Trauma and Gluconeogenesis

Question 1

Where does gluconeogenesis occur?

Answer 1

Predominantly in the liver

Also occurs in kidney

Question 2

What activates and inhibits gluconeogenesis?

Answer 2

Activated by glucagon

Inhibited by insulin

Question 3

When is gluconeogenesis very active?

Answer 3

Very active following trauma

Very active in Type 2 diabetes and is dysregulated (unopposed glucagon effect because of insulin resistance)

Question 4

Name the key precursors for gluconeogenesis.

Answer 4

Lactate - from muscle glycolysis, from anaerobic metabolism
Glycerol - from lipolysis of TAG in adipose tissue
Alanine - from proteins

Question 5

Aerobic vs anaerobic metabolism.

Answer 5

Aerobic - long duration of exercise, occurs in presence of oxygen
Anaerobic - quick bursts of intense exercise, no oxygen

Question 6

Name the two irreversible steps which are needed to overcome when converting pyruvate back to glucose (in gluconeogenesis).

Answer 6

Pyruvate to phosphoenolpyruvate (PEP)

F1,6bisP to F6P

Question 7

List the 5 key enzymes which are important in bypassing the enzymic roadblocks in GNG.

Answer 7

Glucoses-6-phosphatase
Fructose-bi-phosphatase
Pyruvate carboxylase (PC)
PEP carboxykinase (PEPCK) 
Pyruvate dehydrogenase (PDH)

Question 8

What is Beta Oxidation?

Answer 8

Fatty acids into acetyl CoA

Question 9

What is ketogenesis?

Answer 9

Acetyl CoA into ketone bodies

Question 10

What is CAC?

Answer 10

Acetyl CoA into CO2, ATP, NADH, FADH2

Question 11

Describe how we convert pyruvate into phosphoenolypyruvate (PEP).

Answer 11

Accumulation of acetyl CoA from glycolysis and beta oxidation
This inhibits pyruvate dehydrogenase (PDH) - which would normally convert pyruvate into acetyl CoA
Instead PC is activated, transferring pyruvate into oxaloacetate
Oxaloacetate is converted into PEP via PEPCK
Fasting stimulates gluconeogenesis

Question 12

What effect does glucagon have on the enzymes involved in Pyruvate –> PEP.

Answer 12

Glucagon wants to increase glucose - thereby stimulate gluconeogenesis
Promotes phosphorylation of PK - inhibits PK
Activates PEPCK

Question 13

What effect does insulin have on the pathway: pyruvate –> PEP.

Answer 13

Insulin wants to decrease glucose - thereby promote glycolysis.

• Activates PK (promotes dephosphorylation of PK)
• Inhibit PEPCK

Question 14

List things that inhibit PEPCK. (converts oxaloacetate to PEP) (stimulate gluconeogenesis)

Answer 14

Insulin
Metformin
Thiazolidinediones

Question 15

List substances the activate PEPCK (oxaloacetate to PEP)

Answer 15

Cortisol
Thyroid hormone
Glucagon
Adrenaline

Question 16

What are the effects of insulin resistance on gluconeogenesis?

Answer 16

In an insulin resistance state, insulin does not act effectively on PEPCK and G6Pase
So it does not effectively suppress gluconeogenesis

Question 17

What is the function of Fruc-2,6-BP?

Answer 17

Fructose-2,6-BP is an important allosteric effector. It stimulates PFK1 promoting glycolysis. It inhibits F-1,6-BP, thus blocking GNG

Question 18

Fruc-1,6-BP into Fru-6-P via F-1,6-BP
Fruc-6-P via PFK-2 into Fruc-2,6-BP
Fruc-2,6-BP via Fru-2,6-Bpase into Fruc-6-P
Fruc-6-P into Glc-6-P

Answer 18

Second pathway to overcome

Question 19

What are the effects of insulin resistance?

Answer 19

Many steps in gluconeogenesis are downregulated by insulin and upregulated by glucagon.
In an insulin resistant state, the actions which are dependent on insulin won’t be properly executed = leaving the effect of glucagon unopposed
= in type II diabetes - liver makes too much glucose

Question 20

List some conditions with impaired gluconeogenesis.

Answer 20

Premature babies with low glycogen stores and undeveloped livers
High alcohol metabolism (increased NADH, low NAD)
Rare genetic diseases (e.g. F1,6-biphosphatase or G-6 phosphatase deficiency)

Question 21

List some conditions with overactive gluconeogenesis.

Answer 21

Insulin resistance
Diabetes
Trauma

Question 22

What happens in response to trauma?

Answer 22

Elevated metabolic rate
Increased energy needs
Increased gluconeogenesis

Question 23

What are the drivers of the trauma response?

Answer 23

Adrenaline
Glucagon
Cortisol
Cytokines

Question 24

Describe the different phases of metabolic response to injury.

Answer 24

Pre injury: fight or flight response (under adrenaline - similar effects to glucagon)
24 hours following injury: “Ebb phase/shock” - adrenaline secretion & pituitary secretion (cortisol, ACTH, prolactin, glucagon)
Flow Stage: Catabolic: break things down, adrenaline dies out, following 24 hours
Convalescent: Anabolic - things start to normalize

Pre-injury,/Anticipation Injury, Ebb/Shock Phase, Flow Phase (Catabolic) , Convalescent Phase (Anabolic)

Question 25

Describe the effects of injury and sepsis on metabolism.

Answer 25

Both insulin and glucagon are up, but insulin resistance is present. Glucose oxidation is down - gluconeogenesis is taking place Fatty acid oxidation: normal and increased in sepsis Muscle loss, lean body mass loss post injury, catabolic phase

Question 26

Describe the glucose tolerance vs stage of injury.

Answer 26

Day of injury: high glucose before oral load, glucose level shoots up after consumption and remains high 1st day post injury: glucose tolerance test is improved, but not back to normal 4th day post injury: back to normal almost

Question 27

Why does alcoholism impair gluconeogenesis?

Answer 27

Metabolism of alcohol consumes significant NAD NAD is needed to convert lactate into pyruvate for gluconeogenesis Therefore chronic alcoholics may have low pyruvate and develop hypoglycaemia

Question 28

What are the features of the catabolic phase?

Answer 28

Increased metabolic rate Weight loss Evidence of muscle wasting (negative nitrogen balance)

Question 29

What are the contributing factors of the catabolic phase?

Answer 29

Metabolic requirements: tissue repair, immune response Insulin resistance Cytokines and inflammatory mediators (TNFalpha, IL-2) Lack of appetite

Question 30

What are the effects of TNF alpha?

Answer 30

``` Stimulates lipolysis Inhibits lipoprotein lipase Induces PEPCK (stimulates gluconeogenesis) Inhibits insulin secretion Causes insulin resistance ```

Question 31

Describe metabolism in cancer cells.

Answer 31

``` Tumour cells need lots of energy Have altered metabolism, especially involving glucose Tumour cells primarily use glycolysis Known as Warburg effect Increased glycolysis Increased lactate Negative nitrogen balance ```