How is glycolysis different to gluconeogenesis?
o 2 ATPs generated overall in glycolysis
o 6 ATPs/GTPs consumed in gluconeogenesis
o 4 in reaction from pyruvate to PEP (gluconeogenesis)
o 2 in reaction from 3-phosphoglycerate to 1,3 bisphosphoglycerate (gluconeogenesis)
How can triglycerides be used in gluconeogenesis?
- Fats (triglycerides) are made up of a glycerol backbone and 3 fatty acid side chains.
- Glycerol -> can be used to create pyruvate -> gluconeogenesis
- Fatty acids -> acetyl Co-A -> cannot be converted to pyruvate/glucose
- Acetyl Co-A is then used to generate the energy (ATP) needed for gluconeogenesis.
What is the additional role of Acetyl Co-A?
- Acetyl Co-A also regulates enzymes:
o Activates pyruvate carboxylase (PC)
o Inhibits pyruvate dehydrogenase complex (PDC)
How is gluconeogenesis utilised in energy draining conditions such as fasting or exercise?
- In muscle: glucose lactate during anaerobic conditions
- Lactate in liver is oxidized back to glucose by gluconeogenesis
- Glucose sent back to muscle to do work – no net synthesis of glucose.
- Interaction between muscle and liver called the Cori Cycle.
- During fasting same process of gluconeogenesis occurs to maintain constant glucose levels.
What conditions allow the Cori Cycle?
- Cori cycle only works if you conserve pyruvate and avoid its conversion to acetyl Co-A
What does fatty acid metabolism produce and how does this affect energy production?
- Fatty acid metabolism: produces acetyl Co-A which inhibits the function of the PDC (enzyme complex that converts pyruvate to acetyl co-A to enter the Kreb’s cycle) – good or bad?
What are the two functions of fatty acids in gluconeogenesis?
o Supply the energy
o Prevent conversion of pyruvate to acetyl-co-A
How and where does gluconeogenesis from glycerol occur?
- Glycerol is produced from the breakdown of triglycerides (fat).
- Glycerol can then be converted to dihydroxyacetone phosphate only in the liver and kidneys
Where does gluconeogenesis from amino acids occur and which amino acids may be used?
- Mostly in muscle, proteins are broken own (proteolysis) into amino acids that can feed to different stages of gluconeogenesis.
- Examples of amino acids that undergo gluconeogenesis include alanine and glutamine.
- Glucogenic AA can provide carbons to gluconeogenesis
- Ketogenic AA (lysine and leucine) cannot provide carbons, but can be used in fatty acid metabolism to produce energy for gluconeogenesis.
- Together, lactate, glycerol, alanine and glutamine account for 90% of the gluconeogenic molecules!
How is gluconeogenesis controlled hormonally and how is this similar to glycolysis?
- Since gluconeogenesis is the reversal of glycolysis, much of the hormonal control also occurs in reverse of glycolysis.
- Glucagon and adrenaline work towards promoting gluconeogenesis while insulin inhibits gluconeogenesis and promotes glycolysis.
- Cortisol (hormone releases during stress ex. starvation) also promotes gluconeogenesis.
What happens when gluconeogenesis goes wrong? The function of what may be altered?
- Inborn errors of gluconeogenesis exist that alter the function of each of the four enzymes that regulate the uni-directional process of gluconeogenesis.
- General symptoms occur due to the build up of acetyl Co-A (ketosis), lactate (acidosis) and hypoglycaemia (low glucose levels).
- Can cause seizures, coma, hyperventilation, apnea and death!
- Complicates diabetes!
What are the symptoms of diabetic ketoacidosis?
- Nausea/vomiting
- Fatigue
- Weight loss
- Hunger
- Increased urination
- Drowsiness
- Thirst
- Abdominal pain
What is the process that can lead to diabetic ketoacidosis
- Absolute or relative insulin deficiency
- Hyperglycaemia
- Glucosuria (urinary loss of water and electrolytes)
- Dehydration and hypovolemia
- Increased lactate
- Acidosis
- Increased counter-regulatory hormones (glucagon, cortisol, growth hormone, adrenaline)
(all whilst liver produces ketone bodies/beta-hydroxybutyrate and actetone through glycerol gluconeogenesis)
